Evidence of this causal relationship solidified in a Mendelian randomization study

Being genetically predisposed to engage in higher alcohol consumption may increase the risk of stroke and peripheral artery disease, according to a study published online in Circulation: Genomic and Precision Medicine. But, while researchers of this Mendelian randomization (MR) did find evidence of this causal relationship, they did not find evidence of one between this genetic predisposition and other cardiovascular diseases such as heart failure, venous thromboembolism, or aortic valve stenosis.

Although observational studies have shown positive associations between alcohol consumption and the risks of atrial fibrillation, heart failure, and hemorrhagic stroke, such studies have several drawbacks, according to authors led by Susanna C. Larsson, PhD, of the Karolinska Institutet, Stockholm, Sweden.

“Observational studies are unable to fully account for confounding and reverse causation bias, and therefore causality in the associations of alcohol consumption with different CVDs remains uncertain. Furthermore, self-reported alcohol consumption may be underestimated, leading to measurement error in the assessment of alcohol consumption, which may result in attenuated categorical risk estimates,” they wrote.

“[MR] is an epidemiologic technique that utilizes genetic variants that are reliably associated with a potentially modifiable risk factor to determine its causal role for disease risk. MR studies are less vulnerable to bias from confounding, reverse causation, and measurement error compared with conventional observational studies,” they added.

Larsson and colleagues, therefore, conducted this MR study with data for alcohol consumption and outcomes from a meta-analyses of genome-wide association studies and the UK Biobank. Using up to 94 single nucleotide polymorphisms that were positively associated with systolic and diastolic blood pressures and HDL cholesterol levels, and inversely associated with triglyceride levels and not associated with LDL cholesterol levels,

They found that alcohol consumption that was genetically predicted by the genetic variant rs1229984 in ADH1B was associated with both stroke and peripheral artery disease. Upon conducting an inverse-variance weighted analysis, they found that for stroke, the odds ratios per on standard deviation increase of log-transformed alcoholic drinks per week was 1.27 (95% CI: 1.12-1.45; P=2.87 x 10−4P=2.30 x 10−6).

In the same analysis, Larsson and colleagues also found some evidence of positive associations between genetically-predicted alcohol consumption and the following:

  • Coronary artery disease (OR: 1.16; 95% CI: 1.00-1.36; P=0.052).
  • Atrial fibrillation (OR: 1.17; 95% CI: 1.00-1.37; P=0.050).
  • Abdominal aortic aneurysm (OR: 2.60; 95% CI: 1.15-5.89; P=0.022).

However, upon multivariable MR analysis adjusted for smoking initiation, these associations were somewhat mitigated.

Larsson and colleagues found no evidence of any associations between genetically-predicted alcohol consumption with heart failure (OR: 1.00; 95% CI: 0.68-1.47; P=0.996), venous thromboembolism (OR: 1.04; 95% CI: 0.77-1.39; P=0.810), or aortic valve stenosis (OR: 1.03; 95% CI: 0.56-1.90; P=0.926). However, they did find suggestive positive associations between genetically-predicted alcohol consumption and aortic valve stenosis upon weighted median and MR-Egger analyses.

Limitations of the study include a low precision in outcomes analyses, the possible overlap of UK Biobank participants in the genetic variant dataset and both exposure and outcome datasets for most analyses, population stratification, that the majority of participants were of European ancestry, and the failure of researchers to assess potential U- or J-shaped associations.

In their conclusion, Larsson and fellow researchers noted that their findings confirmed those from two previous MR studies. The first was an analysis of over 200,00 participants of European descent, in which researchers found that each additional alcohol-decreasing allele of rs1229984 in ADH1B was associated with a 10% lower odds of coronary heart disease. The second was a study of over 100,000 Chinese participants who had been genotyped for rs1229984 in ADH1B and rs671 in ALDH2, two alcohol-associated single-nucleotide polymorphisms (SNPs), in which researchers found that genetically-predicted higher alcohol consumption was associated with a higher risk of stroke — especially intracerebral hemorrhage — but not with myocardial infarction.

“The present study confirms that those findings for stroke are also valid for individuals of European ancestry and that the association is stronger for intracerebral hemorrhage than ischemic stroke,” they wrote.

The reasons for this association, however, are not clear, although both blood pressure and cholesterol levels may come into play.

“A possible mechanism whereby alcohol consumption may increase the risk of [cardiovascular disease] is through blood pressure. A meta-analysis of randomized trials showed that a reduction in alcohol intake decreased blood pressure in a dose-response manner in individuals who drank more than two alcoholic drinks per day. In addition, genetically-predicted alcohol consumption was positively associated with systolic blood pressure in previous MR studies, and results were replicated by our study with both the overall genetic instrument for alcohol consumption and the ADH1B gene variant,” wrote Larsson and colleagues.

“We confirmed a positive association between genetically-predicted alcohol intake and higher levels of high-density lipoprotein cholesterol. We additionally found that genetically higher alcohol consumption was associated with lower triglyceride levels. A causal positive association between triglyceride levels and risk of coronary artery disease but not ischemic stroke has been shown in MR studies,” they added.

  1. Researchers provide evidence of a causal relationship between the genetic predisposition for higher alcohol intake and an increased risk of stroke and peripheral artery disease.

  2. No evidence of an association between the genetic propensity for higher alcohol intake and heart failure, venous thromboembolism, or aortic valve stenosis was found.

E.C. Meszaros, Contributing Writer, BreakingMED™

Larsson reported no conflicts of interest.

This study was supported by research grants from the Swedish Research Council; the Swedish Research Council for Health, Working Life and Welfare; and the Swedish Heart-Lung Foundation.

Cat ID: 206

Topic ID: 74,206,497,730,206,8,38,192