Conventional and genetic evidence on alcohol and vascular disease aetiology: a prospective study of 500 000 men and women in China
Moderate alcohol intake has been associated with reduced cardiovascular risk in many studies, in comparison with abstinence or with heavier alcohol use. Studies in east Asia can help determine whether these associations are causal, since two common genetic variants greatly affect alcohol consumption patterns. The researchers used these two variants to assess the relationships between cardiovascular risk and genotype-predicted mean alcohol intake in men, contrasting the findings in men with those in women (few of whom use alcohol).
The prospective China Kadoorie Biobank enrolled 512 715 adults between June 25, 2004, and July 15, 2008, from ten areas of China, recording alcohol use and other characteristics. It followed them for about 10 years (until Jan 1, 2017), monitoring cardiovascular disease (including ischaemic stroke, intracerebral haemorrhage, and myocardial infarction) by linkage with morbidity and mortality registries and electronic hospital records. 161,498 participants were genotyped for two variants that alter alcohol metabolism, ALDH2-rs671 and ADH1B- rs1229984. Adjusted Cox regression was used to obtain the relative risks associating disease incidence with self- reported alcohol use patterns (conventional epidemiology) or with genotype-predicted mean male alcohol intake (genetic epidemiology—ie, Mendelian randomisation), with stratification by study area to control for variation between areas in disease rates and in genotype-predicted intake.
33% (69 897/210 205) of men reported consuming alcohol in most weeks, mainly as spirits, compared with only 2% (6245/302 510) of women. Among men, conventional epidemiology showed that self-reported alcohol intake had U-shaped associations with the incidence of ischaemic stroke (n=14930), intracerebral haemorrhage (n=3496), and acute myocardial infarction (n=2958); men who reported consuming about 100 g of alcohol per week (one to two drinks per day) had lower risks of all three diseases than non-alcohol users or heavier alcohol users.
In contrast, although genotype-predicted mean male alcohol intake varied widely (from 4 to 256 g per week—ie, near zero to about four drinks per day), it did not have any U-shaped associations with risk. For stroke, genotype-predicted mean alcohol intake had a continuously positive log-linear association with risk, which was stronger for intracerebral haemorrhage (relative risk [RR] per 280 g per week 1·58, 95% CI 1·36–1·84, p<0·0001) than for ischaemic stroke (1·27, 1·13–1·43, p=0·0001). For myocardial infarction, however, genotype-predicted mean alcohol intake was not significantly associated with risk (RR per 280 g per week 0·96, 95% CI 0·78–1·18, p=0·69).
Usual alcohol intake in current alcohol users and genotype-predicted alcohol intake in all men had similarly strong positive associations with systolic blood pressure (each p<0·0001). Among women, few consumed alcohol and the studied genotypes did not predict high mean alcohol intake and were not positively associated with blood pressure, stroke, or myocardial infarction.
Genetic epidemiology shows that the apparently protective effects of moderate alcohol intake against stroke are largely non-causal. Alcohol consumption uniformly increases blood pressure and stroke risk, and appears in this one study to have little net effect on the risk of myocardial infarction.
Research in context
Evidence before this study
Although conventional epidemiological studies have associated moderate alcohol intake with a reduced risk of stroke and, particularly, coronary heart disease, these apparently protective effects may be largely non-causal. Since genetic variants have only limited effects on alcohol intake in populations of European descent, studies in such populations cannot directly compare the effects of moderate alcohol intake with those of near-total alcohol avoidance. The question of whether moderate intake really is protective can be addressed by genetic epidemiology in east Asian populations where two common genetic variants (ALDH2-rs671 and ADH1B-rs1229984) jointly cause large absolute differences in mean alcohol intake.
To review the genotypic evidence about the relationships between vascular disease and these two genetic variants, the scientists searched PubMed from database inception to Jan 11, 2019, for studies that had investigated the effects of either variant on alcohol exposure or cardiovascular disease, using the search terms (“alcohol” or “blood pressure” or “cholesterol” or “cardiovascular” or “stroke” or “myocardial infarction” or “coronary”) and ([“ADH1B” or “ALDH2” or “rs1229984” or “rs671”] or [(“East Asian” or “Chinese” or “Japanese” or “Korean”) and “genome-wide”]).
In meta-analyses, the incidence of coronary heart disease appears to be increased by the rs1229984 genotype that increases alcohol exposure, but, conversely, may be decreased by the rs671 genotype that increases alcohol exposure. There is insufficient evidence about the effects of these two genetic variants on stroke.
Added value of this study
The researchers’ large prospective study is of a population where both variants are common but, as few women use alcohol, strongly affect alcohol exposure in only one sex. To help assess causal effects of alcohol on the incidence of ischaemic stroke, haemorrhagic stroke, and myocardial infarction, it compares the findings from conventional epidemiological analyses and from genetic analyses (which use Mendelian randomisation to study the effects of genetic variants that strongly influence mean male alcohol intake). Consistent with previous studies, the conventional analyses among men found U-shaped associations of self-reported alcohol intake with stroke and myocardial infarction, with the lowest risks at moderate intake.
In contrast, although genotype-predicted mean male alcohol intake varied from near zero to about four alcoholic drinks per day, it did not have U-shaped associations with risk, and was strongly positively associated throughout its range with blood pressure, ischaemic stroke, and haemorrhagic stroke, suggesting no substantial protective effect of moderate alcohol intake. Based on a smaller number of cases, genotype-predicted mean male alcohol intake had no apparent association with myocardial infarction.
Among women, alcohol intake was low and these genetic variants had little effect on stroke or on myocardial infarction, suggesting that they did not have any substantial non-alcohol-mediated (ie, pleiotropic) net effect on these diseases.
Implications of all the available evidence
Genetic evidence shows that the apparently protective effects of moderate alcohol intake against stroke are not mainly caused by alcohol itself, and are largely artifacts of reverse causation and confounding.
Throughout the range of mean intake that the scientists studied by Mendelian randomisation, increasing mean alcohol intake uniformly increases blood pressure and stroke incidence. Among the men in this population, alcohol was responsible for about 8% of ischaemic strokes and 16% of intracerebral haemorrhages. The effects of alcohol on myocardial infarction are less certain.
Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, National Natural Science Foundation of China, British Heart Foundation, Cancer Research UK, GlaxoSmithKline, Medical Research Council, and Wellcome Trust.