Date Published: March 4, 2008
Publisher: Public Library of Science
Author(s): Lina Chen, George Davey Smith, Roger M Harbord, Sarah J Lewis, Cosetta Minelli
Abstract: BackgroundAlcohol has been reported to be a common and modifiable risk factor for hypertension. However, observational studies are subject to confounding by other behavioural and sociodemographic factors, while clinical trials are difficult to implement and have limited follow-up time. Mendelian randomization can provide robust evidence on the nature of this association by use of a common polymorphism in aldehyde dehydrogenase 2 (ALDH2) as a surrogate for measuring alcohol consumption. ALDH2 encodes a major enzyme involved in alcohol metabolism. Individuals homozygous for the null variant (*2*2) experience adverse symptoms when drinking alcohol and consequently drink considerably less alcohol than wild-type homozygotes (*1*1) or heterozygotes. We hypothesise that this polymorphism may influence the risk of hypertension by affecting alcohol drinking behaviour.Methods and FindingsWe carried out fixed effect meta-analyses of the ALDH2 genotype with blood pressure (five studies, n = 7,658) and hypertension (three studies, n = 4,219) using studies identified via systematic review. In males, we obtained an overall odds ratio of 2.42 (95% confidence interval [CI] 1.66–3.55, p = 4.8 × 10−6) for hypertension comparing *1*1 with *2*2 homozygotes and an odds ratio of 1.72 (95% CI 1.17–2.52, p = 0.006) comparing heterozygotes (surrogate for moderate drinkers) with *2*2 homozygotes. Systolic blood pressure was 7.44 mmHg (95% CI 5.39–9.49, p = 1.1 × 10−12) greater among *1*1 than among *2*2 homozygotes, and 4.24 mmHg (95% CI 2.18–6.31, p = 0.00005) greater among heterozygotes than among *2*2 homozygotes.ConclusionsThese findings support the hypothesis that alcohol intake has a marked effect on blood pressure and the risk of hypertension.
Partial Text: Observational epidemiological studies have generally reported that blood pressure is lower among individuals with a moderate alcohol intake than in nondrinkers, but that heavy alcohol intake is associated with an increase in blood pressure [1–4]. However, associations in observational studies of alcohol intake and blood pressure may be heavily confounded by factors such as diet, smoking, exercise levels, and socioeconomic position. Conversely, the detection of high blood pressure may lead to efforts to reduce alcohol intake, which will attenuate any positive association. In addition, reporting of alcohol is likely to be subject to considerable error, and this error may be differential—e.g., people who have been advised to reduce alcohol intake for medical reasons may under-report alcohol intake.
Table 1 provides details of the studies identified in our systematic review and included in our meta-analysis. The systematic review identified ten articles reporting on associations between ALDH2 and hypertension or blood pressure, the majority of which were cross sectional studies; five of these studies focused on male populations only (Table 1). All studies were population-based and the majority of participants were Japanese except one very small study carried out in the UK . Tables 2 and 3 show associations between genotype and alcohol intake, and between genotype and potential confounders, with p-values taken from the original papers. All studies showed substantial differences in alcohol intake by genotype among men; among women alcohol intake was very low, but studies showed trends in the same direction as men. Whilst it is not possible to combine data on alcohol intake by genotype across all studies due to inconsistent and incomplete reporting of data, the two largest studies [18,19] that contributed most of the weight to the meta-analysis showed alcohol intake levels among men were around 20–30 g/d in *1*1 homozygotes, 10–15 g/d in heterozygotes and 0–2 g/d in *2*2 homozygotes. Table 3 shows that ALDH2 genotype was not consistently or strongly associated with sex, smoking, or physical activity, although there were minor differences in BMI in men but not women in the two largest studies [18,19].
We carried out a meta-analysis of the association between the ALDH2 genotype and blood pressure, in which we used ALDH2 genotype as a marker of differing alcohol intake levels. We found that individuals with the ALDH2 *1*1 genotype, with average alcohol intakes of 20–30 g/d, had strikingly higher systolic and diastolic blood pressure than those with the ALDH*2*2 genotype, who tend to drink only small amounts of alcohol. In addition, the risk of hypertension among *1*1 homozygotes was around 2.5-fold above that among *2*2 homozgotes. Even heterozygotes who tended to be quite modest drinkers had elevated blood pressure and a 70% increased risk of hypertension compared with individuals with the *2*2 genotype. Exploratory analyses using an instrumental variable approach in which the association between genotype and alcohol intake and the association between genotype and blood pressure was triangulated to give an estimate of the effect of alcohol on blood pressure, we obtained estimates of a 0.24 mmHg increase in SBP per gram of alcohol per day over the course of a lifetime (because genotype influences on alcohol intake will represent differences that generally persist throughout adult life).