Prospective Evaluation of the Alcohol Dehydrogenase γ1/γ2 Gene Polymorphism and Risk of Stroke

Abstract

Background and Purpose-Genetic polymorphism of the alcohol dehydrogenase type 3 gene (ADH1C) has recently been associated with reduced risk of myocardial infarction. However, data on risk of stroke are not available. Methods-We examined the possible association between the ADH1C ␥1/␥2 polymorphism and risk of stroke in a prospective, nested case-control sample from the Physicians' Health Study of 14 916 apparently healthy men who were followed over a 12-year period. A total of 320 incident stroke cases and 550 age-and smoking-matched controls were genotyped. Results-All observed genotype frequencies were in Hardy-Weinberg equilibrium. The allele and genotype distributions of the polymorphism tested were similar between cases and controls, such that the relative risk of stroke was 1.04 for ADH1C ␥1/␥2 (95% CIϭ0.85 to 1.28; Pϭ0.65) assuming an additive mode of inheritance. Contrary to prior findings for myocardial infarction, no evidence of association was observed to suggest an effect modification of ADH1C genotypes with the level of alcohol consumption on the risk of stroke. Similar findings were observed in subgroup analysis restricted to ischemic events. Conclusions-In this large, prospective study, we found little evidence that the ADH1C ␥1/␥2 polymorphism is associated with risk of future stroke. These data raise the possibility of important pathologic differences in ischemia between the coronary and cerebral circulations. Key Words: ADH1C Ⅲ prospective studies Ⅲ risk factors Ⅲ stroke S troke, a major cause of permanent disability, has serious public health complications in developed countries. Several studies have reported an association of light to moderate alcohol consumption with reduced risk of cardiovascular diseases including stroke, 1-4 whereas others found an increased risk of stroke with alcohol intake. 5,6 A recent metaanalysis of experimental studies has concluded that heavy alcohol consumption increases the relative risk of stroke while light to moderate alcohol consumption may be protective against total and ischemic stroke. 7 The class I alcohol dehydrogenase (ADH) enzymes, including ADH type 3, are mainly involved in ethanol oxidation. Genetic variants have been found for the ADH type 3 (ADH1C) locus, resulting in ␥1 and ␥2 isoenzymes. 8 The ␥1 subunit differs from ␥2 subunit by 2 amino acid substitutions: arginine (R) for glutamine (Q) at position 271, and isoleucine (I) for valine (V) at position 349. 8 Pharmacokinetic studies have shown that the ␥1 isoenzyme is associated with a fast rate of ethanol oxidation while the ␥2 isoenzyme with a slow rate of ethanol oxidation. 9 Interestingly, the ADH1C ␥2 allele has recently been associated with reduced risk of myocardial infarction (MI), and importantly, to interact with alcohol consumption. 10 However, to date, no data are available for the risk of stroke. We therefore investigated the role of the ADH1C ␥1/␥2 polymorphism as a risk marker for stroke in the Physicians' Health Study (PHS). Subjects and MethodsWe employed a nested case-control de...

Alcohol Consumption, Genetic Variants in Alcohol Deydrogenases, and Risk of Cardiovascular Diseases: A Prospective Study and Meta-Analysis

“…Yet, previous studies analyzing this issue were rather inconsistent showing the strongest inverse association between ADH1C*2/2 genotype and risk of coronary events either in men with the highest alcohol consumption of at least one drink/d [8], [9], or in men with a modest consumption of 1–3 alcoholic beverages/week [12]. Other studies provided little evidence for an association between ADH1C genotype and coronary events [10], [11] or stroke [13] across strata of alcohol consumption and the same applies to the association between ADH1B genotype and acute coronary syndrome [11]. In our study, there was no clear evidence that the slow-metabolizing ADH1C*2/2 genotype decreases risk of CVD in any stratum of alcohol consumption (Table S1).…”

“…A total of 36 references were excluded for the following reasons: no original data (n = 15), no relevant outcome (n = 16), no relevant exposure (n = 3), no relevant study design (n = 2). Thus, eight studies met our inclusion criteria of which one was examining stroke [13]. Eligible studies on ischemic heart disease included studies on CHD [7], [8], [12], MI [9], [10], and acute coronary events [11].…”

“…Eligible studies on ischemic heart disease included studies on CHD [7], [8], [12], MI [9], [10], and acute coronary events [11]. In total, two of the identified studies analyzed SNP rs1229984 in the ADH1B gene [10], [11] and seven analyzed either SNP rs698 [8], [9], [10], [12], [13] or rs1693482 [7], [11] in the ADH1C gene. Because the latter are in very high linkage disequilibrium [5], we combined this data.…”

“…A few prospective studies have investigated the association between alcohol consumption and risk of cardiovascular diseases (CVD) in combination with variations in genes coding for ADH1C or ADH1B [7], [8], [9], [10], [11], [12], [13]. In line with the hypothesis that ethanol is largely responsible for the inverse association between alcohol consumption and coronary events, individuals with the slow ADH1C*2/2 genotype had a lower risk of myocardial infarction (MI) in a study among male physicians [9].…”

Sex-specific differences in the association of a common aldehyde dehydrogenase 2 gene polymorphism and alcohol consumption with stroke risk in a Korean population: a prospective cohort study

“…A cross-sectional study first examined brain magnetic resonance imaging in 376 men and women and found that men without the ALDH2 * 504Lys variant are more likely to have multiple lacunar infarcts [ 20 ]. No studies have reported the association between ALDH2 polymorphisms and stroke, whereas some studies have investigated the association between ADH polymorphisms and stroke [ 21 , 22 ]. In our study, analysis stratified by sex showed that the risk of stroke was significantly associated with the wild-type ALDH2 polymorphism in men, but not in women.…”