Using a very large dataset from subjects of European descent, the authors have carried out a Mendelian randomization analysis to estimate the effects of alcohol consumption on cardiovascular disease (CVD), using as the instrumental variable an uncommon allele affecting alcohol metabolism, the ADH1B rs1229984 variant. People with this variant are unusually sensitive to alcohol (developing flushing and other uncomfortable symptoms from alcohol) and it has been well demonstrated that they are less likely than people without this variant to consume alcohol, and are unlikely to be heavy drinkers. The authors conclude that since the 7% of their subjects with the uncommon allele had less cardiovascular disease, this indicates that alcohol consumption is unrelated to CVD.
Forum members agree that the analyses were done correctly, but strongly disagree with the premise of the study and the conclusions of the authors, and consider the genetic factor chosen as inappropriate to use as the instrumental variable in Mendelian randomization. The gene studied explains only a fraction of alcohol consumption in the population (not stated in the paper) and it may have effects on CVD beyond those explained by alcohol consumption. Thus, this ADH1b allele violates the assumptions required for a variable for Mendelian randomization and would be inappropriate for judging the effects of alcohol on CVD. Further, in the present study, the authors report little relation of their estimate of alcohol consumption with HDL-cholesterol, while essentially all observational studies, clinical trials, and experimental studies have shown that alcohol is an important determinant of HDL. This further suggests that the use of the ADH1B allele provides an inadequate estimate of alcohol consumption.
Even without the weakness of the allele chosen to reflect alcohol effects, conclusions derived from Mendelian randomization in general are heavily dependent on the assumption that the instrumental chosen is appropriate, of which you can rarely be confident. Forum reviewers consider this method to be a very blunt instrument and subject to considerable bias for variables that are weakly correlated with exposure and not true instruments.
Some reviewers were concerned by the conclusion of the authors that this Mendelian randomization paper shows that all persons should drink less; this does not necessarily mean for people to completely avoid drinking. The protection of moderate drinking against CVD that is generally observed shows a non-linear gradient: it is better manifested at a low alcohol consumption, while it is less strong as the consumption levels rise above optimum and finally disappears and is transformed into harm with heavy alcohol consumption. This would be in agreement with the conclusions of most prospective studies and meta-analyses that drinking alcohol at low doses offers the best protection against CVD, as there is a J-shaped curve. Reference: Holmes MV, Dale CE, Zuccolo L, et al (a total of 155 authors). Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. BMJ 2014;349:g4164 doi: 10.1136/bmj.g4164.