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Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data

BMJ 2014; 349 doi: (Published 10 July 2014) Cite this as: BMJ 2014;349:g4164

Re: Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data

This article in The BMJ (Holmes MV et al. doi July 10, 2014) applies a recent technique, the Mendelian randomization analysis, to determine whether low alcohol consumption reduces cardiovascular disease. Cardiovascular disease was compared in two sets of subjects according to their alcohol intake. One of the groups carried a polymorphic gene coding for an alcohol dehydrogenase that metabolizes ethanol at a very fast rate, which deters subjects from alcohol intake. The second group carried the gene for the more common slow alcohol dehydrogenase. Subjects carrying the fast variant drank 20% less alcohol and showed less cardiovascular disease, at all levels of alcohol intake. This is expected when reducing a high intake of ethanol, a drug known to be cardiotoxic, but it was unexpected when the intake of very low levels was reduced, as it has been proposed that at low intakes, ethanol has a protective effect on cardiovascular disease. Thus, these studies could be taken as a demostration that the putative protective effect of low ethanol intake on cardiovascular disease actually does not exist, and that ethanol is cardiotoxic at any level. This may indeed be the case, as there are very few controlled prospective studies where low alcohol levels are administered for prolonged times, versus total abstinence.

However, a word of caution is needed. The gene examined codes for an alcohol dehydrogenase that is 40-times more active than the control enzyme; a high activity leads to increases in acetaldehyde (as indeed implied by the authors) . One can ask if the higher levels of acetaldehyde in these subjects counter any putative protective cardiovascular effect of low ethanol intakes. It is noted that two variables change in this study (acetaldehyde and ethanol intake) while only one outcome is measured (cardiovascular disease). Changes in cardiovascular disease are purported to be due to alcohol intake. It is also assumed (vide infra) that these data applies to 95% of Caucasians who carry the gene that codes for the slow, rather than the fast alcohol dehydrogenase. Acetaldehyde has been proposed by many authors to have tissue deleterious effects and to bind to DNA, as well as binding to proteins, generating neoantigens that correlate with organ damage. This damage might start at lower levels of ethanol consumption in a population that carries the more active alcohol dehydrogenase, which generates acetaldehyde at a higher rate. Without taking issue as to whether low ethanol intake protects or does not protect from cardiovascular disease, a word of caution is needed vis-a-vis the extrapolation of these findings. In their highlighted chart (p 10) the study indicates: “Under the principles of mendelian randomisation, the(se) findings suggest that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health”. This recommendation is certainly correct for a small subset of Caucasian (European) subjects who carry the fast alcohol dehydrogenase-coding gene; but generalizing this recommendation to other populations requires caution

Competing interests: No competing interests

06 September 2014