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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

Rapid Response:

I ought to be happy with this paper and its conclusions because I have contributed to the emergence of Mendelian Randomization [1] and because I oppose the promotion of alcohol for preventing CHD. [2] However, the lack of an association of HDL cholesterol levels with ADH1B genotype is worrying. HDL levels are consistently and universally associated with alcohol intake (cf. Figure S3 in the Supplementary Appendix) and are even used as a biomarker for intake. [3] So why do people with higher alcohol intakes not have higher HDL levels in this study?

In the study of Hines et al. [4] – which the authors did not discuss --, people with a genetically less active form of another alcohol dehydrogenase, ADH1C (a.k.a. ADH3), had a lower risk of CHD than those with the gene for the more active form. They also had higher HDL levels. This may explain why there was no association of HDL – and CHD? -- with ADH1B genotype in the present study: gram for gram, alcohol may have raised HDL more in those with an impaired ability to metabolize alcohol than in subjects with the more active form of the enzyme, compensating for the difference in intake.

Thus the lack of an effect of alcohol on CHD in this study could mean that the smaller amount of alcohol consumed by carriers of the minor allele has the same physiological effect as the larger amount consumed by the others.

There is also a possibility that something went wrong with data management and analyses. This is not a nice thing to say, and I have no concrete reason to believe that there are errors in this study, but those who have been involved in complicated data analyses know how easily things can go wrong. An independent re-analysis could lay this issue to rest.

1. Keavney B. Commentary: Katan’s remarkable foresight: genes and causality 18 years on. Int J Epidemiol 2004;33(1):11 –14.
2. Katan MB. [Alcohol should not be recommended for the prevention of heart disease]. Ned Tijdschr Geneeskd 2007;151(49):2717.
3. Berger D, Williams EC, Bryson CL, Rubinsky AD, Bradley KA. Alcohol questionnaires and HDL: screening scores as scaled markers of alcohol consumption. Alcohol Fayettev N 2013;47(6):439–45.
4. Hines LM, Stampfer MJ, Ma J, et al. Genetic Variation in Alcohol Dehydrogenase and the Beneficial Effect of Moderate Alcohol Consumption on Myocardial Infarction. N Engl J Med 2001;344(8):549–55.

Competing interests: No competing interests

17 September 2014
Martijn B. Katan
emeritus professor of nutrition
VU University Amsterdam, Dept of Health Sciences
De Boelelaan 1081, Amsterdam