Genetic determinants of the dynamics and kinetics of alcohol as an environmental modifier of blood pressure

It took George Mendel half a century to have his major discovery recognized and Lian waited for 60 years to have his observations of French servicemen in the First World War appreciated: ‘heavy’ drinkers of 3 l of wine per day have a four-fold higher prevalence of hypertension than ‘moderate’ drinkers of 1 l per day [1]. Presently, particularly when abused, the impact of alcohol consumption on hypertension is clearly recognized [2], usually with a J-shaped association, where abstainers are barely better off than heavy drinkers [3,4]. The impact of alcohol on blood pressure interacts with other components of the environment, including lifestyle habits such as smoking and diet [5,6]. Thus, for example, the level of Na+ intake is associated with increased blood pressure only at low Ca2+ intake, particularly in those subjects who consume high amounts of alcohol [7]. Moderate alcohol consumption actually decreases the risk of heart failure in older subjects [8]. Recently, it was noted that abstinence from alcohol consumption is even a risk factor for metabolic syndrome, which appears to be present in more than 20% of the US adult population [9]. Although alcohol is clearly an environmental factor, the development of alcohol abuse and dependence is under genetic influence. It has been estimated that multiple genetic influences, when combined, explain 40–60% of alcohol abuse risk [10]. The endophenotypes that contribute to alcoholism include alcohol-metabolizing enzymes and low response to alcohol. Among the candidate genes for alcohol dependence, the GABA receptor genes have been identified most prominently by regression analysis of the polymorphism with the diagnosis of alcohol-dependency [11]. There appears to be a consistent association between alleles of the GABAA gene cluster on chromosome 15 and alcoholism, which is modulated by genetic imprinting because these genes are expressed uniparentally from paternal chromosomes [12]. Animal models have contributed to the understanding of dopamine D2 receptor binding as a determinant of the alcohol stimulant response [13]. Although still scarce, genome-wide scans have identified quantitative trait loci of alcoholism. For the low level of response to alcohol as an endophenotype, four chromosomal regions with LOD scores exceeding 2 have been described by Schuckit et al. [14]. It should be noted that low scores of the subjective response to ethanol were also identified in Asian subjects in the predicted direction, especially in those presenting defects in alcohol- metabolizing enzyme patterns. The pharmacodynamics of the alcohol effect are possibly the best example of gene–environment interaction. The apolipoprotein E gene (APOE) locus, which accounts for approximately 7% of the population variance in total low-density lipoprotein (LDL) cholesterol levels, exercises its heightening impact on LDL cholesterol through the APOE4 allele, while carriers of the APOE2 allele have lower LDL cholesterol levels [15]. Corella et al. [16] evaluated the plasma lipid response to alcohol across APOE genotypes in the Framingham Offspring Study noting that, in men, the expected increases of LDL with the APOE4 allele, over that of the APOE2 allele, were observed only among alcohol drinkers [16]. Other studies showed that alcohol consumption in adults, although correlating with APOC-III concentrations, did not demonstrate any interaction between APOC3 covariants and genetic polymorphism [17]. In this case, the environmental impact was simply additive (and not interactive) with genetic determinants. APOE alleles even appear to play a role in hypertension, although this idea is still controversial [18]. Nevertheless, in studies by Kauma et al. [19], systolic blood pressure was 16 mmHg higher in high alcohol consumers in those subjects with the APOE2 allele, while the gradient of blood pressure was not significant in subjects with the APOE4 allele, which clearly demonstrates a gene–environment interaction as influenced by alcohol. Larger studies and future confirmation are nevertheless required [16,20]. Gene and environmental determinants certainly play a significant, yet variable role in different endophenotypes. Thus, in four European population studies, although genetically determined factors are significant, lifestyle factors, including alcohol, only have a small influence on heart rate and heart rate variability [21]. Finally, both the impact of alcohol and the development of alcohol dependence and consumption are related to its pharmacokinetics. Main alcohol-metabolizing enzymes, including cyp2e1, adh2, adh3 and aldh2 genes, have a highly variable prevalence of their polymorphisms in different populations complicated by admixture [22], such as in Mexican Americans. Several studies from Japan have demonstrated genetic differences in ethanol-metabolizing enzymes and their impact on blood pressure [23], as well as coronary heart disease risk factors [24]. In the current issue of the journal, Saito et al. [25] investigated whether ethanol-metabolizing enzymes modify the relationship between alcohol consumption and blood pressure. They demonstrated, in 335 randomly selected men, that a significantly stronger relationship between alcohol and blood pressure depends on the presence of the superactive subunits of alcohol dehydrogenase-2 (ADH2) genotype, the ADH22 allele being highly prevalent among Asians. Specific alleles resulting in high ethanol-oxydizing capacity are less related to blood pressure increases. It is possible that this kinetic property of alcohol dehydrogenase, resulting in maintenance of the high level of ethanol, has a direct impact on blood pressure. While this observation partly contrasts with other findings [23], taken together, these studies clearly point in the direction that the kinetics of environmental factors, such as alcohol, must also be considered in addition to its dynamic characteristics. Clearly, we are at the beginning of a complex, yet relevant understanding of gene–environment interaction in the pathogenesis, complications and treatment of cardiovascular disease [26]. Acknowledgements Special thanks to Johanne Tremblay and Zdenka Pausova for their helpful comments, and to Ginette Dignard and Ovid Da Silva for their assistance in preparing this manuscript.

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