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Cerebrovascular
accidents occur by the interaction of multiple environmental factors and mutations
in different genes. These genetic polymorphisms determine susceptibility or
resistance to disease and response to treatment. Due to the interaction between
genes and environment, diseases are preventable through action on the
environmental factors with an adequate prevention plan.
Genetic
testing for cerebrovascular diseases establishes the susceptibility, risk or
probability of an individual suffering the disease. For this reason, the
results of the tests merely indicate that a person may have a greater
probability, risk or susceptibility to suffering the disease than the
population at large, but it does not mean that the person will necessarily
suffer this disease, as this risk is influenced by other variables, such as
external conditioning factors.
Genetic
panels for cerebrovascular risk study different genetic polymorphisms or
variations in the DNA sequence, which are involved in the development,
prognosis and evolution of these pathologies, and represent a key tool in
medical practice.
In cerebrovascular
treatments, variability in efficacy and serious adverse effects continue to
plague therapy. There are many sources of variability in response to drug
therapy, such as noncompliance and unrecognized drug interactions, but
translating pharmacogenomic discoveries to individual patients and populations
is a challenge for genomic and personalized medicine.
We review different findings in the field of
predictive genomics and pharmacogenomics to improve prevention, diagnosis and
treatments.This review describes environmental and genetic factors involved in
the disease as well as major pharmacogenes coding for enzymes, receptors and
transporters involved in ADME processes, such as absorption, distribution,
metabolism and excretion of drugs, used in cerebrovascular therapy: antithrombotic agents, antihypertensives,
antiarrhythmics, beta-blockers, and lipid modifying agents.
Keywords: Antiarrhythmics, Antihypertensives, Antithrombotic agents, Atherosclerosis, Beta-blockers, Calcium channel blockers, Genetic risk, Genomics, Lipid modifying agents, Pharmacogenetics, Stroke, Vascular risk factors
INTRODUCTION
Cerebrovascular
accidents occur by the interaction of multiple environmental factors and
mutations in different genes. These genetic polymorphisms determine
susceptibility or resistance to disease and response to treatment. Due to the
interaction between genes and environment, some diseases are preventable
through action on the environmental factors with a personalized prevention
plan.
17.5
million people died from cardiovascular diseases in 2012, representing 31% of
all global deaths. Of these deaths, an estimated 7.4 million were due to
coronary heart disease and 6.7 million were due to cerebrovascular accident or
stroke [1]. Cerebrovascular disorders and stroke are the fourth leading cause
of death behind diseases of the hearth, cancer, and chronic lower respiratory
disease, in the US and in Europe with around 200 cases per 100,000 inhabitants
per year [2] and almost six million victims every year, according to the
American Heart Association [3].
Prevalence of stroke was 33 million, with 16.9 million people having a
first stroke. 5.2 million (31%) first strokes were in those <65 years of age
[4]. There were an estimated 11.6 million events of incident ischemic stroke
and 5.3 million events of incident hemorrhagic stroke, 63% and 80%,
respectively [5]. Stroke was the second-leading global cause of death behind
ischemic heart disease, accounting for 11.13% of total deaths worldwide [6].
2.8 million individuals died of ischemic stroke and 3.0 million of hemorrhagic
stroke (57% and 84%, respectively) [5].
Genetic susceptibility is the probability of an individual of
developing a particular disease as a result of their genetic profile and
external conditions. Genetic testing of cerebrovascular disorders determines
susceptibility of an individual developing the disease. Therefore, the test
result indicates only that the patient may be more likely than most people to
suffer the disease, but does not mean that it will be suffered, as this risk is
conditioned by other variables. Design of a personalized health strategy based
on a particular genetic profile will adapt the external conditions such as diet
and lifestyle (exercise, alcohol consumption, smoking, etc.), plus drug
treatment and use of nutraceuticals or functional foods, to intervene in the
individual's susceptibility to develop the disease.
Cerebrovascular diseases refer to disorders of the brain blood vessels
that affect the blood supply to the brain. According to its etiology they are
usually classified into ischemic or hemorrhagic strokes, and depending of the
origin of the disorder, susceptibility genes involved in the increase of risk
will be different.
Ischemic Stroke
Ischemic stroke (cerebral infarction) is due to occlusion of one of the
arteries supplying blood to the brain, usually by atherosclerosis. We can
distinguish: a) transient ischemic attack (TIA), episode of a focal deficit of
cerebral circulation, with sudden onset, with alterations that usually last
about 2-10 minutes but may persist for up to 24 hours, b) reversible ischemic
neurologic deficit (RIND), the duration of the deficit is more than 24 hours,
but the clinical signs and symptoms disappear totally during the three weeks
following the episode, c) cerebral infarction, as the result of the lack of blood
supply to a brain territory, a neurological deficit of more than 24 hours
duration is presented, the infarction may be silent (SCI), but usually gives
neurological manifestations according to the affected territory, d)
atherothrombotic cerebral infarction (ACI), injury of the vessel wall that
causes a stenosis or occlusion of the arterial lumen and an injury occurs
within its territory irrigation that can be total or partial, depending on the
possible compensation of collateral circulation.
Hemorrhagic Stroke
Hemorrhagic stroke (cerebral hemorrhage) is due to rupture of a
cerebral blood vessel due to a hypertensive peak or a congenital aneurysm.
Types of brain hemorrhages: a) cardioembolic cerebral infarction (CI), heart
valve injury, infarction and/or heart rhythm disorders give rise to blood clots
that reach the brain arteries, b) hemorrhagic cerebral infarction, it occurs on
ischemic hemorrhagic injury background altering the blood brain barrier in an
area of reperfusion, usually after lysis of the thrombus, c) lacunar
infarctionis a small, less than 15 mm, resulting from occlusion of one of the
penetrating arteries that provides blood to the brain's deep structures, d)
intracerebral hemorrhage is a collection of blood within the brain parenchyma
due to rupture of a cerebral vessel.
Atherosclerosis
Disabling and often fatal complications of cerebrovascular disease
appear in the last stage of life. However, atherosclerosis, the main
pathological process leading to cerebrovascular disease, begins in youth or
adulthood, remaining asymptomatic for 20 or 30 years until the onset of the
disease [7,8].
Atherosclerosis is a specific form of arteriosclerosis that affect
arterial blood vessels due to the invasion and accumulation of white blood
cells (monocyte-derived macrophages and T cells) resulting from interaction
between modified lipoproteins and the normal cellular elements of the arterial
wall. This inflammatory process leads to complex lesions, or atheroma plaques,
that protrude into the arterial lumen. Plaque rupture and thrombosis results in
the acute clinical complications of myocardial infarction and stroke [9,10].
Lipid Metabolism
In the late 1970s, different authors postulated the importance of
oxidation of LDL cholesterol as an initiating event of the atherogenic process
and the accumulation of modified LDL-cholesterol within macrophages resulting
in so-called foam cells [11-13].
Description of the
molecular mechanisms underlying cholesterol biosynthesis and regulation of
serum cholesterol levels by Goldstein and Brown [14], highlighted the
importance of different proteins involved in lipid metabolism as ApoB,
ApoC-III, and ApoE, as well as the LDL receptor, which is essential in recognizing ApoB in LDL, as
well as LPL that hydrolyzes the triglyceride in plasma chylomicrons and VLDL,
releasing free fatty acids for uptake by peripheral tissues [15].
Endothelial Function
and Hypertension
Progression from the initial fatty streak to
more complex lesions involves several changes in the artery wall. The genetic
and environmental factors associated with the development of arterial
hypertension are highly informative markers of the risk for developing
cerebrovascular pathologies. Enzymes that are related to the endothelial
stability, such as the endothelial nitric oxide synthase (NOS3), which
synthesizes nitric oxide from the amino acid arginine and is a constituent of
vascular endothelial cells. Contribution of endothelial nitric oxide synthase (eNOS) in
LDL-cholesterol oxidation, foam cell formation and endothelial equilibrium have
been described by Knowles et al. [16], who suggest that deletion of the eNOS
gene in the background of ApoE deficiency results in hypertension and
increased atherosclerosis.
The angiotensin-converting enzyme (ACE),
which plays an important role in regulating blood pressure and electrolyte
balance, and angiotensinogen (AGT), associated with an increased risk of
essential hypertension, both play crucial roles in endothelial function and in
profusion of the atherosclerotic plaque [17-20].
Immune Response and
Inflammation
Oxidized LDL particles are cytotoxic and proinflammatory, and
monocyte/macrophage recruitment is regulated by cell adhesion molecules and
cytokines expressed by endothelial cells [21].
Circulating markers of inflammation are associated with risk of
atherosclerosis and stroke, although the reasons for these associations remain
unclear. It is now widely recognized that atherosclerosis is a specific example
of a chronic inflammatory response mainly to dyslipidemia and other risk
factors. The foam cells and activated endothelium may also produce
proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor
necrosis factor alpha (TNF-α), which promote further development of the
inflammatory response [22-30].
Plaque Rupture and
Thrombosis
Thickening of the plaque eventually leads to a break in the same and
subsequent atherothrombotic process. Extracellular accumulation of cholesterol,
the release of metalloproteinases by macrophages and initiation of the
coagulation cascade favor the formation of clots, emboli and thrombi ultimately
lead to stroke [31,32]. At this stage,
variations in coagulation factor II or prothrombin (F2), coagulation factor V
Leiden (F5), and methylenetetrahydrofolate reductase (MTHFR), are especially
important, increasing atherothrombotic risk [33-37].
Cerebrovascular Risk
Factors
More than 300 risk factors have been associated with cardiovascular
disease and stroke. 80% of all strokes are preventable and it starts with
managing key risk factors (Table 1).
Risk factors for stroke should meet three basic criteria: i) high
prevalence in different populations,ii) clear cause and effect relationship,
and, iii) treatment and control reduce the incidence of stroke.
Hypertension
High blood pressure (hypertension) is defined as a systolic blood
pressure (SBP) above 140 mmHg and/or a diastolic blood pressure (DBP) above 90 mmHg.
In most developed countries, up to 30% of people aged up to 25 years suffer
from high blood pressure [38].
In 2000, it was estimated that 972 million adults worldwide had
hypertension [39] and it is know that high blood pressure (HBP) is a major risk
for cardiovascular disease and stroke. Approximately 77% of people who have a
first stroke have BP ≥140/90 mmHg [40].
Numerous risk factors and markers for development of hypertension have
been identified, including age, ethnicity, family history of hypertension and
genetic factors, lower education and socioeconomic status, greater weight,
lower PA, tobacco use, psychosocial stressors, sleep apnea, and dietary factors
(including dietary fats, higher sodium intake, lower potassium intake, and
excessive alcohol intake) [38].
Dyslipidemia
Dyslipidemia is an abnormal amount of lipids in the blood. In developed
countries, most dyslipidemias are hyperlipidemias, and usually due to high
total cholesterol and/or low-density lipoprotein-cholesterol (LDL-cholesterol)
levels [41]. Dyslipidemias cover a broad spectrum of lipid abnormalities, some
of which are of great importance in cerebrovascular disease prevention.
Dyslipidemias may be related to other diseases (secondary dyslipidemias) or to
the interaction between genetic predisposition and environmental factors.
Hypercholesterolemia is defined as total cholesterol above 220 mg/dl
and/or LDL-cholesterol above 160 mg/dl. Elevated levels of cholesterol in the
blood may be a consequence of diet, obesity, inherited diseases, as familial
hypercholesterolemiadue to LDLR
mutations, or diabetes, and is considered one of the major risk factors leading
to heart disease, heart attack and stroke [42]. A meta-analysis of 17
prospective trials found hypertriglyceridemia to be an independent risk factor
for cardiovascular disease [43]. Other types of dyslipidemias appear to
predispose to premature cardiovascular disease. A particular pattern, termed
the atherogenic lipid triad [42] or atherogenic lipid phenotype [43], is more
common than others, and consists of the co-existence of increased very low
density lipoprotein (VLDL) remnants manifested as mildly elevated triglycerides
(TG), increased small dense low-density lipoprotein (LDL) particles, and
reduced high-density lipoprotein-cholesterol (HDL-C) levels.
Smoking
In 2010, tobacco smoking was the second-leading risk factor of death in
USA, after dietary risks [44]. Annually from 2005 to 2009, smoking was
responsible for a half million premature deaths in among those ≥ 35 years of
age. Furthermore, almost one third of deaths of coronary heart disease are
attributable to smoking and secondhand smoke exposure [45].
Worldwide, tobacco smoking (including secondhand smoke) was one of the
top three leading risk factors for disease and contributed to an estimated 6.2
million deaths in 2010 [46]. On average, male smokers die 13.2 years earlier
than male nonsmokers, and female smokers die 14.5 years earlier than female
nonsmokers [47].
Several studies performed across various ethnicities and populations
demonstrate a strong association between smoking and stroke risk, with current
smokers having at least a two- to fourfold increased risk of stroke compared
with lifelong nonsmokers or individuals who had quit smoking more than 10 years
prior[48-53]. Even more, there is substantial scientific evidence showing a
strong dose-response relationship between smoking and the risk of stroke [54].
Physical Inactivity
Physical activity improves risk factors for cardiovascular disease
(such as high blood pressure and high cholesterol) and reduces the likelihood
of diseases related to cardiovascular disease, including coronary heart
disease, stroke, type 2 diabetes mellitus, and sudden heart attacks [55].
Chronic physical inactivity contributes to a poor level of
cardiorespiratory fitness, which is a stronger predictor of adverse
cardiovascular outcomes than traditional risk factors. Although both physical
activity and cardiorespiratory fitness are inversely related to the risk of
cardiovascular disease and other clinical outcomes, they are in part distinct
measures in the assessment of cardiovascular disease risk [56].
Overweight and
Obesity
Overweight and obesity are typically classified by use of BMI (Body
Mass Index) cutoffs, but variations in body fat distribution (larger waist
circumference) are also associated with increased cardiovascular risk [57].
Overweight and obesity are major risk factors for cardiovascular disease,
including coronary heart disease, stroke [58,59], atrial fibrillation [60],
venous thromboembolism [61], and congestive heart failure. BMI<25 kg/m2 (for
adults aged ≥20 years) is considered as healthy normal weight.
Obesity is associated with subclinical atherosclerosis including
coronary artery disease
and carotid
intima-media thickness, and this association persists after adjustment for
cardiovascular risk factors, as shown in MESA (Multi-Ethnic Study of Atherosclerosis)
[62].
A systematic review of prospective studies examining overweight and
obesity as predictors of major stroke subtypes in >2 million participants
over ≥4 years found an adjusted RR for ischemic stroke of 1.22 (95% CI,
1.05-1.41) in overweight individuals and an RR of 1.64 (95% CI, 1.36-1.99) for
obese individuals relative to normal-weight individuals. RRs for hemorrhagic
stroke were 1.01 (95% CI, 0.88-1.17) and 1.24 (95% CI, 0.99-1.54) for
overweight and obese individuals, respectively. These risks were graded with
increasing BMI and were independent of age, lifestyle, and other cardiovascular
risk factors [63].
A recent meta-analysis of 15 prospective studies demonstrated the
increased risk for Alzheimer's disease or vascular dementia and any dementia
was 1.35 and 1.26 for overweight, respectively, and 2.04 and 1.64 for obesity,
respectively [64].
Unhealthy Diet
Dietary habits affect multiple cardiovascular risk factors: blood pressure, cholesterol, glucose,
obesity, inflammation, cardiac arrhythmias, endothelial cell function,
triglycerides, lipoprotein (a), and heart rate.
A DASH (Dietary Approaches to Stop Hypertension) dietary pattern with
low sodium reduced SBP by 7.1 mmHg in adults without hypertension and by 11.5
mm Hg in adults with hypertension [65].
In a meta-analysis of 60 randomized controlled feeding trials,
consumption of 1% of calories from saturated fat in place of carbohydrate
raised LDL cholesterol concentrations but also raised HDL cholesterol and
lowered triglycerides, with no significant effects on apolipoprotein B
concentrations [66].
In a pooled analysis of 25 randomized trials totaling 583 men and women
both with and without hypercholesterolemia, nut consumption significantly
improved blood lipid levels [67].
In meta-analyses of prospective cohort studies, each daily serving of
fruits or vegetables was associated with a 4% lower risk of coronary heart
disease (RR, 0.96, 95% CI, 0.93-0.99) and a 5% lower risk of stroke (RR, 0.95,
95% CI, 0.92-0.97) [68,69].
In the WHI (Women’s Health Initiative) randomized clinical trial
(N=48835), reduction of total fat consumption from 37.8% energy (baseline) to
24.3% energy (at 1 year) and 28.8% energy (at 6 years) had no effect on
incidence of coronary heart disease (RR, 0.98, 95% CI, 0.88-1.09), stroke (RR,
1.02, 95% CI, 0.90-1.15), or total cardiovascular disease (RR, 0.98, 95% CI,
0.92-1.05) over a mean of 8.1 years [70].
In a cohort of 380296 US men and women, greater versus lower adherence
to a Mediterranean dietary pattern, characterized by higher intakes of
vegetables, legumes, nuts, fruits, whole grains, fish, and unsaturated fat and
lower intakes of red and processed meat, was associated with a 22% lower
cardiovascular mortality (RR, 0.78, 95% CI, 0.69-0.87) [71]. Similar findings
have been seen for the Mediterranean dietary pattern and risk of incident
coronary heart disease and stroke [72] and for the DASH-type dietary pattern
[73].
Diabetes Mellitus
(DM)
Epidemiological studies have shown that patients with diabetes mellitus
and glucose intolerance are at increased risk for cardiovascular disease and
stroke [74]. Untreated fasting blood glucose levels <100 mg/dL isan
indisputable feature for ahealthy cardiovascular profile [75].
At least 68% of people >65 years of age with DM die of some form of
heart disease and 16% die of stroke. The heart disease death rates among adults
with DM are 2 to 4 times higher than the rates for adults without DM [76].
A meta-analysis of prospective randomized controlled trials of
interventions that targeted people with pre-diabetes revealed a 24% relative
risk reduction in fatal and nonfatal strokes (HR, 0.76, 95% CI, 0.58-0.99)
[77].
In people with a history of TIA or minor stroke, impaired glucose
tolerance nearly doubled the stroke risk compared with those with normal
glucose levels and tripled the risks for those with DM [78].
The ACCORD study showed that in patients with type 2 DM, targeting SBP
to <120 mmHg did not reduce the rate of cardiovascular events compared with
subjects in whom the SBP target was <140 mm Hg, except for the end point of
stroke, for which intensive therapy reduced the risk of any stroke (HR, 0.59,
95% CI, 0.39-0.89) and nonfatal stroke (HR, 0.63, 95% CI, 0.41-0.96) [79].
Alcohol
The complex relationship between alcohol consumption and stroke
includes both benefits and risks. Regular light-to-moderate consumption of
alcohol seems to decrease the risk for ischemic stroke by reducing
atherothrombotic events, but the underlying mechanism is still unclear. Regular
heavy drinking increases the risk for both hemorrhagic and ischemic strokes.
Alcoholic cardiomyopathy is a cause of cardioembolic brain infarction. Cardiac
arrhythmias caused by regular heavy drinking or binge drinking can precipitate
thrombus formation and propagate already existing thrombi from the heart. The
maintenance of high blood pressure by heavy drinking may promote cerebral
arterial degeneration. Acute increases in systolic blood pressure and/or
alterations in cerebral arterial tone could serve as mechanisms triggering
hemorrhagic strokes during alcoholic intoxication [80].
Psychosocial Stress
and Mental Disorders
The National Health and Nutrition Examination Survey showedthat higher
levels of anxiety and depressive symptoms were associated with increased risk of
incident stroke after adjustment for demographic, cardiovascular, and
behavioral risk factors (HR, 1.14, 95% CI, 1.03-1.25) [81].
In the Chicago Health and Aging Project, higher psychological distress
was associated with higher stroke mortality (HR, 1.29, 95% CI, 1.10-1.52) and
incident hemorrhagic strokes (HR, 1.70, 95% CI, 1.28-2.25) [82].
The Australian Longitudinal Study on Women’s Healthshowed that
depression was associated with a nearly 2-fold increased odd of stroke after
adjustment for age, socioeconomic status, lifestyle, and physiological risk
factors (OR, 1.94, 95% CI, 1.37-2.74) [83].
In a meta-analysis of 17 community-based or population-based
prospective studies people with a history of depression experienced a 34%
higher risk for the development of subsequent stroke after adjustment for
potential confounding factors (RR, 1.34, 95% CI, 1.17-1.54) [84].
A meta-analysis of 28 prospective cohort studies comprising 317540
participants with a follow-up period that ranged from 2 to 29 years found that
depression was prospectively associated with an increased risk of total stroke
(HR, 1.45, 95% CI, 1.29-1.63), fatal stroke (HR, 1.55, 95% CI, 1.25-1.93), and
ischemic stroke (HR, 1.25, 95 CI, 1.11-1.40) [85].
Lipoprotein(a)
Lipoprotein(a) is formed by joining a lipoprotein that is structurally
similar to LDL in protein and lipid composition to a carbohydrate-rich,
hydrophilic protein called apo(a). The physiology and function of Lp(a) are
still poorly understood, but the apolipoprotein(a) molecule demonstrates high
sequence homology (75-90%) with plasminogen [86]. This suggests that Lp(a)
might contribute to the thrombotic, as well as to the atherogenic, aspects of
IHD [87].
The meta-analysis made by Craig et al. [88] showed that Lp(a) is an
independent prospective risk factor for IHD. This finding, together with
evidence for a dose-response relationship between Lp(a) and IHD, provides
support for a causative role for Lp(a) in the development of atherosclerosis.
In the PRIME study [89] Lp(a) appeared significantly related to
coronary heart disease development as a significant risk factor
(P<0.0006).The PRIME study evidence that subjects with levels of Lp(a) in
the highest quartile had more than 1.5 times the risk than subjects in the
lowest quartile.
Homocysteine
Impaired homocysteine metabolism has been implicated as a factor in
atherosclerosis, cerebrovascular disease, and peripheral vascular disease and
several case-control and cohort studies have linked hyperhomocysteinemia with
coronary heart disease [90-92]. The British Regional Heart Study showedthat
homocysteine levels were significantly (P=0.004) higher in patients with stroke
[93].
The Supplementation with Antioxidant Vitamins and Minerals Study
suggested that to control homocysteine, decreasing coffee and alcohol
consumption may be important in women, whereas increasing physical activity,
dietary fiber, and folate intake may be important in men [94].
Atrial Fibrillation
Atrial fibrillation(AF) is a powerful risk factor for stroke,
independently increasing risk 5-fold throughout all ages. The percentage of
strokes attributable to AF increases steeply from 1.5% at 50 years of age to
23.5% at 80 years of age [95,96].
Advancing Age
Stroke patients >85 years of age make up 17% of all stroke patients
[97]. Over the next 40 years (2010-2050), the number of incident strokes is
expected to more than double, with the majority of the increase among the
elderly (aged ≥75 years) and minority groups [98].
Heredity or Family
History
Heritability is the ratio of genetically caused variation to the total
variation of a trait or measure. Genetic markers discovered thus far have not
been shown to add to cardiovascular risk prediction tools beyond current models
that incorporate family history [99]. Genetic markers also have not been shown
to improve prediction of subclinical atherosclerosis beyond traditional risk
factors [100].
In the Framingham Heart Study, a documented parental ischemic stroke by
the age of 65 years was associated with a 3-fold increase in ischemic stroke
risk in offspring, even after adjustment for other known stroke risk factors.
The absolute magnitude of the increased risk was greatest in those in the
highest quintile of the Framingham Risk Score. By age 65 years, people in the
highest Framingham Risk Score quintile with an early parental ischemic stroke
had a 25% risk of stroke compared with a 7.5% risk of ischemic stroke for those
without such a history [101].
The 9p21.3 region polymorphisms [102-104] and the histone deacetylase 9
(HDAC9) on chromosome 7p21.1[104,105]
showed evidence of correlation with ischemic stroke.
Gender
The Framingham Heart Study reveals that women with natural menopause
before 42 years of age had twice the ischemic stroke risk of women with natural
menopause after 42 years of age [106].
Randomized clinical trial data indicate that the use of estrogen plus
progestin, as well as estrogen alone, increases stroke risk in postmenopausal,
generally healthy women and provides no protection for postmenopausal women
with established CHD [107-110] and recent stroke or TIA [111].
Low-estrogen-dose oral contraceptives are associated with a 93%
increased risk of ischemic stroke, but the absolute increased risk is small
(4.1/100000 ischemic strokes in nonsmoking, normotensive women) [112,113].
Migraine with aura is associated with ischemic stroke in younger women,
particularly if they smoke or use oral contraceptives. The combination of all 3
factors increases the risk 9-fold compared with women without any of these
factors [114,115].
Preeclampsia is a risk factor for ischemic stroke remote from pregnancy
[116]. The increase in stroke risk related to preeclampsia may be mediated by
later risk of hypertension and diabetes [117].
Genetic Markers in
Cerebrovascular Disorders
Due to the interaction between genes and environment, complex diseases
may be forestalled by acting on the environmental factors with an appropriate
prevention plan. Knowledge of the genes involved in the development of these
diseases (Table 2) enables us to
make certain predictions regarding the risks, susceptibilities or resistance to
developing them [118]. Genetic testing for cerebrovascular diseases establishes
the susceptibility, risk or probability of an individual suffering the disease.
For this reason, the results of the tests merely indicate that a person may
have a greater probability, risk or susceptibility to suffering the disease
than the population at large, but it does not mean that the person will
necessarily suffer this disease, as this risk is influenced by other variables,
such as external conditioning factors.
Genetic tests of this type are integrated in multigenic panels, as
development of these diseases is not caused by a single gene, but by the
interaction of a number of genes (Figure
1). These genetic panels study different genetic polymorphisms or variations
in the DNA sequence, which are involved in the development, prognosis and
evolution of these pathologies, and represent a key tool in medical practice.
Cerebrovascular Risk
and Lipid Metabolism
Among the many genetic and environmental
risk factors that have been identified by epidemiologic studies, elevated
levels of serum cholesterol are probably unique in being sufficient to drive
the development of atherosclerosis in humans and experimental animals, even in
the absence of other known risk factors. Allelic variants for apolipoproteins
such as APOB, APOCIII and APOE, as well as the cholesterol ester transfer
protein (CETP) and the lipoprotein lipase (LPL) (Table 3), play a key role in lipoprotein metabolism and are linked
to the development of atherosclerosis and increased vascular risk [119-126].
APOA2-Apolipoprotein A-II
Apolipoprotein A2 (APOA2) is the second most
abundant apolipoprotein in HDL [118]. Several studies describe relationships between APOA2 variants with
insulin resistance, obesity and atherosclerosis susceptibility.
Corella et al. [127,128] founded thatAPOA2*-265CC (rs5082) genotype is
associated with obesity and increased appetite. Individual homozygous APOA2*-265CCwith
high saturated fat levels in their diet was strongly associated with increased
BMI and obesity.
APOA5-Apolipoprotein A-V
APOA5 is a component of high-density
lipoprotein and play a role in triglyceride concentration, a risk factor for
cardiovascular disease [118].APOA5 haplotypes *2 and *3 are associated
with increased plasma triglyceride concentrations [129,130]. Mutations in this
gene have been associated with hypertriglyceridemia and hyperlipoproteinemia
type 5 [131,132].
Moleres et al. [133] found that APOA5*-644T
allele (rsrs662799) has been associated with greater weight andweight
lossresponse.
The APOA5*-1131C was associated with
an increased risk for the development of carotid plaque in patients with Type
III hyperlipoproteinemia with an odds ratio of 3.69. Evaluation of the genotype
distribution was compatible with an independent effect of APOA5. The
development of atherosclerosis in patients with Type III hyperlipoproteinemia
is modulated by variation in the APOA5 gene [134].
Both the natural variants of the
apolipoprotein A5 (APOA5) and the glucokinase regulatory protein gene (GCKR)
have been shown to associate with increased fasting triglyceride levels. Járomi
et al. [135] investigated the possible association of the functional variants
of these two genes with non-fasting triglyceride levels and their susceptibility
nature in ischemic stroke. A total of 513 stroke patients and 172 healthy
controls were genotyped. All the APOA5 variants (T-1131C, IVS3+G476A,
C56G, and T1259C) were associated with increased triglyceride levels in all
stroke patients and controls, except for T1259C, they all conferred risk for
the disease. No such association was found for the examined GCKR rs1260326
(C1337T) variant. They examined the effects of specific combinations of the GCKR
rs1260326 and APOA5 polymorphisms. These findings confirmed the
previous results regarding the association of APOA5 variants with
triglyceride-level increase and stroke susceptibility of these alleles. By
contrast, no association could be detected of the studied GCKR allele
with triglyceride levels or with the susceptibility of stroke in the same
cohort of patients. The effect of APOA5 did not change significantly
when specific combinations of the two genes were present.
APOB-Apolipoprotein B
Apolipoprotein B is the main apolipoprotein
of chylomicrons and low-density lipoproteins [118]. Increased levels of ApoB
are directly associated with atherogenic lipoproteins, VLDL, IDL and LDL. It is
synthesized primarily in the liver and intestine. The APOB*7545C allele
(rs693) is associated with lower levels of triglycerides, cholesterol and LDL
cholesterol. However, individuals carrying the APOB*7545T allele respond
better to a low fat diet, with significantly greater reduction in their levels
of LDL and ApoB. Mutations in this gene or its regulatory region cause
hypobetalipoproteinemia and hypercholesterolemia due to ligand-defective apoB,
diseases affecting plasma cholesterol and apoB levels [136]. APOB K4154K
homozygosity predicts a 3- to 5-fold reduction in risk of ischemic
cerebrovascular disease and ischemic stroke. This may be explained by lower
plasma levels of apolipoprotein B and LDL cholesterol caused by an increased
catabolism of LDL particles, although another yet-unknown mechanism is also
possible [137].
APOC3-Apolipoprotein C-III
Apolipoprotein C-III is a very low-density lipoprotein (VLDL) protein [118]. APOC3 inhibits lipoprotein
lipase and hepatic lipase, it is thought to delay catabolism of
triglyceride-rich particles [138]. An increase in ApoC-III levels induces the
development of hypertriglyceridemia [139].
APOC3*3175G (S2) variant is associated with
greater stability and higher levels of expression of ApoC-III, as it relates to
increased risk of vascular disease due to its involvement in the metabolism of
triglycerides [139]. Absence of APOC3, the natural LPL inhibitor, enhances
fatty acid uptake from plasma triglycerides in adipose tissue, which leads to
higher susceptibility to diet-induced obesity followed by more severe
development of insulin resistance. Therefore, APOC3 is a potential target for
treatment of obesity and insulin resistance.
APOE-Apolipoprotein E
ApoE, a main apoprotein of the chylomicron,
binds to a specific receptor on liver cells and peripheral cells [118]. The E2
variant binds less readily. A defect in the receptor for ApoE on liver and
peripheral cells might also lead to dysbetalipoproteinemia [140]. Although
nearly every type III hyperlipoproteinemic person has the E2/E2 phenotype, 95
to 99% of persons with this phenotype do not have type III hyperlipoproteinemia
nor do they have elevated plasma cholesterol levels. Rall et al. [141] founded that
apoE2 of hypo-, normo-, and hypercholesterolemic subjects showed the same
severe functional abnormalities. Type III hyperlipoproteinemia is strongly
associated with the homozygous presence of the E2 allele of the APOE
gene. However only about 10% of subjects with APOE-2/2 genotype develop
hyperlipidemia and it is therefore assumed that further genetic and
environmental factors are necessary for the expression of disease [140].
Alterations in lipid metabolism associated
with ApoEdys function may influence AD-related pathology. It has been proposed
that the linkage of the APOE-4 to AD may represent dysfunction of the lipid
transport system associated with compensatory sprouting and synaptic remodeling
central to the AD process. ApoE may have a role in recycling cholesterol in
membrane components in the brain where focal accumulation of ApoE in dystrophic
axons is observed in cases of cerebrovascular disease. In AD there is a lower
proportion of the HDL sub-fraction of largest particle size (HDL2b, mean diameter
10.57 nm) that contains the bulk of ApoE and a higher proportion of HDL3b of
intermediate particle size (8.44 nm) than in the control population. No
difference is observed in any of the HDL sub-fractions between AD with APOE-4
and those with APOE-2 or APOE-3. The differences between patients and controls
are greater in APOE-4 carriers. There is no major difference in the
concentrations of the major lipoprotein fractions, suggesting that altered HDL
sub-fraction profile in AD is a general feature of AD and is not a consequence
of the APOE-4 phenotype. These data also indicate that the decreased
concentration of HDL2b, which contains most of the HDL-associated ApoE, in AD
may be related to the impaired ability of these patients to provide
regenerating nerve cells with an adequate supply of cholesterol. The APOE
gene promoter (-219G/T) polymorphism may influence the postprandial response of
triacylglycerol-rich lipoproteins prolonging postprandial lipemia in subjects
with the TT genotype [118].
CETP-Cholesteryl Ester Transfer Protein, Plasma
This gene encodes cholesterol ester transfer
protein (CETP) that facilitates the exchange of triglycerides and cholesterol
esters, stimulating the recovery of cholesterol [118]. The CETP*+279A>G
polymorphism (rs708272) is associated with low levels of HDL cholesterol and
high levels of plasma CETP activity (presence of the +279G allele), which
contribute to an increased risk of cardiovascular disease [124].
CETP expression leads
to a moderate increase in atherosclerosis in apoE-0 and LDLR-0 mice,
and suggests a pro-atherogenic effect of CETP activity in metabolic settings in
which clearance of remnants or LDL is severely impaired. However, apoA1
overexpression has more dramatic protective effects on atherosclerosis in apoE-0
mice, which are not significantly reversed by concomitant expression of CETP
[118].
FABP2-Fatty Acid Binding
Protein 2, Intestinal
The intracellular fatty acid-binding proteins (FABPs) belong to a
multigene family divided into at least three distinct types, namely hepatic,
intestinal and cardiac types. They are thought to participate in the uptake,
intracellular metabolism and transport of long-chain fatty acids. Fatty acid
binding protein (FABP) is found in the small intestine epithelial cells where
it strongly influences fat absorption and metabolism [118]. The FABP2*163G>Apolymorphism(rs1799883,
Ala54Thr) is associated with obesity, elevated BMI, increased abdominal fat,
higher leptin levels, insulin resistance, higher insulin levels, and
hypertriglyceridemia. FABP2*163A
allele (54Thr variant) carriers have greater fat absorption and tend to have
slower metabolism, leading to a tendency for weight gain, slower weight loss
and difficulty in losing abdominal fat [142-146].
LPL-Lipoprotein Lipase
Lipoprotein lipase plays a key role in
lipoprotein metabolism by hydrolyzing the triglycerides that are part of VLDL
and the chylomicrons, and removing lipoproteins from the circulation [118]. LPL
influences the interaction of atherogenic lipoproteins with cell surface
receptors and the vascular wall [125]. Recent studies link the LPL*1421C>G
polymorphism (rs328) [Ser447Stop] (truncated protein of 446 amino acids instead
of 448) with a lower risk of coronary heart disease due to its relationship
with increased HDL and decreased triglycerides [126]. Therefore, the 447X
variant has higher enzymatic activity and should therefore have a protective
effect against the development of atherosclerosis and subsequent coronary
artery disease (CAD).
Genome-wide association studies in European
Americans have reported several SNPs in the lipoprotein lipase gene associated
with plasma levels of high-density lipoprotein cholesterol (HDL-C) and
triglycerides [118]. However, the influences of the lipoprotein lipase SNPs on
longitudinal changes of these lipids have not been systematically examined. On
the basis of data from 2045 African-Americans and 2116 European Americans in
the Coronary Artery Risk Development in Young Adults study, cross-sectional and
longitudinal associations of lipids with 8 lipoprotein lipase SNPs, including 2
that had been reported in genome-wide association studies, were investigated
[147]. Plasma levels of HDL-C and triglycerides were measured at 7 examinations
during 20 years of follow-up. In European Americans, rs328 (Ser447Stop), rs326,
and rs13702 were significantly associated with cross-sectional inter individual
variations in triglycerides and HDL-C and with their longitudinal changes over
time. The minor alleles in rs326, rs328, and rs13702 that predispose an
individual to lower triglycerides and higher HDL-C levels at young adulthood
further slowed down the trajectory increase in triglycerides and decrease in
HDL-C during 20 years of follow-up. In African-Americans, these 3 SNPs were
significantly associated with triglycerides, but only rs326 and rs13702 were
associated with HDL-C. rs328 showed a stronger association in European
Americans than in African-Americans, and adjustment for this did not remove all
of the associations for the other SNPs. Longitudinal changes in either trait
did not differ significantly by SNP genotypes in African-Americans. Aging
interacts with LPL gene variants to influence the longitudinal lipid
variations.
There are some papers that reveal the
importance of genetic screening for LPL gene mutations in a population at risk
to develop hypertriglyceridemia. Some of these mutants, e.g. T-39C and T-93G,
are located in the promoter region. The transcriptional activity of the -39
mutant promoter was less than 15% of wild-type, and that of the -93 mutant
promoter was less than 50% of wild-type, as determined by transfection studies
in a human macrophage-like cell line. Some other mutants are amino acidic
changes, such as Asn291Ser, Asp9Asn and Ser447Ter. An association was demonstrated
between the Asn291Ser substitution and decreased HDL cholesterol [148].
Familial combined hyperlipidemia (FCHL) patients carrying this mutation showed
decreased HDL cholesterol and increased triglyceride levels compared to
non-carriers. Presence of the D9N mutation was associated with
hypertriglyceridemia and reduced plasma high-density lipoprotein cholesterol
concentrations. LPL-Asp9Asn carriers had higher diastolic blood pressure than
non-carriers.
Cerebrovascular Risk
and Hypertension
There is substantial evidence to suggest
that blood pressure (BP) is an inherited trait. The introduction of gene
technologies in the late 1980s generated a sharp phase of over-inflated
prospects for polygenic traits such as hypertension. Not unexpectedly, the
identification of the responsible loci in human populations has nevertheless
proved to be a considerable challenge. Common variants of the RAS
(renin-angiotensin system) genes, including those of ACE
(angiotensin-converting enzyme) and AGT (angiotensinogen) were some of
the first shown to be associated with BP. Presently, ACE and AGT are the only
gene variants with functional relevance, where linkage studies showing
relationships with hypertension have been reproduced in some studies and where
large population-based and prospective studies have demonstrated these genes to
be predictors of hypertension or BP. Nevertheless, a lack of reproducibility in
other linkage and association studies has generated skepticism that only a
concerted effort to attempt to explain will rectify. Without these
explanations, it is unlikely that this knowledge will translate into the
clinical arena. Angiotensinogen (AGT) gene polymorphisms have been
linked to increased risk of hypertension, but the data remain controversial
[118].
The genetic and environmental factors
associated with the development of arterial hypertension are highly informative
markers of the risk for developing cerebrovascular pathologies. Enzymes that
are related to the endothelial stability, such as the endothelial nitric oxide
synthase (NOS3), which synthesizes nitric oxide from the amino acid arginine
and is a constituent of vascular endothelial cells, the angiotensin-converting
enzyme (ACE), which plays an important role in regulating blood pressure and
electrolyte balance, and angiotensinogen (AGT), associated with an increased
risk of essential hypertension, plays a crucial role in endothelial function
and in profusion of the atherosclerotic plaque.
The endothelial function and hypertension panel
deals with the study of genes involved in cell migration and their contribution
to the development of the atherosclerotic plaque as a trigger of stroke (Table 4).
ACE-Angiotensin I
Converting Enzyme
Angiotensin I converting enzyme is a dipeptidyl carboxypeptidase that
plays an important role in regulating blood pressure and electrolyte balance [118]. Hydrolyses angiotensin I to
angiotensin II, that is a potent vasopressor and aldosterone-stimulating peptide.
The enzyme is also capable of inactivating bradykinin, a potent vasodilator. ACE mutations are associated with a high
predisposition to develop essential hypertension [149,150], which predisposes
to the suffering of other cardiovascular diseases. Several studies described
that there was a significant association between ACE polymorphisms and brain lacunar infarction, intracranial
hemorrhage and ischemic stroke [20,151-154], although other investigators could
not detect the association [155-157].
Genetic variants of ACE are
suspected risk factors in cardiovascular disease, but the alleles responsible
for the variations remain unidentified. Johnson et al. [158] searched for
regulatory polymorphisms, and allelic angiotensin I-converting enzyme (ACE)
mRNA expression was measured in 65 heart tissues, followed by genotype scanning
of the ACE locus. Marked allelic expression imbalance (AEI) detected in five
African-American subjects was associated SNPs rs7213516, rs7214530, and rs4290,
residing in conserved regions 2-3 kb upstream of ACE. Moreover, each of the
SNPs affected transcription in reporter gene assays. SNPs rs4290 and rs7213516
were tested for associations with adverse cardiovascular outcomes in
hypertensive patients with coronary disease (International Verapamil SR
Trandolapril Study Genetic Substudy [INVEST-GENES]). Both SNPs were associated
with adverse cardiovascular outcomes, largely attributable to nonfatal
myocardial infarction in African Americans, showing an odds ratio of 6.16 for
rs7213516. The high allele frequency in African Americans (16%) compared to
Hispanics (4%) and Caucasians (< 1%) suggests that these alleles contribute
to variation between populations in cardiovascular risk and treatment outcomes.
The polymorphisms of angiotensinogen (AGT)
and angiotensin-converting enzyme (ACE)
genes have been linked to increased risk of essential hypertension in multiple
populations, but results have been inconsistent. Ji et al. [159] evaluated the
associations of these polymorphisms with essential hypertension through a
meta-analysis of the association studies within the Han Chinese population.
They reviewed the two most commonly investigated polymorphisms, AGT*M235T and ACE*I/D, and provided summary estimates regarding their
associations with essential hypertension. PubMed and China Biological Medicine
Database were searched, and a total of 71 studies (31 studies for AGT*M235T and 40 studies for ACE*I/D) comprising 10547 essential
hypertension patients and 9217 controls from 23 provinces and special districts
in China were finally included in the study. Statistically significant
associations with essential hypertension were identified for the TT genotype of AGT*M235T polymorphism and the DD
genotype of ACE*I/D polymorphism.
Under dominant, recessive, and additive genetic models, positive associations
were also found. The heterogeneity existed among the studies, whereas the
publication bias did not exist in both AGT
analysis and ACE analysis. The
meta-analysis suggests that AGT*M235T
and ACE*I/D modulate the risk of
essential hypertension in the Han Chinese population. There has been an
increase in research into the association between ACE gene deletion polymorphism and cardiovascular disease, with
conflicting results. To evaluate whether the DD genotype could also be
associated with a higher prevalence of hypertension in healthy subjects over 6
years of follow-up, Di Pasquale et al. [160] conducted a long-term study on
684 healthy volunteers (aged 25-55 years), normotensive and free of
cardiovascular diseases, with acceptable echocardiographic window. All subjects
had to have a normal electrocardiogram (ECG) and echocardiogram (ECHO) at
entry, and underwent a complete physical examination, 12-lead ECG and ECHO, and
venous blood samples were drawn for DNA analysis and cholesterol. All subjects
had a clinical evaluation each year for the 6-year duration of the study. All
684 subjects completed 6 years of follow-up. Three genetically distinct groups
were identified. The ACE-DD group had 42 hypertensive subjects, 5 heart failure
(HF) subjects and 6 subjects with acute coronary syndromes (ACS). There was no
association between family history, smoking habit, hypercholesterolemia and
events. The ACE-ID group had 16 hypertensive subjects and 3 subjects with ACS.
The ACE-II group had 2 hypertensive subjects and 1 HF subject. The incidence of
hypertension and cardiovascular events was significantly higher in the ACE-DD
group than in the ACE-ID and ACE-II groups. The higher incidence of
hypertension was observed in the older age groups (36-45 and 46-55 years) with
ACE-DD and ACE-ID genotypes. These data suggest that the ACE-DD polymorphism is
associated with a higher incidence of hypertension in baseline healthy
subjects, irrespective of other risk factors. The higher incidence of
hypertension was apparent predominantly in the older age groups.
AGT-Angiotensinogen
As a part of the Renin-Angiotensin system,
the angiotensinogen precursor is expressed in the liver and is cleaved by renin
in response to lowered blood pressure [118]. The resulting product, angiotensin
I, is then cleaved by angiotensin converting enzyme (ACE) to generate the
physiologically active enzyme angiotensin II. AGT is involved in maintaining
blood pressure and in the pathogenesis of essential hypertension and
preeclampsia [161,162].
To review the most commonly investigated
polymorphisms at the AGT locus (other than M235T) and to provide summary
estimates regarding their association with essential hypertension, while
addressing heterogeneity as well as publication biases, data on 26818 subjects
from 46 studies for the four most-studied AGT variants (T174M in exon 2
and 3 promoter variants: A-6G, A-20C,
and G-217A) were meta-analyzed [163]. Statistically significant associations
with hypertension were identified for the T174M and G-217A polymorphisms. A
dual but consistent effect was observed for the -20C allele, which was
associated with a decreased risk of hypertension in populations of mixed and
European ancestries, but with a 24% increase in the odds of hypertension in
Asian subjects. No association was detected of the A-6G variant with
hypertension. Current studies support the notion that single variants at AGT
might modulate the risk of hypertension. Intervention studies have indicated an
interaction between the blood pressure response to a low-sodium or a low-fat
and high-fruit and -vegetable diet and the angiotensinogen gene (AGT)
polymorphisms G-6A and M235T. To investigate whether this interaction is also
present in a large free-living population, urinary sodium and potassium as
biomarkers of intake, and blood pressure, were measured in 11384 men and women
aged 45-79 years participating in the Norfolk arm of the European Prospective
Investigation of Nutrition and Cancer (EPIC). Highly significant associations
between sodium and blood pressure were shown for all genotypes, but the
regression coefficient for systolic blood pressure associated with each unit of
sodium for each of the MT and TT genotypes was approximately double that for
the MM homozygotes. Differences were evident at high exposures to sodium but
not at low exposures. There were no significant associations between blood
pressure and dietary or urinary potassium. This large cross-sectional study
supports public health recommendations to reduce salt consumption in the
population as a whole, and confirms intervention trial data showing the
greatest response to intervention in persons with the AA and TT genotype in the
AGT G-6A and M235T polymorphisms. Genotype effects in populations at low
exposure to sodium are not likely to be seen. T174M (rs4762) showed complete
linkage disequilibrium with M235T (rs699). T174M showed no correlation with any
of the 4 clinical entities included in the study (essential hypertension, left
ventricular hypertrophy, ischemic heart disease, and myocardial infarction),
but the T235 allele occurred more frequently in the essential hypertension
group and less frequently in the group of myocardial infarction survivors. The
frequency of T235 homozygotes was 70%, with 28% for T235 heterozygotes and only
2% for M235 homozygotes, the corresponding figures were 12%, 46%, and 42% in
Caucasians.
Angiotensinogen and its cleaved forms
angiotensin II and I, are important regulators of blood pressure. The gene for
angiotensinogen (AGT) carries two common polymorphisms, T207M and M268T
(previously described as T174M and M235T). To investigate the role of
haplotypes formed by these polymorphisms for angiotensinogen levels, blood
pressure, coronary artery disease (CAD), myocardial infarction (MI), and AGT
genotypes and haplotypes were examined in 2575 patients with angiographically
documented CAD and 731 individuals in whom CAD had been ruled out by
angiography [164]. Three haplotypes, designated as Hap1 (T207, M268), Hap2 (T207,
T268) and Hap3 (M207, T268), accounted for over 99% of alleles. The AGT
Hap2 haplotype was significantly associated with angiotensinogen levels, one
additional Hap2 allele accounted for an approx. 8% increase in angiotensinogen.
This association was stronger than that of either single polymorphism. AGT
genotypes or haplotypes were not related to hypertension, CAD or MI. A common
haplotype of the angiotensinogen gene is linked to angiotensinogen levels but
has no major impact on blood pressure, hypertension, or cardiovascular risk.
The association of renin C-4063T and angiotensinogen (AGT) T174M, M235T
and A-6G polymorphisms with ischemic stroke of atherosclerotic etiology was
investigated in 329 Tunisian patients with stroke, and 444 controls [165]. AGT*235T
and AGT*-6G allele and AGT*235TT, AGT*-6AG and AGT*-6GG
genotype frequencies were higher in patients. Linkage disequilibrium (LD) was
noted for AGT*174T with AGT* 235M and AGT*-6A in patients,
while AGT*235M was in LD with AGT*-6A in controls and AGT*235T
was in LD with AGT*-6G in both groups. The AGT*174T/235T/-6A and AGT*174T/235M/-6G
haplotypes were positively and negatively associated with stroke, respectively.
Multivariate regression analysis identified AGT*174T/235M/-6A, AGT*174T/235T/-6G,
AGT*174T/235T/-6A and AGT*174M/235T/-6A haplotypes to be
significantly associated with an increased risk of stroke.
Renin-angiotensin-aldosterone system polymorphisms influence the risk of
atherosclerotic stroke in Tunisians [165].
AGT polymorphisms are
associated with susceptibility to essential hypertension [17], and can cause
renal tubular dysgenesis, a severe disorder of renal tubular development [166]
and non-familial structural a trial fibrillation [167].
NOS3-Nitric Oxide Synthase 3
This gene encodes one of the three isoforms
of the nitric oxide synthase, the endothelial (eNOS) nitric oxide synthase
[118]. The enzyme eNOS synthesizes nitric oxide from L-arginine. Nitric oxide
acts as a biologic mediator in several processes, including neurotransmission
and antimicrobial and anti-tumoral activities and blood pressure regulation.NOS3
polymorphisms are described as a risk factor for endothelial dysfunction and
hypertension [19], Alzheimer's disease [168,169], ischemic stroke [170],
coronary spams and myocardial infarction [171].
NO-endothelium-dependent vasodilation is a
mechanism that may affect blood pressure response and endothelial NO synthase (eNOS
or NOS3) gene is a good candidate for the regulation of exercise blood
pressure. Rankinen et al. [19] investigated the associations between
theNOS3*Glu298Asp(894G>T) polymorphism and endurance training-induced
changes in resting and submaximal exercise blood pressure in 471 white subjects
of the HERITAGE Family Study. Both systolic and diastolic blood pressure at 50W
decreased in response to the training program, whereas resting blood pressure
remained unchanged. The decrease in diastolic blood pressure at 50W was greater
(P=0.0005, adjusted for age, gender, baseline body mass index, and baseline
diastolic blood pressure at 50 W) in the Glu298Glu homozygotes (4.4 [SEM 0.4]
mm Hg, n=187) than in the heterozygotes (3.1 [0.4] mm Hg, n=213) and the
Asp298Asp homozygotes (1.3 [0.7] mm Hg, n=71). The genotype accounted for 2.3%
of the variance in diastolic blood pressure at 50W training response. Both the
Glu298 homozygotes and the heterozygotes had a greater (P=0.013)
training-induced reduction in rate-pressure product at 50W than the Asp298
homozygotes. These data suggest that polymorphism in NOS3 gene locus is
associated with the endurance training-induced decreases in submaximal exercise
diastolic blood pressure and rate-pressure product in sedentary normotensive
white subjects.
Molecular epidemiologic studies have
presented contradictory results concerning a potential role of NOS3*894G>T
polymorphism in Alzheimer's disease [168,169]. To define a possible association
of this polymorphism with late onset AD in an Iranian population, a
case-control study was conducted, including a clinically well-defined group of
100 AD patients and 100 age-matched controls. A significantly increased number
of individuals with the NOS3*894GG genotype was observed in AD patients
compared with controls.
Berger et al. [170] performed 2 large
case-control studies involving 1901 hospitalized stroke patients and 1747
regional population controls and found that Glu298Asp was significantly
associated with ischemic stroke independent of age, gender, hypertension,
diabetes, and hypercholesterolemia.
Cerebrovascular Risk
and Inflammation
Atherosclerosis can be considered to be a form of chronic inflammation
resulting from interaction between modified lipoproteins, monocyte-derived
macrophages, T cells, and the normal cellular elements of the arterial wall
[10,24]. This inflammatory process can ultimately lead to the development of
complex lesions, or plaques that appear in the arterial lumen. Plaque rupture
results in the acute clinical complications of myocardial infarction and stroke
[172].
Pro-inflammatory cytokines participate in the induction of ischemic
stroke. Several studies showed increased concentration of the pro-inflammatory
cytokines interleukin-1 (IL1) and interleukin-6 (IL6), as well as tumor
necrosis factor TNF-alpha in blood and cerebrovascular fluid during ischemic
stroke [173-175]. Polymorphisms in the 5'
flanking region of these genes (promoter region) (Table 5) may alter the levels of expression and thus the
concentration of this cytokines in the brain damaged regions [22,23,27-30].
IL1B-Interleukin 1 Beta
IL-1β is produced by activated macrophages
as a proprotein, which is proteolytically processed to its active form by
caspase 1 (CASP1/ICE) [118]. IL-1βis an important mediator of the inflammatory
response, and is involved in a variety of cellular activities, including cell
proliferation, differentiation, and apoptosis. Interleukin-1 gene cluster
polymorphisms have been related with increased risk of hypochlorhydria induced
by Helicobacter pylori and gastric cancer [176], inflammatory bowel disease
[177], Alzheimer's disease [178], and Parkinson's disease [179], as well as
myocardial infarction and ischemic stroke [23].
Iacoviello et al. [23] found that patients
carrying the IL1B*512TT genotype showed a decreased risk of myocardial
infarction (OR, 0.36, 95% CI, 0.20-0.64) and stroke (OR, 0.32, 95% CI,
0.13-0.81) after adjustment for conventional risk factors. Mononuclear cells
from volunteers carrying the T allele showed a decreased release of IL1and a
decreased expression of tissue factor after stimulation with lipopolysaccharide
compared with CC homozygotes.
Rios et al. [180] investigated the
association of IL1B and IL6 gene polymorphisms and
angiographically assessed coronary artery disease (CAD) in African- and
Caucasian-Brazilians. The authors analyzed the IL1B*-511C>T and IL6*-174G>C
polymorphisms in 667 patients (253 African-Brazilians and 414
Caucasian-Brazilians) who underwent coronary angiography. Patients with a
coronary obstructive lesion presented a higher frequency of the IL1B*-511CC
genotype (30.4%) compared to lesion-free individuals (16.5%) in African- but
not in Caucasian-Brazilians. No significant genotype frequency difference was
identified for the IL6*-174G>C polymorphism in either ethnic groups.
However, after correction for other CAD risk factors using multivariate
logistic regression, both the IL1B*-511CC and the IL6*-174GG
genotypes were considered independent CAD risk predictors in
African-Brazilians. The IL1B*-511C>T and IL6*-174G>C
polymorphisms were associated with CAD risk in African-Brazilians and no
association was detected among Caucasian-Brazilians.
IL6-Interleukin 6
The cytokine encoded by the IL6 gene
functions in inflammation and the maturation of B cells [118]. IL-6 has been
shown to be an endogenous pyrogen capable of inducing fever in people with
autoimmune diseases or infections. The protein is primarily produced at sites
of acute and chronic inflammation, where it is secreted into the serum and
induces a transcriptional inflammatory response through interleukin 6-receptor
alpha. This cytokine is implicated in a wide variety of inflammation-associated
disorders, including diabetes mellitus, systemic juvenile rheumatoid arthritis,
coronary artery disease, Intracranial hemorrhage, systemic lupus erythematosus,
and others [181-186].
Interleukin-6 (IL6) is a pleiotropic
cytokine involved in the regulation of the acute phase reaction, immune responses,
and hematopoiesis. A polymorphism in the 5' flanking region of the IL6
gene alters the transcriptional response to stimuli such as endotoxin and
interleukin-1. This IL6*-174G>Cpolymorphism has been found to be
associated to different plasma IL6 levels in healthy volunteers [182]. Patients
IL6*-174CC homozygotes showed significantly lower platelet count than
carriers of the IL6*-174G allele, despite similar age, sex, body mass
index and proportion of smokers [185].
It has been found that carriers of the IL6*-174G
allele, which is associated with increased secretion of IL-6, have increased
levels of plasma triglycerides, VLDL and free fatty acids, as well as lower
levels of HDL-cholesterol. On the other hand, a strong association between the IL6*-174CC
genotype and lacunar infarction has been described [29].
Multivariable logistic regression analysis
with adjustment for conventional risk factors revealed that the IL6*-573G>C
polymorphism was significantly (P<0.001) associated with both
atherothrombotic cerebral infarction and intracerebral hemorrhage [33].
IL6R - Interleukin 6 Receptor
This gene encodes a subunit of the
interleukin 6 (IL6) receptor complex. The IL6 receptor is a protein complex
consisting of this protein and interleukin 6 signal transducer (IL6ST/GP130/IL6-beta),
a receptor subunit also shared by many other cytokines [118]. Disregulated
production of IL6 and this receptor are implicated in the pathogenesis of many
diseases, such as multiple myeloma, autoimmune diseases and prostate cancer [187-189].
The IL6R*1510A>C polymorphism
(rs8192284) is significantly associated with circulating levels of IL6SR. The IL6R*1510Cvariant
has an incidence of 35% in Europeans and only 4% in Africans, accounting for
differences in the concentration of circulating IL6SR, that is formed by
cleavage of IL6R from the cell membrane [190].
In an Alzheimer's case-control study in
Chinese population, Wang et al. [191] screened the IL6R promoter and the
proteolytic cleavage site of IL-6R.The IL6R*-530T allele located in a
putative regulatory region and the IL6R*+48867C allele at the splice
site may elevate the risk of Alzheimer's disease.
TNF-Tumor Necrosis Factor
Tumor necrosis factor (TNF) is a
multifunctional proinflammatory cytokine secreted predominantly by macrophages
that is involved inregulation of lipid metabolism, coagulation, insulin
resistance, and endothelial function [118,192,193].
The TNF-308G>A
polymorphism(rs1800629) in the promoter region of the gene is associated with
reduced circulating levels of TNF-alpha [194], and this variability may be
related with a variety of diseases, including autoimmune diseases, insulin
resistance, and cancer [195-197].
It is not clear what can be considered a
risk variant, because the findings published are contradictory. On the one
hand, the TNF*-308AAhomozygoteshas been associated with increased levels
of cortisol in saliva and obesity [30]. An association has also been described
between TNF*-308G variant in homozygosis and an increased risk of
migraine, probably due to the effect of this polymorphism on cerebral blood
flow [27].
Cerebrovascular Risk
and Thrombosis
Although advanced atherosclerotic lesions can lead to ischemic symptoms
as a result of the progressive narrowing of the vessel lumen, acute
cardiovascular events that result in myocardial infarction and stroke are
generally thought to result from plaque rupture and thrombosis.
Patients with atrial fibrillation have a 5-fold increased risk of
thromboembolic stroke, probably attributable to activation of blood coagulation
[198].
Variations in coagulation factor II or
prothrombin (F2), coagulation factor
V Leiden (F5), and
methylenetetrahydrofolate reductase (MTHFR),
are especially important, increasing atherothrombotic risk (Table 6).
F2-Coagulation factor II, Thrombin
Coagulation factor II is proteolytically
cleaved to form thrombin in the first step of the coagulation cascade, which
ultimately results in the stemming of blood loss. Thrombin also plays a role in
maintaining vascular integrity during development and postnatal life. Mutations
in F2 lead to various forms of thrombosis and dysprothrombinemia [118].
Thrombin, which cleaves bonds after arginine and lysine, converts fibrinogen to
fibrin and activates factors V, VII, VIII, XIII, and, in complex with
thrombomodulin, protein C.
The F2*20210G>A polymorphism
(rs1799963) is found in 3% of the population of southern Europe. This
alteration is associated with increased plasma levels of prothrombin. People
who carry one copy of this mutation (20210A allele) are 6 times more likely to
suffer a thrombosis. Pregnant women or those treated with contraceptives have a
16.3 times greater risk of thrombosis if they are carriers of the mutation
[35].
Martinelli et al.
[199] founded that the 20210G-A mutation in the prothrombin gene is associated
with ‘idiopathic’ cerebral vein thrombosis. The presence of both the
prothrombin gene mutation and oral contraceptive use raised further the risk of
cerebral vein thrombosis. Cerebral vein thrombosis is a frightening event due
to the severity of the clinical manifestations and the high mortality rate,
estimated to be 5 to 30%. Clinically, cerebral vein thrombosis presents with a
wide range of symptoms, including headache, focal deficits (motor or sensory),
dysphasia, seizures, and impaired consciousness.
F5-Coagulation Factor V
This gene encodes Factor V Leiden, one of
the factors involved in blood clotting. Factor V function is inactivated by
protein C, which is one of the most important anticoagulant mechanisms.
Thrombin, when bound to thrombomodulin on the endothelial surface, activates
protein C and this in turn, inactivates factors V and VIII. The G1691A
polymorphism (rs6025, Arg506Gln) in F5 has a high prevalence in
Caucasians, between 5 and 10% [118]. The presence of the 1691A mutation prevents
inactivation of factor V by protein C, resulting in a state of
hypercoagulability and increased thrombotic risk. Studies suggest an increase
from 50 to 100 times the risk of venous thrombosis for homozygous carriers of
the 506Q allele and 5 to 10 times for heterozygous carriers of R506Q [35].
Factor V is the plasma cofactor for the
prothrombinase complex that activates prothrombin to thrombin. Congenital
factor V deficiency is a bleeding disorder associated with mild to severe
hemorrhagic symptoms and prevalence in the general population of 1 in a million
in the homozygous form [200]. Patients with FV deficiency and clinically
significant manifestations show very low or immeasurable plasma FV levels and
are usually homozygous or compound heterozygous for mutations located in the F5
gene [201]. Heterozygous carriers have approximately half-normal levels of FV
and are usually asymptomatic. More than 60 mutations associated with FV
deficiency and more than 700 polymorphisms that do not have a clinical phenotype
have now been identified [118]. More than two thirds of these are null
mutations, with the remaining being missense mutations.
Gain-of-function variants of genes encoding
coagulation factor V (F5*1691G>A) and prothrombin (F2*20210G>A)
cause hypercoagulability and are established risk factors for venous
thrombosis. Manucci et al. [202] developed a meta-analysis of 66155 cases and
91307 controls and found that both polymorphisms are associated with a
moderately increased risk of coronary artery disease (CAD). In 1880 patients
with myocardial infarct (1680 men and 210 women) and an equal number of
controls, the minor F5*1691Aallele (2.6% frequency in cases and 1.7% in
controls) was associated with an increased risk of myocardial infarct, the
association remaining significant after adjustment for traditional risk
factors.
Allele and genotype frequencies of three
SNPs in the factor V gene leading to nonsynonymous changes (M385T in exon 8,
and R485K and R506Q (Leiden mutation) in exon 10) were studied in 133 Caucasian
women with pre-eclampsia and 112 healthy controls [203]. Haplotype frequencies
were estimated using an expectation-maximization algorithm. Comparison of
single-point allele and genotype distributions of SNPs in exons 8 and 10 of the
factor V gene revealed statistically significant differences in R485K allele
and genotype frequencies between the patients and the control subjects. The A
allele of SNP R485K was over-represented among the patients (12%) vs the
control subjects (4%), at an odds ratio (OR) of 2.8 for combined A genotypes
(GA+AA vs GG). Allele and genotype differences between the patients and control
subjects as regards M385T and Leiden mutation were not significant. In
haplotype estimation analysis, there was a significantly elevated frequency of
haplotype T-A-G encoding the M385-K485-R506 variant in the pre-eclamptic group
vs the control group, at an OR of 2.6. The T-A-G haplotype was more frequent
among the patient group than in the control group, and genetic variations in
the factor V gene other than the Leiden mutation may play a role in disease
susceptibility.
Ridker et al. [204] found that the R506Q
mutation of the F5 gene was present in 25.8% of men over the age of 60 in whom
primary venous thrombosis developed. There was no increased risk for secondary
venous thrombosis. The presence of the mutation was not associated with an
increased risk of myocardial infarction or stroke. In a follow-up study, of 77
study participants who had a first idiopathic venous thromboembolism, Ridker et
al. [205] found that factor V Leiden was associated with a 4- to 5-fold
increased risk of recurrent thrombosis. The data raised the possibility that
patients with idiopathic venous thromboembolism and factor V Leiden may require
more prolonged anticoagulation to prevent recurrent disease compared to those
without the mutation.
HDAC9-Histone Deacetylase
9
Histones play a critical role in
transcriptional regulation, cell cycle progression, and developmental events.
Histone acetylation/deacetylation alters chromosome structure and affects
transcription factor access to DNA. The protein encoded by HDAC9 gene
has sequence homology to members of the histone deacetylase family. HDAC9 may
play a role in hematopoiesis. A GWAS of the International Stroke Genetics
Consortium (ISGC) identified a novel association for the polymorphism
rs11984041within the histone deacetylase 9 (HDAC9) gene on chromosome
7p21.1 which was associated with large vessel stroke in a further 735 cases and
28583 controls (P=1.87×10-11, OR, 1.42, 95% CI, 1.28-1.57) [104].
HDAC9 is ubiquitously
expressed, with high levels of expression in cardiac tissue, muscle and brain.
Although known as histone deacetylases, these proteins also act on other
substrates and lead to both upregulation and down regulation of genes. To date
no associations have been reported between rs11984041 or correlated SNPs and
hypertension, hyperlipidaemia, or diabetes from large-scale GWAS of these risk
factors [104].
MTHFR-Methylenetetrahydrofolate Reductase
(NAD(P)H)
This gene encodes for Methylenetetrahydrofolate reductase, which
catalyzes the conversion of 5,10-methylenetetrahydrofolate to
5-methyltetrahydrofolate, a co-substrate for remethylation of homocysteine to
methionine[118]. The 677C>T
polymorphism (rs1801133, A222V) gives rise to a protein with reduced enzymatic
activity and increased thermolability when the 222V variant is present. MTHFR*677TT individuals have high plasma
homocysteine levels and have a risk of premature cardiovascular disease up to
three times higher than the rest. Another mutation also related to a reduction
in enzyme activity is A1298C (rs1801131, E429A), but this reduction in activity
does not appear to be related to increased plasma homocysteine levels or lower
concentrations of plasma folate as is the with 677T homozygotes. An increased
intake of folate (folic acid 0,8 mg) reduces the risk of ischemic heart disease
by 16% and that of stroke by 24% [37].
In a comprehensive meta-analysis of 22 case-control studies including
3387 white adult patients, Casas et al. [34] found a statistically significant
association between ischemic stroke and the 677C>T substitution. Kelly et
al. [206] performed a meta-analysis to determine the risk for ischemic stroke
associated with hyperhomocysteinemia and the MTHFR*677C>T polymorphism. The data support an association
between mild to moderate hyperhomocysteinemia and ischemic stroke. The MTHFR*677TT genotype may have a small
influence in determining the susceptibility to ischemic stroke.
From studies of the 677C>T mutation in cardiovascular patients and
controls, Kluijtmans et al. [207] found that homozygosity for this frequent
mutation in the MTHFR gene is
associated with a 3-fold increase in risk for premature cardiovascular disease.
Klerk et al. [208] performed a meta-analysis of the risk of coronary heart
disease related to the 677C>T polymorphism. They reported that individuals
with the 677TT genotype have a significantly higher risk of coronary heart
disease, particularly in the setting of low folate status. These results
supported the hypothesis that impaired folate metabolism, resulting in high
homocysteine levels, is causally related to increased risk of coronary heart
disease. Schwartz et al. [209] concluded that this polymorphism was not a risk
factor for myocardial infarction in their population. Schwartz et al. studied allele frequencies of the MTHFR*677C>T polymorphism in 69
non-Hispanic white female survivors of myocardial infarction and 338 controls.
They found a similar distribution of alleles in both groups.
Pharmacogenetics of
Cardiovascular Drugs
Pharmacogenetics offers the opportunity to
greatly improve treatment through its personalization, avoiding problems such
as high-risk interactions, adverse reactions or therapeutic inefficacy. This is
a step towards eliminating the current trial-and-error method of drug
prescription, where patients are subjected to different doses of drugs and/or
different therapeutic options. The information provided by pharmacogenetic
analysis is valuable, as a single genetic analysis will provide information on
our metabolism of drugs that will be valid throughout our lifetime.
Bearing in mind the patient's genomic profile, the physician will
choose from the list of drugs metabolized by each of the enzymes analyzed (Table 7). If the patient has a genetic
variation (Ultra-rapid Metabolizer or Poor Metabolizer) in any of the genes
analyzed, this means that this enzyme does not function "normally",
and therefore, the drugs it metabolizes will be processed abnormally (Figure 2).
In cardio and cerebrovascular treatments, variability in efficacy and
serious adverse effects continue to plague therapy. There are many sources of
variability in response to drug therapy, such as noncompliance and unrecognized
drug interactions, but translating pharmacogenomic discoveries to individual
patients and populations is a challenge for genomic and personalized medicine.
Now, we will review
the different findings in the field of pharmacogenetics to improve treatments,
as well as major pharmacogenes coding for enzymes, receptors and transporters
involved in ADME processes (Table 8),
such as absorption, distribution, metabolism and excretion of drugs, used in
cardiovascular therapy: antithrombotic agents, antihypertensives,
antiarrhythmics, beta-blockers, and lipid modifying agents.
ABCB1-ATP-binding Cassette, Sub-family B
(MDR/TAP), Member 1
The ABCB1 gene encodes for
P-glycoprotein (P-gp), considered the responsible for the multidrug resistance
(MDR) phenotype. P-gp is expressed in various human tissues, such as the liver,
kidney, pancreas, and the blood-brain barrier, although it is of particular
interest to observe that P-gp is functionally expressed in the enterocytes
surrounding the epithelium of the intestinal tract, where it plays an important
role, in conjunction with metabolic processes, in the intestine’s function as a
barrier to medicines and xenobiotics in general. In the case of drugs, P-gp may
determine the bioavailability of the same, independently of their chemical
nature [118].
The three most widely studied polymorphisms
of ABCB1 are 1236C>T, Gly412Gly (rs1128503), 2677G>T/A,
Ala893Thr/Ser (rs2032582) and 3435C>T, Ile1145Ile (rs1045642), which define
the haplotypes most frequently associated with multidrug resistance: ABCB1*1 (CGC) (high resistance), with
a frequency of 36.84% in Europeans, and ABCB1*2 (TTT) (low resistance),
with a frequency of 40.89% in Europeans. The TTT haplotype (ABCB1*2) is
associated with reduced methylation of the gene promoter, which gives rise to a
reduced expression of ABCB1, while the CGC haplotype (ABCB1*1) is
associated with hypermethylation of the promoter and over-expression of ABCB1.
Clopidogrel absorption and thereby active
metabolite formation are diminished by P-gp-mediated efflux and are influenced
by the ABCB1*3435C>T genotype. Pharmacogenetic determinants of the
response of patients to clopidogrel contribute to variability in the biologic
antiplatelet activity of the drug. The effect of these determinants on clinical
outcomes after an acute myocardial infarction is unknown. Patients with two
variant alleles of ABCB1 (3435TT) had a higher rate of cardiovascular
events at 1 year than those with the ABCB1 wild-type genotype (3435CC)
[210].
ABCB1 polymorphisms,
particularly 3435C>T, may affect drug transport and efficacy. Mega et al.
[211] assessed the effect of this polymorphism by itself and alongside variants
in CYP2C19 on cardiovascular outcomes in patients treated with clopidogrel or
prasugrel in TRITON-TIMI 38. Mega et al.[211] genotyped ABCB1 in
2932 patients with acute coronary syndromes undergoing percutaneous
intervention who were treated with clopidogrel (n=1471) or prasugrel (n=1461)
in the TRITON-TIMI 38 trial. They evaluated the association between ABCB1*3435C>T
and rates of the primary efficacy endpoint (cardiovascular death, myocardial
infarction, or stroke) until 15 months, and then assessed the combined effect
of ABCB1*3435C>T genotype and reduced-function alleles of CYP2C19.
In patients treated with clopidogrel, ABCB1*3435C>T genotype was
significantly associated with the risk of cardiovascular death, myocardial
infarction, or stroke. TT homozygotes had a 72% increased risk of the primary
endpoint compared with CT/CC individuals. ABCB1*3435C>T and CYP2C19
genotypes were significant, independent predictors of the primary endpoint, and
681 (47%) of the 1454 genotyped patients taking clopidogrel who were either CYP2C19
reduced-function allele carriers, ABCB1*3435 TT homozygotes or both,
were at increased risk of the primary endpoint.
Digoxin is a cardiotonic glycoside obtained
mainly from Digitalis lanata, it consists of three sugars and the
aglycone digoxigenin. Digoxin has positive inotropic and negative chronotropic
activity. It is used to control ventricular rate in atrial fibrillation and in
the management of congestive heart failure with atrial fibrillation. Its use in
congestive heart failure and sinus rhythm is less certain. The margin between
toxic and therapeutic doses is small. No influence is noted of ABCB1*2677G>A/T
and ABCB1*3435C>T polymorphisms on digoxin concentration. Although
some studies [212-214] have shown that digoxin pharmacokinetics might be
affected by ABCB1 genetic polymorphism, those modest changes are
probably clinically irrelevant, and digoxin dose adjustment should include P-gp
inhibitor co-administration rather than ABCB1 genotyping. Carriers of
two T alleles for the C3435T polymorphism in exon 26 of ABCB1 tend to
have a lower apparent volume of distribution than carriers of a C allele. ABCB1*1236C>T,
2677G>T, and 3435C>T variants and the associated TTT haplotype were
associated with higher digoxin serum concentrations in a cohort of elderly
European digoxin users in the general population. 2677T (Ser893) has been
associated with increased efflux of digoxin in vitro. In vitro expression of ABCB1
encoding Ala893 (ABCB1*1) or a site-directed Ser893 mutation (ABCB1*2)
indicated enhanced efflux of digoxin by cells expressing the ABCB1*Ser893
variant. 3435TT genotypes have higher plasma levels and lower intestinal
expression.
Takara et al. [213] examined ABCB1
(P-glycoprotein)-mediated interaction between digoxin and 29 antihypertensive
drugs. Most of the Ca2+ channel blockers used markedly inhibited
basal-to-apical transport and increased apical-to-basal transport. Exceptions
were diltiazem, nifedipine and nitrendipine, which hardly showed inhibitory
effects on transcellular transport of [3H] digoxin. Alpha-blocker doxazosin and
beta-blocker carvedilol also inhibited transcellular transport of [3H] digoxin,
but none of the angiotensin converting enzyme inhibitors and AT1 angiotensin II
receptor antagonists used were active.
In the PLATO trial of ticagrelor vs
clopidogrel for treatment of acute coronary syndromes, ticagrelor reduced the
composite outcome of cardiovascular death, myocardial infarction, and stroke,
but increased events of major bleeding related to non-coronary artery bypass
graft (CABG). CYP2C19 and ABCB1 genotypes are known to influence
the effects of clopidogrel. Wallentin et al. [215] investigated the effects of
these genotypes on outcomes between and within treatment groups. DNA samples
obtained from patients in the PLATO trial were genotyped for CYP2C19
loss-of-function alleles (*2, *3, *4, *5, *6, *7, and *8), the CYP2C19
gain-of-function allele *17, and the ABCB1 SNP 5C>T. For the CYP2C19
genotype, patients were stratified by the presence or absence of any
loss-of-function allele, and for the ABCB1 genotype, patients were
stratified by predicted gene expression (high, intermediate, or low). The
primary efficacy endpoint was the composite of cardiovascular death, myocardial
infarction, or stroke after up to 12 months' treatment with ticagrelor or
clopidogrel. 10285 patients provided samples for genetic analysis. The primary
outcome occurred less often with ticagrelor vs clopidogrel, irrespective of CYP2C19
genotype: 8.6% vs 11.2% in patients with
any loss-of-function allele, and 8.8% vs 10.0% in those with no
loss-of-function allele. For the ABCB1 genotype, event rates for the
primary outcome were also consistently lower in ticagrelor than in the
clopidogrel group for all genotype groups. In the clopidogrel group, the event
rate at 30 days was higher in patients with than in those without loss-of-function
CYP2C19 alleles (5.7% vs 3.8%), leading to earlier separation of event
rates between treatment groups in patients with loss-of-function alleles.
Patients on clopidogrel who had any gain-of-function CYP2C19 allele had
a higher frequency of major bleeding (11.9%) than did those with no
gain-of-function or loss-of-function alleles (9.5%), but interaction between
treatment and genotype groups was not significant for any type of major
bleeding. Ticagrelor is a more efficacious treatment for acute coronary
syndromes than is clopidogrel, irrespective of CYP2C19 and ABCB1
polymorphisms. Use of ticagrelor instead of clopidogrel eliminates the need for
the currently recommended genetic testing before dual antiplatelet treatment.
ADRB1-Adrenoceptor Beta 1
The adrenergic receptors (subtypes alpha 1,
alpha 2, beta 1, and beta 2) are a prototypic family of guanine nucleotide
binding regulatory protein-coupled receptors that mediate the physiological
effects of the hormone epinephrine and the neurotransmitter norepinephrine.
ADRB1 encodes the
adrenoceptor beta 1, the primary target of beta-blocking agents [118]. Two
specific polymorphisms in this gene, ADRB1*145A>G (Ser49Gly,
rs1801252) and ADRB1*1165G>C (Gly389Arg, rs1801253) have been shown
to correlate with hypertension and myocardial infarction risk, and
antihypertensive (atenolol) and beta-blocker (bisoprolol, metoprolol, timolol,
verapamil) responses to these conditions [216].
The Ser49Gly polymorphism was associated
with lower resting heart rate in hypertensive patients, independent of
beta-blocker therapy [217]. In two studies, Ser49 homozygotes experienced a
significantly greater blood pressure reduction than Gly carriers after
treatment with metoprolol [217]. Haplotype analysis of the variants at codons
49 and 389 revealed that those with the Ser49Gly389/Gly49Arg389 (ADRB1*H2/H3)
haplotype were virtually unresponsive to metoprolol, whereas the greatest
response was observed in subjects with the ADRB1*H1/H1 haplotype
(Ser49Arg389/Ser49Arg389) (other combinations were intermediate) [218].
CACNB2-Calcium Voltage-Gated Channel Auxiliary
Subunit Beta 2
CACNB2 encodes the beta 2
subunit of the L-type voltage-dependent calcium channel protein that is a
member of the voltage-gated calcium channel superfamily. The beta 2 regulatory
subunit control the cell surface expression of the alpha 1c subunit, the
pore-forming subunit to which all calcium channel blockers bind.
The INVEST-GENES study showsa different
genotype-dependent outcome in antihypertensive treatment with beta-blockers or
calcium channel blockers. Rs2357928*GG patients randomized to calcium channel
blockers were more likely to experience an adverse outcome than those
randomized to bets-blockers treatment strategy, with adjusted hazard ratio (HR)
of 2.35 (95% CI, 1.19-4.66, P=0.014) [219].
CYP1A2-Cytochrome P450, Family 1, Subfamily A,
Polypeptide 2
The cytochrome P450 1A2 acts on 5-10% of
drugs in current clinical use. CYP1A2 is
responsible for more than 95% of the primary metabolism of caffeine [220], and
has been shown to be important in the metabolism of clozapine [221].
CYP1A2 activates several aromatic amines and
thus is a key enzyme in chemical carcinogenesis. Several studies on the
CYP1A2-dependent metabolism of caffeine or phenacetin have demonstrated that
this enzyme is expressed in human livers at various levels amongst individuals,
suggesting polymorphic control of enzyme activity [222].
CYP1A2 plays a major role in the metabolism
of many commonly used cardiovascular drugs, including antithromboticagents
(acenocoumarol, apixaban, clopidogrel, cilostazol, warfarin), antiarrhythmics
(amiodarone, flecainide, lidocaine, mexiletine), betablockers (betaxolol,
carvedilol, propranolol), and other relevant drugs as losartan, simvastatin and
verapamil [118].
Clopidogrel is metabolically activated by
several hepatic cytochrome P450 (CYP) isoenzymes, including CYP1A2. Cigarette
smoking induces CYP1A2 and may, therefore, enhance the conversion of
clopidogrel to its active metabolite. Clopidogrel therapy in smokers is
associated with increased platelet inhibition and lower aggregation as compared
with non-smokers. The mechanism of the smoking effect deserves further study
and may be an important cause of response variability to clopidogrel therapy
[223,224].Enhanced clopidogrel response in smokers, known as the smokers'
paradox, is not universal but was observed only in CYP1A2*-163A allele
carriers, suggesting a genotype-dependent effect of smoking on clopidogrel
responsiveness [225].
Ishida et al. [226] studied the enzyme
responsible for the stereoselective metabolism of carvedilol in the cells. The
expression of CYP1A1and CYP1A2 mRNA, but not CYP2D6, CYP3A4,
and CYP2C9 mRNA, was increased in beta-NF-treated Caco-2 cells, as
compared with non-treated cells.
CYP2C19-Cytochrome P450, Family 2, Subfamily C,
Polypeptide 19
CYP2C19 acts on 5-10% of drugs in current
clinical use. About 2-6% of individuals of European origin, 15-20% of Japanese,
and 10-20% of Africans have a slow acting, poor metabolizer form of this
enzyme. However there is wide variability among populations. For example, the
percentage of Polynesians who are poor metabolizers ranges from 38-79%
depending on location. CYP2C19 is an important drug metabolizing enzyme that
catalyzes the biotransformation of many other clinically useful drugs including
antidepressants, barbiturates, proton pump inhibitors, antimalarial and
antitumor drugs [118].
In cardiovascular therapy CYP2C19 is
involved in the metabolism of antithrombotic agents (cilostazol, clopidogrel,
prasugrel, ticlopidine, and warfarin), betablockers (carvedilol, metoprolol,
propranolol, sotalol, timolol), antihypertensives (ambrisentan, doxazosin),
indometacin, losartan, verapamil and others.
Yoo et al. [227] investigated the influence
of genetic polymorphisms in the CYP3A5, CYP2C19 and ABCB1
genes on the population pharmacokinetics of cilostazol in healthy subjects. The
genetic polymorphisms of CYP3A5 had a significant influence on the
apparent oral clearance of cilostazol. When CYP2C19 was evaluated, a significant
difference was observed among the three genotypes (extensive metabolizers,
intermediate metabolizers and poor metabolizers) for the apparent oral
clearance. A combination of CYP3A5 and CYP2C19 genotypes was
found to be associated with a significant difference in the apparent oral
clearance. When including these genotypes, the inter individual variability of
the apparent oral clearance was reduced from 34.1% in the base model to 27.3%
in the final model. However, no significant differences between the ABCB1
genotypes and cilostazol pharmacokinetic parameters were observed. CYP3A5
and CYP2C19 polymorphisms explain the substantial inter individual
variability that occurs in the metabolism of cilostazol.
Several clinical studies have confirmed the
effect of CYP2C19 polymorphisms on the pharmacokinetics and/or
pharmacodynamics of clopidogrel. Hulot et al. [228] determined whether frequent
functional variants of genes coding for candidate CYP450 isoenzymes involved in
clopidogrel metabolic activation (CYP2C19*2, CYP2B6*5, CYP1A2*1F,
and CYP3A5*3 variants) influence platelet responsiveness to clopidogrel.
In healthy subjects, carriers of the CYP2C19*1/*2genotype had a reduced
response to clopidogrel compared to the wild-type carriers during maintenance
treatment at 75 mg daily. The CYP2C19*2 allele was associated with
higher platelet aggregability and residual platelet reactivity in high-risk
vascular patients on dual antiplatelet treatment. Kim et al. [229] found that
the AUC of clopidogrel for PMs of CYP2C19 was 1.8-and 2.9-fold higher
than that for heterozygous and homozygous EMs of CYP2C19, respectively.
The Cmax of clopidogrel in PMs of CYP2C19 was 1.8- and 4.7- fold higher
than that of heterozygous and homozygous EMs, respectively. PMs of CYP2C19
showed a significantly lower antiplatelet effect than EMs.
Prasugrel is a newly marketed antiplatelet
drug with improved cardiac outcomes as compared with clopidogrel for acute
coronary syndromes involving percutaneous coronary intervention (PCI). Analysis
of a subset of the TRITON-TIMI 38 trial [230] demonstrated that CYP2C19
reduced-function genotypes are associated with differential clinical responses
to clopidogrel, but not prasugrel. An exploratory, secondary analysis was
undertaken to estimate the clinical benefit of prasugrel over clopidogrel in
subgroups defined by CYP2C19 genotype, by integrating the published
results of the genetic substudy and the overall TRITON-TIMI 38 trial.
Individuals with a CYP2C19 reduced-metabolizer genotype were estimated
to have a substantial reduction in the risk of the composite primary outcome
(cardiovascular death, myocardial infarction, or stroke) with prasugrel as
compared with clopidogrel. For CYP2C19 extensive metabolizers (~70% of
the population), however, the composite outcome risks with prasugrel and
clopidogrel were not substantially different. Integration of the TRITON-TIMI 38
data suggests that the CYP2C19 genotype can discriminate between
individuals who receive extensive benefit from using prasugrel instead of clopidogrel,
and individuals with comparable clinical outcomes with prasugrel and
clopidogrel.
CYP2C9-Cytochrome P450, Family 2, Subfamily C,
Polypeptide 9
CYP2C9 acts on 15% of drugs in current
clinical use. About 35% of Caucasians have a slow acting form of this enzyme.
CYP2C9 is an important drug-metabolizing enzyme that catalyses the
biotransformation of many other clinically useful drugs including angiotensin
II blockers (candesartan, irbesartan, losartan, olmesartan, valsartan),
antithrombotics (acenocoumarol, aspirine, clopidogrel, prasugrel,
phenprocoumon, treprostinil, warfarin), antiarrhythmics (amiodarone, lidocaine,
quinidine), antihypertensives (ambrisentan, bosentan, sitaxentan), statins
(atorvastatin, fluvastatin, pitavastatin, rosuvastatin, simvastatin),
non-steroidal anti-inflammatory drugs, alkylating anticancer pro-drugs,
sulfonylureas and many others.
Of special interest are those drugs with
narrow therapeutic window, such as S-warfarin, tolbutamide and phenytoin, where
impairment in CYP2C9 metabolic activity might cause difficulties in dose
adjustment as well as toxicity. Indications for testing include lack of
therapeutic effect or difficulties with side effects to any of the drugs
metabolized by CYP2C9.
Acenocoumarol, an analogue of warfarin, is a
short-acting coumarin anticoagulant with a half-life of 8 h. The main metabolic
route of racemic acenocoumarol is 6- and 7- monohydroxylation, while
8-hydroxylation is a minor pathway. All hydroxylated metabolites are further
conjugated to their corresponding O-glucuronides and O-sulfates. The metabolic
clearance of S-acenocoumarol is high with a short plasma t½ of 2 h, thus the
pharmacological effect lies almost exclusively with the R-enantiomer, unless
there is a decreased CYP2C9 activity (for example, presence of a CYP2C9*3
allele). Only CYP2C9 hydroxylated S- and R-acenocoumarol at the 6-, 7-,
and 8-position, R-acenocoumarol was also metabolized by CYP1A2
(6-hydroxylation) and CYP2C19 (6-, 7-, and 8-hydroxylation). There is
increasing clinical evidence that the CYP2C9*3 allele is related to a
low-dose requirement for this drug, a higher frequency of over-anticoagulation
and an unstable or delayed stable anticoagulant response, and even one copy of CYP2C9*3
might profoundly reduce the oral drug clearance. Spreafico et al. [231]
performed a prospective study during the initial phase of acenocoumarol
therapy, analyzing the effect of CYP2C9 variant alleles and VKORC1
haplotypes, single and in combination, in 220 Italians. CYP2C9*3 was
associated with a 25% dose reduction and an increased risk of
over-anticoagulation (INR>6).
Candesartan is a long-acting, nonpeptide,
and selective angiotensin receptor antagonist used in the treatment of hypertension
and congestive heart failure. Candesartan is released from its ester racemic
prodrug (candesartan cilexitil) by presystemic hydrolysis in the intestinal
wall. Candesartan is primarily excreted as unchanged drug (75%) in the urine
(33%) and feces (67%) with a smaller proportion (20-25%) inactivated via
O-deethylation by hepatic CYP2C9 to an inactive metabolite (CV-15959).Since the
contribution of CYP2C9 to the overall clearance of candesartan is moderate in
vivo (~20-25%), it can be expected that polymorphisms of CYP2C9 would
produce a moderate effect on the clearance of candesartan. However, a deficient
allele of CYP2C9 could cause a significant effect on candesartan
clearance (48% lower) and plasma levels (2.5-fold higher), and it appears that
the contribution of CYP2C9 to the overall clearance of candesartan is close to
48% in some patients in vivo, probably due to reduced renal and biliary
excretion of the parent drug which normally accounts for about 75% of a total
dose [232].
Brandt et al. [233] determined the
relationship between genetic variation in CYP450 isoenzymes and the
pharmacokinetic/pharmacodynamic response to prasugrel and clopidogrel. In
patients receiving clopidogrel treatment, carriers of CYP2C9*2 or *3
variants had significantly lower AUC and Cmax values of clopidogrel active
metabolite and reduced inhibition of platelet aggregation and poor response
compared to those with the wild-type genotype. Twelve out of 16 subjects
(75.0%) with the CYP2C9*2/*2 or *3 allele were poor responders, while
only 41.4% (24/58) of the patients without the CYP2C9*2/*2 or *3 allele
were poor responders.
Inhibitors of HMG-CoA reductase, also known
as "statins", represent an important group of therapeutic agents for
the treatment of hypercholesterolemia, a major risk factor for the development
of coronary artery disease. Fluvastatin is 50-80% metabolized by CYP2C9 to
5-hydroxy-, 6-hydroxy-, and N-deisopropyl-fluvastatin.The CYP2C9*3/*3
genotype was associated with 3-fold higher concentrations of the more active
(+)-3R,5S-fluvastatin than the wild-type in healthy subjects, while individuals
carrying the CYP2C9*1/*3 and *2/*3 genotypes had intermediate
concentrations. Pharmacokinetics of both enantiomers showed statistically
significant differences according to the number of CYP2C9*3 alleles
[234].
Hallberg et al. [235] studied whether the CYP2C9
genotype influences the blood pressure-decreasing response to antihypertensive
treatment with irbesartan. Hypertensive patients with the CYP2C9*1/*2
genotype treated with irbesartan showed a greater decrease in diastolic blood
pressure than the patients with the wild-type genotype, with a trend for a
reduction in systolic blood pressure. However, there was no correlation between
the CYP2C9 genotype and blood pressure response to atenolol, a drug not
metabolized via CYP2C9. The CYP2C9 genotype seems to predict the
diastolic blood pressure response to irbesartan, but not to atenolol, in
patients with essential hypertension.
Phenprocoumon is used for the prophylaxis
and treatment of thromboembolic disorders. The AUC of phenprocoumon metabolites
after oral intake of 12 mg racemic phenprocoumon was significantly lower in
volunteers expressing the CYP2C9*2 or CYP2C9*3 allele. Increasing
plasma AUC metabolic ratios in CYP2C9*2 and CYP2C9*3 variant
allele carriers were found for each hydroxylation reaction and the CYP2C9*3/*3
genotype corresponded to an about 10-fold higher metabolic ratio of
S-7-hydroxylation relative to CYP2C9*1/*1. CYP2C9 polymorphisms
cause a markedly compromised S-7-hydroxylation of phenprocoumon [236].
CYP2C9 polymorphisms
have been shown to have a significant impact on incidence of bleeding episodes
in patients receiving warfarin therapy. Patients with CYP2C9 variants
were more likely to have difficulties in achieving target INR range at the time
of induction of warfarin therapy, and to have increased risk of major bleeding
complications [237]. In this study, 56% of patients receiving a low daily dose
of warfarin (≤1.5 mg) had INR values greater than 4, compared to 17% in the
control group receiving a wide range of dosages. Patients with CYP2C9*2
or *3 alleles had a greater risk of bleeding. The relative bleeding risk
for CYP2C9*2 was 1.91 and for CYP2C9*3 1.77, while the relative
risk was 2.26 for either variant [238]. The reason for the unstable INR values
and increased bleeding risks in patients with variant CYP2C9 alleles is
unclear, but may be associated with decreased hydroxylation of S-warfarin in
vivo with increased levels of warfarin exposure, and thus over-anticoagulant
activity is expected to occur in individuals carrying these mutant alleles.
CYP2D6-Cytochrome P450, Family 2, Subfamily D,
Polypeptide 6
CYP2D6 acts on 25%
of all prescription drugs. 7-14% of the population has a slow acting form of
this enzyme and 7% a super-fast acting form.35% are carriers of a
non-functional CYP2D6 allele, which especially elevates the risk of adverse
drug reactions when these individuals are taking multiple drugs [118].
Drugs that CYP2D6
metabolizes include selective serotonin reuptake inhibitors (SSRI), tricyclic
antidepressants (TCA), opiates, neuroleptics and a variety of toxic plant
substances. Specific cardiovascular drugs are antiarrhythmics (amiodarone,
flecainide, lidocaine, mexiletine, procainamide, propaphenone, vernakalant) and
beta-blockers (betaxolol, bisoprolol, carvedilol, metoprolol, nebivolol,
pindolol, propranolol, sotalol, timolol). CYP2D6 is also responsible for
activating the pro-drug codeine and other opioids into their active forms. The
analgesic activity of these drugs is therefore reduced or absent in CYP2D6 poor
metabolizers [118].
The association
between CYP2D6*4 and blood pressure or heart rate was examined in 1533
users of beta-blockers in the Rotterdam Study, a population-based cohort study [239].
InCYP2D6 *4/*4 PMs, the adjusted heart rate in metoprolol users was 8.5
beats/min lower compared with *1/*1 extensive metabolizers (EMs), leading to an
increased risk of bradycardia in PMs. The diastolic blood pressure in PMs was
5.4 mm Hg lower in users of beta-blockers metabolized by CYP2D6 and 4.8 mm Hg
lower in metoprolol users compared with EMs. PMs are at increased risk of
bradycardia. Patients with cardiovascular diseases are often treated by
concurrent multiple drug therapy. It is therefore plausible that with an
increasing number of drugs the risk of drug interactions increases. Such
interactions can be either pharmacodynamic (and are due to the mechanism of the
administered drugs) or they can be pharmacokinetic (resulting in a reduction or
enhancement of drug elimination). Pharmacokinetic interactions can be either
due to interactions at the level of drug metabolizing enzymes (most importantly
CYP450 enzymes), or interactions at the level of drug transporter proteins (for
example P-glycoprotein (ABCB1)). It is important to distinguish between both
mechanisms since interactions at transporter proteins can be attributed to
those drugs that are not enzymatically metabolized. Four beta-blockers are
widely used in the therapy of cardiovascular diseases, namely atenolol,
bisoprolol, metoprolol, and carvedilol. Among these beta-blockers, atenolol is
mainly eliminated by renal excretion, bisoprolol is in part excreted as parent
compound via the renal route (50%), the other 50% are hepatically metabolized,
whereas metoprolol and carvedilol are metabolized by CYP2D6. Evidence is
accumulating that carvedilol is a substrate for P-glycoprotein. For these four
beta-blockers various pharmacodynamic and pharmacokinetic interactions have
been demonstrated. Such interactions that result in altered pharmacokinetics
are mainly observed with those beta-blockers that are excreted via metabolism
(metoprolol and carvedilol).
Carvedilol is a
beta-adrenoceptor antagonist used for treating chronic heart failure (CHF). For
40 Japanese patients evaluated in a clinical study, the CYP2D6 *1, *10,
and *5 genotypes were determined using allele-specific primer PCR, and
individual patients' oral clearance (CL/F) of both enantiomers were estimated
by the empirical Bayes method. Individual CL/F values for carvedilol were
significantly lower in Japanese CHF patients with the CYP2D6 *1/*5,
*5/*10 and *10/*10 genotypes. Estimation of the population pharmacokinetic
parameters and their covariates for each enantiomer in patients with CHF showed
that the CL/F values for R- and S-carvedilol were dependent on body weight,
alpha1-acid glycoprotein and CYP2D6 genotype [240].
Statin therapy,
although generally well tolerated, leads not infrequently to significant
subjective and at times objective adverse effects, mainly of a muscular nature.
The genetic background of these adverse effects is not clear and possibly side
effects and lipid lowering efficacy may be linked. None of the assessed CYP450
polymorphisms appeared to be related to an increased incidence of adverse
effects. The CYP2D6 *1/*4 and *4/4* poor metabolizer (PM) status was
associated with a higher efficacy of statins metabolized by this system and, in
addition, the APOE-2 genotype was, in this series, linked to increased
HDL-C levels after therapy. Patients with statin-associated myopathy are not
characterized by significantly different genotypes for the CYP450s responsible
for statin metabolism. CYP2D6 PM status is associated to an increased
efficacy of statins metabolized by this system [241].
Mexiletine is an
antiarrhythmic agent pharmacologically similar to lidocaine. It may have some
anticonvulsant properties. Mexiletine is used for the control of ventricular
arrhythmias and for neuropathic pain from cancer or diabetes mellitus. It is
metabolized mainly by CYP2D6 and, to a lesser extent, by CYP1A2. In vitro
studies with human liver microsomes have shown that the oxidative conversion of
mexiletine (MX) to its metabolites is catalyzed by CYP2D6 and is significantly
impaired in microsomes with the CYP2D6*10/*10 genotype [242]. Clearance of MX
in the CYP2D6*5/*10 subjects was comparable to that in poor
metabolizers. Carriers of the CYP2D6*10 allele showed a decreased
clearance of MX. Subjects with CYP2D6*5/ *10 showed significantly
increased plasma levels of MX, and homozygotes for CYP2D6*10 also showed
an increase, although to a lesser extent. Thus, the CYP2D6*10 allele
plays an important role in MX pharmacokinetics.
CYP3A4/5-Cytochrome P450, Family 3 Subfamily A,
Polypeptides 4/5
Cytochrome P450 3A4
(CYP3A4) and their isoform CYP3A5 act on approximately half of drugs in
clinical use. About 5% of individuals of European origin have a slow acting,
intermediate metabolizer form of CYP3A4. Prevalence of CYP3A5 variants differs
widely by ethnic origin. People of African ancestry have an increased
prevalence of CYP3A5 Rapid (*1/*3) or Ultra Rapid (*1/*1) metabolizer status.
CYP3A4 and CYP3A5 are closely related and may process many of the same drugs.
Substrates include opioid pain medications, statins, chemotherapeutic drugs and
combined oral contraceptives [118].
Aliskiren is a renin
inhibitor used in the treatment of hypertension. Itraconazole, a strong CYP3A4
inhibitor, raises the peak plasma aliskiren concentration 5.8-fold (range 1.1-
to 24.3-fold) and the area under the plasma aliskiren concentration-time curve
6.5-fold (range 2.6- to 20.5-fold) but has no significant effect on aliskiren
elimination half-life [243]. Itraconazole increases the amount of aliskiren
excreted into the urine during 12 hours 8.0-fold and its renal clearance
1.2-fold. Plasma renin activity 24 hours after aliskiren intake is 68% lower
during the itraconazole phase than during the placebo phase. Itraconazole
markedly raises the plasma concentrations and enhances the renin-inhibiting
effect of aliskiren. The interaction is probably mainly explained by inhibition
of the P-glycoprotein-mediated efflux of aliskiren in the small intestine, with
a minor contribution from inhibition of CYP3A4. Concomitant use of aliskiren
and itraconazole is best avoided.
Amiodarone has been
reported to be involved in a significant number of drug interactions. It is
mainly metabolized by CYP3A4 and is a potent inhibitor of CYP1A2, 2C9, 2D6 and
3A4. In addition, amiodarone may interact with other drugs (such as digoxin)
via the inhibition of the P-glycoprotein membrane transporter system.
Close correlations
between amiodarone N-monodesethylase activities and the amounts of CYP3A4, and
the rates of lidocaine N-monodesethylation were observed [244]. Lidocaine
inhibited amiodarone N-monodesethylation competitively, inversely, amiodarone
suppressed lidocaine N-monodesethylase activity in the same manner. The
interaction between amiodarone and lidocaine may be explained by the inhibition
of CYP3A4 by amiodarone and/or by its main metabolite DEA.
To predict the drug
interactions of amiodarone and other drugs, the inhibitory effects and
inactivation potential for human CYP enzymes by amiodarone and its
N-dealkylated metabolite, desethylamiodarone, were examined [245]. Amiodarone
weakly inhibited CYP2C9, CYP2D6, and CYP3A4-mediated activities with Ki values
of 45.1-271.6 μM. Desethylamiodarone competitively inhibited the catalytic
activities of CYP2D6 and noncompetitively inhibited CYP2A6, CYP2B6, and CYP3A4.
The catalytic activities of CYP1A1, CYP1A2, CYP2C9, and CYP2C19 were inhibited
by desethylamiodarone with mixed type. Amiodarone inactivated CYP3A4, while desethylamiodarone
inactivated CYP1A1, CYP1A2, CYP2B6, and CYP2D6. The interactions between
amiodarone and other drugs might occur via the inhibition of CYP activities by
its N-dealkylated metabolite, desethylamiodarone, rather than by amiodarone
itself. The inactivation of CYPs by desethylamiodarone as well as by amiodarone
would also contribute to the drug interactions.
Ticagrelor is a
platelet inhibitor used to reduce the risk of thrombotic cardiovascular events
for patients with acute coronary syndrome. It is metabolized by CYP3A4, and to
a lesser extent, CYP3A5. There is a FDA label for this drug, which suggests
avoiding using ticagrelor with CYP3A inhibitors (such as atazanavir,
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir,
ritonavir, saquinavir, telithromycin and voriconazole) and inducers (such as
rifampin, dexamethasone, phenytoin, carbamazepine, and phenobarbital).
Ticagrelor also inhibits ABCB1, so digoxin levels should be monitored. In vitro
studies have shown no inhibitory effect on human CYP1A2, CYP2C19 and CYP2E1
activity. Finally, the PLATO trial showed that bleeding with ticagrelor was not
significantly affected by CYP2C19 genotype [246]. Ticagrelor will result in
higher serum concentrations of simvastatin and lovastatin because these drugs
are metabolized by CYP3A4.
Clopidogrel and statins are frequently
administered in patients with ischemic heart disease or other atherothrombotic
manifestations and are effective in the prevention of cardiovascular disease.
The thienopyridine clopidogrel is a pro-drug metabolized in the liver via the
cytochrome P450 (CYP) 3A4 system to the active compound, which inhibits the
P2Y(12) ADP platelet receptor. The assumption exists that the effect of
clopidogrel in inhibiting platelet aggregation is attenuated by
co-administration of lipophilic statins such as atorvastatin or simvastatin,
which are metabolized by the CYP3A4 system to inactive substrates [247].
G6PD-Glucose-6-Phosphate Dehydrogenase
The G6PD gene
encodes glucose-6-phosphate dehydrogenase. The protein is a cytosolic enzyme
encoded by a housekeeping X-linked gene whose main function is to produce
NADPH, a key electron donor in the defense against oxidizing agents and in
reductive biosynthetic reactions. G6PD is remarkable for its genetic
diversity. Many variants of G6PD, mostly produced from missense
mutations, have been described with wide-ranging levels of enzyme activity and
associated clinical symptoms. G6PD deficiency may cause neonatal jaundice,
acute haemolysis, or severe chronic non-spherocytic haemolytic anaemia. Several
transcript variants encoding different isoforms have been found for this gene.
G6PD is in the hexose monophosphate pathway, the only NADPH-generation process
in mature red cells, which lack the citric acid cycle. For this reason G6PD
deficiency has adverse physiologic effects. It produces pentose sugars for
nucleic acid synthesis. The G6PD variants have been divided into 5 classes
according to the level of enzyme activity. These are: class 1:
enzyme deficiency with chronic non-spherocytic haemolytic anaemia, class
2: severe enzyme deficiency (less than
10%), class 3: moderate to mild enzyme
deficiency (10-60%), class 4: very mild
or no enzyme deficiency (60%), class 5:
increased enzyme activity [118].
NAT2-N-Acetyltransferase 2 (Arylamine
N-Acetyltransferase)
N-Acetyltransferase
2 (NAT2) plays an important role in the detoxification and/or metabolic
activation of certain therapeutic drugs, occupational chemicals and carcinogens.
The enzyme produced by NAT2 acts on 1% of drugs in current clinical use
including isoniazid, a common tuberculosis treatment, and numerous chemicals.
Approximately 50% of people in the United States are slow acetylators and 40%
intermediate acetylators [118].
Arylamine N-acetyltransferase 2 is a
polymorphic phase II enzyme responsible for slow or rapid acetylation of the
antihypertensive hydrazine, the antiarrhythmic procainamide and different high-
and low-ceiling diuretics belonging to sulfonamides. Various combinations of
SNPs have been identified as NAT2 alleles or haplotypes. Different
combinations of these SNPs in the NAT2 coding region result in proteins
with altered stability, degradation, and/or kinetic characteristics. These
effects of SNPs on NAT2 proteins are the basis for slow, intermediate, and
rapid acetylator phenotypes. Individuals homozygous for rapid NAT2 acetylator
alleles are deduced as rapid acetylators, individuals homozygous for slow
acetylator NAT2 alleles are deduced as slow acetylators, and individuals
possessing one rapid and one slow NAT2 allele are deduced as intermediate
acetylators. Haplotype definition
includes the seven most frequent single nucleotide polymorphisms (SNPs) of NAT2
including 191G>A, 282C>T, 341T>C, 481C>T, 590G>A, 803A>G, and
857G>A. The NAT2*4 allele encodes for a fully active enzyme and is
traditionally considered the wild type (rapid acetylator) allele. The
representative four common alleles (haplotypes) that possess signature
nucleotide substitutions at positions 341, 590, 857, and 191 are designated NAT2*5,
NAT2*6 andNAT2*7, respectively, and several studies have shown
that the members of these clusters are responsible for the slow acetylator
phenotype. In addition to the NAT*4 haplotype, variants NAT2*11, NAT2*12,
NAT2*13 and NAT2*14 are responsible for the rapid acetylator
phenotype.
Hydralazine is a vasodilator used to treat
hypertension. Hydralazine is thought to be metabolized by two pathways, both of
which involve acetylation. One is via direct acetylation, forming the
metabolite 3-methyl-s-triazolo [3,4-a]-phthalazine (MTP), and 3-OH-MTP [248].
Another is via oxidation to form an unstable intermediate compound that is
acetylated to form N-acetylhydrazinophthalazine (NAcHPZ). Acetylation status has
been associated with PK parameters of hydralazine. After oral dose, rapid
acetylators display lower hydralazine plasma concentrations and area under the
concentration-time curve (but no real difference in drug half life) compared to
slow acetylators [249]. MTP/hydralazine ratio can be used to divide a
population into slow and rapid acetylators, with a lower and higher ratio,
respectively [250]. In one study, patients with a slow acetylator genotype
displayed significant reductions in blood pressure measurements at 24 hours
before and after hydralazine, whereas significant effects were not observed in
rapid or intermediate acetylators [251]. Three out of a total of four patients
who presented hydralazine-induced adverse reactions had a slow acetylator genotype
[251]. However, evidence for hydralazine dose adjustment based on acetylator
status is not clear.
Okumura et al. [252] studied the genotypes of polymorphic
N-acetyltransferase (NAT2) in 145 Japanese subjects. They found that the
acetylation activity substantially varied interindividually (procainamide to
N-acetylprocainamide) but this variability was considerably reduced after
classification according to the genotype. The N-acetylprocainamide/procainamide
ratio in urinary excretion was 0.60±0.17 for those with NAT2*4/*4, 0.37±0.06 for NAT2*4/*6A,
0.40±0.03 for NAT2*4/*7B, and 0.17
for NAT2*6A/*7B. The results
indicated that the NAT2 genotype
correlates with acetylation of procainamide.
One detoxification
pathway for sulfonamides is N-acetylation of the parent drug by
N-acetyltransferases (NATs), leading to an inactive metabolite that is
eliminated in the urine. Polymorphisms in the NAT2 gene that lead to a
defective “slow” N-acetylation phenotype are well described, and slow NAT2
phenotype and genotypes have been reported to be overrepresented in patients
with sulfonamide hypersensitivity [253]. However, since slow NAT2
polymorphisms are found in about half of Caucasians and African Americans,
these genotypes alone are not sufficient to lead to sulfonamide
hypersensitivity in most patients.
SLCO1B1-Solute Carrier Organic Anion Transporter
Family, Member 1B1
The solute carrier
organic anion transporter family member 1B1 (SLCO1B1) gene encodes for a
membrane-bound sodium-independent organic anion transporter protein (OATP1B1)
that is involved in active cellular influx of many endogenous and xenobiotic
compounds. OATP1B1 mediates active transport of many endogenous substrates,
such as bile acids, xenobiotic compounds, and a wide panel of pharmaceutical
compounds [118].
OATP1B1-dependent
transport is an important step in mediating drug hepatic clearance. We would
like to highlight one class of drugs, the HMG-CoA reductase inhibitors
(statins) because statins are widely prescribed for cardiovascular disease
(CVD) risk reduction. OATP1B1 transport is particularly important for hepatic
accessibility of pravastatin, as this compound is too hydrophilic to gain
significant hepatocellular entry through passive transport. OATP1B1-dependent
transport could well be important for the acid (active) form of simvastatin,
(and other statins less hydrophobic than pravastatin) as SLCO1B1
variants were recently associated with simvastatin-induced myopathies, implying
that OATP1B1 was involved with simvastatin transport [248]. Nine studies with
1360 cases and 3082 controls were included. Cases of statin-related myopathy
were found to be significantly associated with the variant C allele, especially
when statin-related myopathy was defined as an elevation of creatine kinase
(CK) >10 times the upper limit of normal (ULN) or rhabdomyolysis. When
stratified by statin type, the association was significant in individuals
receiving simvastatin, but not in those receiving atorvastatin. The available
evidence suggests that SLCO1B1 gene T521C polymorphism is associated
with an increased risk of statin-related myopathy, especially in individuals
receiving simvastatin. Thus, a genetic test before initiation of statins may be
meaningful for personalizing the treatment [254].
In 2011 and updated
in 2013, the FDA added warnings to the simvastatin product label to direct
providers away from initiating at the 80 mg simvastatin dose. The FDA
recommends against 80mg daily simvastatin dosage. In patients with the C allele
at SLCO1B1 rs4149056, there are modest increases in myopathy risk even
at lower simvastatin doses (40mg daily), if optimal efficacy is not achieved
with a lower dose, alternate agents should be considered [255].
UGT1A1-UDP Glucuronosyltransferase 1 Family,
Polypeptide A1
The uridine
diphosphate glucuronosyltransferase (UGT) enzymes are a superfamily of enzymes
responsible for the glucuronidation of target substrates. The transfer of
glucuronic acid renders xenobiotics and other endogenous compounds water
soluble, allowing for their biliary or renal elimination. The UGT family is
responsible for the glucuronidation of hundreds of compounds, including
hormones, flavonoids and environmental mutagens.
One of the main
functions of UGT1A1 is in the liver, where it is the only enzyme responsible
for the metabolism of bilirubin, the hydrophobic breakdown product of heme
catabolism. In general, UGT1A enzymes have considerable overlap in substrate
specificities, however no other isozyme can substitute for the bilirubin
glucuronidation activity of UGT1A1 [118].
UGT1A1*28 occurs with a frequency of 26-31% in Caucasians, and 42-56% in African
Americans, and only 9-16% in Asian populations. UGT1A1*6 has allele
frequencies in Japanese, Korean and Chinese populations of 13%, 23% and 23%,
respectively [118].
There is also
evidence suggesting that the UGT1A1*28 allele may offer protection from
cardiovascular disease. Bilirubin is a known antioxidant, and is thought to be
capable of preventing plaque formation leading to atherosclerosis [256]. Since
the *28 allele impairs transcription of the UGT1A1 gene, it is associated with
significantly increased bilirubin concentrations, and therefore could be an
important biomarker for predicting those at decreased risk of cardiovascular
disease [257].
Both the *28 and *6
alleles have been well studied in regard to pharmaceutical toxicities. In
particular, both alleles have shown associations with the development of
irinotecan toxicities. Besides irinotecan, UGT1A1 is also responsible for the
glucuronidation of drugs such as raloxifene and etoposide, and some
associations have been reported between the *28 allele and pharmacokinetic and
pharmacodynamic parameters for these drugs. Additionally, the development of
hyperbilirubinemia during treatment with inhibitors of UGT1A1, such as
atazanavir and tranilast, has also been linked to the presence of the *28
allele.
VKORC1-Vitamin K Epoxide Reductase Complex,
Subunit 1
The VKORC1
gene encodes the vitamin K epoxide reductase (VKORC1) protein, which is a key
enzyme in the Vitamin K cycle. VKORC1 is a 163 amino acid integral membrane
protein associated with the endoplasmic reticulum, and VKORC1 mRNA is broadly
expressed in many different tissues. VKORC1 is responsible for the conversion
of Vitamin K-epoxide to Vitamin K, which is the rate-limiting step in the
physiological process of Vitamin K recycling [118]. The availability of reduced
Vitamin K is of particular importance for several coagulation factor proteins
that require it as a cofactor, including Factor VII, Factor IX, and Factor X.
VKORC1 is of therapeutic interest both for its role in contributing to high
inter-patient variability in coumarin anticoagulant dose requirements and as a
potential player in vitamin K-deficiency disorders [258].
Warfarin is an anticoagulant used as a prophylaxis and to treat venous
thrombosis, pulmonary embolism, thromboembolic complications from atrial
fibrillation and cardiac valve replacement, and to reduce the risk of stroke
after a myocardial infarction. The FDA recommends genetic testing for CYP2C9 and VKORC1 variants prior to initiating treatment with warfarin [259].
CYP2C9 and VKORC1 variation greatly affect the
half-life of warfarin and time to a stable dose. The level of the enzyme is
under genetic control according to the DNA sequence present in the control
region of the gene. Inherited differences in VKORC1 increase or decrease the amount of warfarin needed to
inhibit the formation of the clotting factors. When the amount of warfarin
exceeds what is needed, the risk of bleeding is increased. Indications for
testing include lack of therapeutic effect or difficulties with side effects to
warfarin.
The VKORC1*-1639G>A
polymorphism is associated with lower dose requirements for warfarin in
Caucasian and Asian patients [260]. Increased bleeding risk and lower initial
warfarin dose requirements have been associated with the CYP2C9*2 and CYP2C9*3
alleles. Approximately 30% of the variance in warfarin dose could be attributed
to genetic variation in VKORC1, and
about 40% of dose variance could be explained taking into consideration both VKORC1 and CYP2C9 genetic polymorphisms [261]. Accounting for genetic
variation in both VKORC1 and CYP2C9, age, height, body weight,
interacting drugs, and indication for warfarin therapy explained about 55% of
the variability in warfarin dose.
The initial and maintenance dosing of warfarin must be individualized
for each patient. The goal of warfarin therapy is to achieve an international
normalized ratio (INR) in a target range for the condition being treated (most
commonly 2-3). This involves selecting an initial starting dose, followed by
regular testing of the INR so that the dose of warfarin can be adjusted until the
appropriate daily maintenance dose is determined. In general, the duration of
anticoagulant therapy varies by clinical indication and should be continued
until the danger of thrombosis and embolism has passed.
The variants that are routinely tested for are CYP2C9*2, CYP2C9*3, and VKORC1*-1639G>A. These variants are
used in the FDA table to guide therapy, and also in the International Warfarin
Pharmacogenomics Consortium (IWPC) algorithm [262].
The pharmacogenetic algorithms available on the warfarindosing.org
website [263] should be used whenever possible to determine the dose of
warfarin required. Such algorithms have been derived from large studies across
different ethnic populations, and they take into account both the genetic and
non-genetic factors that influence the variability in warfarin response.
CONCLUSIONS
- Cerebrovascular disorders and
stroke are multifactorial and polygenic-related disorders that occur by
the interaction of multiple environmental factors and sequence variations
in different genes.
- Atherosclerosis, the main
pathological process leading to cerebrovascular disease, begins in youth
or adulthood, remaining asymptomatic for 20 or 30 years until the onset of
the disease.
- Vascular genetic risk can be
detected early and can affect healthy recommendations to prevent the
development of cerebrovascular diseases.
- Knowledge of genes involved
in the development of cerebrovascular diseases enables us to make certain predictions regarding the risks,
susceptibilities or resistance to developing them.
- The ability to identify
high-risk patients through genetic testing could make screening for
treatable intermediate phenotypes more cost-effective.
- Predictive genetic tests must
integrate multigenic panels identifying variations in the DNA sequence related
with development, prognosis and evolution of cerebrovascular disorders,
representing a key tool in medical practice.
- Pharmacogenetics
offers the opportunity to greatly improve treatment through its
personalization, avoiding problems such as high-risk interactions, adverse
reactions or therapeutic inefficacy.
- Pharmacogenetics is
responsible for over 80% of the efficacy and safety of drugs, however,
unawareness of the pharmacogenetic profile of the population and the lack
of pharmacogenetic information in the leaflet of drugs cause over 50% of
medical prescriptions to prove unsuitable.
- The
information provided by pharmacogenetic analysis is very valuable. A single genetic analysis provides
information on response to drugs that will be valid throughout lifetime.
1. World
Health Organization (WHO) Cardiovascular diseases (CVDs). Fact sheet N°317.
2. National
Center for Health Statistics (2016) Mortality multiple cause micro-data files,
2011: public-use data file and
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