Critique 152: Specific genetic factors modify the reduction in heart disease risk from alcohol consumption — 27 November 2014

Mehlig K, Strandhagen E, Svensson P-A, Rosengren A, Torén K, Thelle DS,  Lissner L.  CETP TaqIB genotype modifies the association between alcohol and coronary heart disease: The INTERGENE case-control study.  Alcohol 2014;48:695e700.

Authors’ Abstract

Alcohol consumption at moderate levels has been associated with decreased risk of coronary heart disease (CHD). However, the cardio-protective effect of alcohol may be restricted to subjects with a particular genotype of the cholesteryl ester transfer protein (CETP) polymorphism.  There is evidence for this from one study in men, but the finding has not been confirmed since.  

The present study specifically re-examines the potential modification of the association between alcohol consumption and CHD by the CETP TaqIB (rs708272) polymorphism in a sample including both men and women.  The INTERGENE case-control study consists of 618 patients with CHD and 2,921 control subjects, of whom 19% were homozygous for the CETP TaqIB B2 allele.  Alcohol consumption was categorized into sex-specific tertiles of ethanol intake, with non-drinkers constituting a separate category.  Logistic regression was used to determine the association between CHD with genotype, ethanol intake, and their interaction.

Participants with intermediate ethanol intake (2nd tertile) had lower risk of CHD than those with low ethanol intake (odds ratio [OR] = 0.65; 95% confidence interval [CI] 0.50-0.85).  The strongest protective association was seen in the CETP TaqIB B2 homozygotes for intermediate vs. low ethanol intake (odds ratio OR = 0.21; 95% CI 0.10-0.44). The interaction between ethanol intake and genotype was statistically significant (p = 0.008), and of similar size in men and women though significant only in men (p = 0.01).  The effect modification could not be explained by differences in lifestyle, socioeconomics, or alcohol-related biological variables such as HDL cholesterol.   

Our study is the first to replicate previous findings of an effect modification in men.  It gives only suggestive results for women, possibly due to the small number of female cases (n = 165). The prevented fraction for the favorable combination of genotype and alcohol consumption is about 6%, a value suggesting that the cardio-protective effect of moderate alcohol consumption applies only to a small segment of the general population.

Forum Comments

It has long been assumed, and is being increasingly shown, that genetic factors modify the association between alcohol and a variety of diseases, especially coronary heart disease (CHD).  One important mechanism is an increase in HDL-cholesterol, the “good cholesterol.”  HDL’s effects relate especially to the reverse transport of cholesterol from peripheral arteries to the liver, an effect that is partly regulated by the glycoprotein cholesteryl ester transfer protein (CETP).

In 1995, Fumeron et al (JCI 1995;96:1664-1671) showed an interaction between the CETP TaqIB polymorphism and alcohol consumption on the risk of CHD among men in a study from Northern Ireland and France.  In that study, this linkage was observed only among men who were consuming 50 or more grams of alcohol/day, but especially among those consuming 75 g/day or more.  In the present study, the investigators have carried out a population-based case-control study based in southwest Sweden to determine if they could replicate the findings of Fumeron et al and to see if similar findings are present among women as well as men.

Specific comments on paper:  There are some unusual aspects of this study, as the authors included as cases not only those subjects with a first-time myocardial infarction but a larger number of subjects who “had an exacerbation of previously diagnosed coronary heart disease.”  This may make comparisons with other studies more difficult.   

In this study, there were striking differences between cases of CHD and controls in terms not only of age but a history of diabetes, smoking, cholesterol-lowering drugs, etc.  While the authors adjusted for most of these in their analyses, there is always a problem of residual confounding by some of these factors.  Especially, it is unclear why controls were not selected to be closer in age and in their medical histories to those of the cases.

It is noted that the number of CHD cases with the B2 allele that reported “intermediate” alcohol intake was very low, only 13 subjects, so it may not be appropriate for the authors to base their conclusions primarily on this consumption category.  Given conflicting results from other and larger studies on this association, the overall conclusions of the authors that only a certain minority of people (those with a certain genotype) show a reduced risk of CHD with alcohol may be too broad a statement.  A comment from reviewer Finkel: “I suspect that this is just one of several, or even many, such genetically distinct populations we are composed of.”  It will be important that further studies on this association be carried out in larger populations.

The main message of this paper is that moderate alcohol consumption was associated with a striking decrease in the risk of CHD among subjects who were homozygotes for the CETP TaqIB B2 genotype.  For subjects with only one B2 allele, the effect was less, as it was for subjects with no B2 allele.  Previous studies on this relation have had conflicting results.  In the present study, the B1B1 subjects were combined with the B1B2 subjects for the comparisons with the 19% of subjects who had the B2B2 genotype; presumably, the heterozygotes may have had effects somewhere in between the B1B1 and B2B2 subjects, but this is not clear.  Further, among subjects with the B2B2 geneotype, even abstainers had a suggestion of lower risk of CHD as well (although there were wide confidence limits), which complicates the interpretation and implications of this paper. 

An overall summary on the subject by Forum member Skovenborg:  “The purpose of the study was to examine the possibility that the cardio-protective effect of alcohol is restricted to a subset of the population with a certain CEPT TaqIB genotype.  The authors state that the common attitude today is that moderate alcohol intake will decrease everyone’s risk of coronary heart disease, but it is well recognized that this is not true.  Just to mention the two most accepted exceptions: the protective effect of alcohol is restricted by age (middle-aged and older men and older women vs young men and women) and drinking pattern (a regular, moderate intake vs. binge drinking). The protective effect may also be modified by risk factor status, e.g. insulin resistance, as observed by Hein et al in the Copenhagen Male Study.(1)

“The association of alcohol, HDL cholesterol and coronary heart disease is poorly understood as observational studies cannot distinguish between a causal role in the pathological process and a marker of the underlying pathophysiology.  For LDL cholesterol, the results of both randomised trials of LDL-cholesterol-lowering treatments and from human Mendelian diseases are concordant and suggest that plasma LDL cholesterol is causally related to risk of myocardial infarction.  However, the available evidence for the causal relevance of HDL cholesterol from randomised trials or Mendelian diseases is scarce and inconsistent.(2-4)

“Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters (CEs) from HDL to apoprotein B (apoB) – containing lipoproteins in exchange for triglycerides.  As a result of CETP action, HDL-C is decreased (impairing reverse cholesterol transport), and the cholesterol content of very-low-density lipoprotein (VLDL) and LDL is increased, which could result in a pro-atherogenic profile.  However, because the cholesteryl ester transfer process may stimulate reverse cholesterol transport by providing a route for delivery of HDL-derived cholesteryl esters to the liver via VLDL and LDL and the hepatic LDL receptor, it is debated whether circulating CETP may act in an atherogenic or even in an antiatherogenic manner. (5-6)  Despite the consistent association between cholesteryl ester transfer protein (CETP) gene variation and plasma HDL-C, huge controversy still rages on its association with coronary heart disease (CHD).  To this controversy has been added the results from the Framingham cohort (7) in which they found that lower plasma CETP activity was associated with greater incidence of CHD, contrary to expectations.

“Biological mechanisms underlying the positive association between alcohol and HDL-C are not fully understood.  One pathway could be through regulation of CETP activity; the concentration of CETP is inversely associated with HDL-C levels.  Observational studies have reported lower CETP activity among both alcohol abusers and young men with moderate alcohol intake.(8-9)  In addition an initial case-control study showed that high alcohol consumption not only strongly increased HDL-C in B2 carriers, but also reduced to a greater extent CHD risk in those individuals. (10) However, other later studies in the general population have not been able to replicate the interaction between alcohol consumption and the CETP genotype, whether in increasing HDL-C (11-12) or reducing CHD risk.(13)   Thus, although in a recent and wide-ranging meta-analysis (14) the effect of the CETP genotype on HDL-C concentrations and CHD risk was estimated, the possible modulating effect of alcohol consumption on these phenotypes was not addressed and may be one reason for the lack of an interaction.

“When estimating the results of the present study, the conflicting results of these previous studies must be borne in mind.  The significant interaction between the CETP TaqIB polymorphism and alcohol consumption on the risk for coronary heart disease in the ECTIM study was observed at an ethanol intake of ≥ 50 g/day compared to lower or no intake.  In the present study, Mehlig et al compare the effects of an intake of < 3.2 (“low”) and 3.2 – 6.3 (“intermediate”) grams of alcohol/day in women and < 6.5 and 6.5 – 13.1 g/day for “low” and “intermediate” categories in men.  It is difficult to understand the biological mechanisms behind the large effect modification (OR of CHD 0.21 (0.10-0.44) in men with intermediate alcohol intake by such very modest differences in alcohol intake.

“In a public health context, the effect of health behaviours in a population will depend on the distribution of age, sex and genotypes of the population.  In the INTERGENE cohort that formed the population for the present study, the mean alcohol intake among users of alcohol was very low: 3.3 – 4.7 g/day for women, 9.0 – 9.7 g/day for men and the prevalence of the B2B2 genotype was 18.6%.  In other populations the results might have been different.”  

References from Skovenborg summary 

1. Hein HO, et al. Alcohol consumption, Lewis phenotypes, and risk of ischaemic heart disease. Lancet 1993;341:392-396.

2. Voight BF, et al.  Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomization study.  Lancet 2012;380:572-580.

3. Keene D, et al. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomized controlled trials including 117,411 patients.  BMJ 2014;349:g4379.

4. Magnus P, et al.  Controling for high-density lipoprotein cholesterol does not affect the magnitude of the relationship between alcohol and coronary heart disease.  Circulation 2011;124:2296-2302.

5. Fielding CJ, et al.  Cholesteryl ester transfer protein: friend or foe?  J Clin Invest 1996;97:2687–2688.

6. Shah PK. The Yin and Yang of Cholesteryl Ester Transfer Protein in Cardiovascular Disease. Circulation 2009;120:2408-2410.

7. Vasan RS, et al.  Association of circulating cholesteryl ester transfer protein activity with incidence of cardiovascular disease in the community.  Circulation 2009;120:2414–2420.

8. Hannuksela M, et al.  Reduction in the concentration and activity of plasma cholesteryl ester transfer protein by alcohol.  J Lipid Res 1992;33:737-744.

9. Boekholdt SM, et al.  Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13,677 subjects. Circulation 2005;111:278-287.

10. Fumeron F, et al. Alcohol intake modulates the effect of a polymorphism of the cholesteryl ester transfer protein gene on plasma high density lipoprotein and the risk of myocardial infarction.  J Clin Invest 1995;96:1664–1671.

11. Corella D, et al. Association of TaqIB polymorphism in the cholesteryl ester transfer protein gene with plasma lipid levels in a healthy Spanish population.  Atherosclerosis 2000;152:367–376.

12. Talmud PJ, et al.  Genetic and environmental determinants of plasma high density lipoprotein cholesterol and apolipoprotein AI concentrations in healthy middle-aged men.  Ann Hum Genet 2002;66:111–124.

13. Jensen MK, et al.  Alcohol consumption. TaqIB polymorphism of cholesteryl ester transfer protein, high-density lipoprotein cholesterol, and risk of coronary heart disease in men and women.  Eur Heart J 2008;29:104–112.

14. Thompson A, et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk.  JAMA 2008;299:2777–2788.

Forum Summary

It has long been known that genetic and other environmental factors modify the association between alcohol consumption and a variety of diseases, especially coronary heart disease (CHD).  Foremost among these modifying factors are genes that affect alcohol metabolism, age (effects seen only in older individuals), and drinking patterns (regular moderate versus binge drinking).  Also, certain cholesteryl ester transfer protein (CETP TaqIB) polymorphisms, that relate to HDL-cholesterol activity, may interact with alcohol consumption for their effects on the risk of CHD.  In the present study, the investigators have carried out a population-based case-control study among subjects in southwest Sweden to determine if there was an interaction between CETP genotypes and alcohol consumption for its effects on the risk of CHD.  The authors conclude that a significant reduction in the risk of CHD from moderate drinking was seen only among the 18.6% of their subjects who had a particular CETP polymorphism.

Forum members considered this to be an interesting paper, but had some questions about the selection of cases, as they included not only new cases of CHD but subjects “who had an exacerbation of previously diagnosed coronary heart disease;” this makes it somewhat difficult to compare their results with other papers.  Further, despite a large number of potential “control” subjects from their base population, the controls chosen were considerably younger than the cases and had different medical histories.  While they adjusted for some of these factors in their analysis, residual confounding remains possible. 

The major concern of Forum members was the broad conclusion of the authors (that only a small proportion of the population will show any cardio-protective effects of moderate drinking) based on such a small number of subjects.  For example, among their “intermediate” category of drinkers with the supposedly “protective” CETP polymorphism, there were only 13 cases of CHD.  Further, a number of previous large studies have had quite conflicting results regarding the effects of CETP polymorphisms on the alcohol-CHD association.  While this paper adds information on one (of many) factors that affect the association between alcohol consumption and CHD, larger studies in different populations will be needed to determine the overall importance of this particular genetic polymorphism.

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Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:

Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark

Andrew L. Waterhouse, PhD, Marvin Sands Professor, Department of Viticulture and Enology, University of California, Davis; Davis, CA, USA

Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA

R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA

Note on Potential Conflict of Interest:  It should be noted that Professor Dag S. Thelle, one of the co-authors of this paper, is a member of the International Scientific Forum on Alcohol Research.  Professor Thelle had no input into the preparation of this critique.