Exploring causal associations of alcohol with cardiovascular and metabolic risk factors in a Chinese population using Mendelian randomization analysis.

Amy E Taylor,Yun Qian,Sijun Liu,George Davey Smith,Hongbing Shen,Jiaping Chen,Feng Lu,Zhibin Hu,David Carslake

doi:10.1038/srep14005

Abstract

Observational studies suggest that moderate alcohol consumption may be protective for cardiovascular disease, but results may be biased by confounding and reverse causality. Mendelian randomization, which uses genetic variants as proxies for exposures, can minimise these biases and therefore strengthen causal inference. Using a genetic variant in the ALDH2 gene associated with alcohol consumption, rs671, we performed a Mendelian randomization analysis in 1,712 diabetes cases and 2,076 controls from Nantong, China. Analyses were performed using linear and logistic regression, stratified by sex and diabetes status. The A allele of rs671 was strongly associated with reduced odds of being an alcohol drinker in all groups, but prevalence of alcohol consumption amongst females was very low. The A allele was associated with reduced systolic and diastolic blood pressure and decreased total and HDL cholesterol in males. The A allele was also associated with decreased triglyceride levels, but only robustly in diabetic males. There was no strong evidence for associations between rs671 and any outcomes in females. Our results suggest that associations of alcohol consumption with blood pressure and HDL-cholesterol are causal. Alcohol also appeared to have adverse effects on triglyceride levels, although this may be restricted to diabetics.

Highlights

Evidence emerging from Mendelian randomization studies indicates that some of these observed beneficial effects are probably due to residual confounding or reverse causality, and that drinking even small amounts of alcohol is unlikely to be beneficial for cardiovascular health[4,5]
There is growing evidence from genetic studies that alcohol-related variants conferring higher alcohol consumption are associated with higher blood pressure and body mass index[4,5,8,9,10], which are strong risk factors for cardiovascular disease
In East Asian populations, the main genetic variant used in Mendelian randomization studies of alcohol use is located in the Aldehyde dehydrogenase 2 (ALDH2) gene, which is the major enzyme involved in the breakdown of acetaldehyde, a metabolite of alcohol

Summary

Introduction

Evidence emerging from Mendelian randomization studies indicates that some of these observed beneficial effects are probably due to residual confounding or reverse causality, and that drinking even small amounts of alcohol is unlikely to be beneficial for cardiovascular health[4,5]. In Mendelian randomization, genetic variants that are associated with alcohol drinking are used as proxies for measured alcohol consumption, which minimises biases from confounding and removes the possibility of reverse causality[6,7]. Carriers of a single A allele have a reduced ability to clear acetaldehyde and tend to consume lower levels of alcohol, whilst individuals with two A alleles are unable to clear acetaldehyde and, many do not drink alcohol at all[14]. The associations of this variant with alcohol consumption have been widely replicated in Asian populations[4]. Using data from a case control study of diabetes in China, we performed a Mendelian randomization study, using rs[671], to further explore the causal role of alcohol in determining cardiovascular and metabolic traits

Methods

Results

Conclusion