Conventional and genetic evidence on alcohol and vascular disease aetiology: a prospective study of 500 000 men and women in China

Abstract

Background: Moderate alcohol intake has been associated with reduced cardiovascular risk in many studies, in comparison with abstinence or with heavier drinking. Studies in east Asia can help determine whether these associations are causal, since two common genetic variants greatly affect alcohol drinking patterns. We 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 drink).

Methods: 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 drinking 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.

Findings: 33% (69 897/210 205) of men reported drinking 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=14 930), intracerebral haemorrhage (n=3496), and acute myocardial infarction (n=2958); men who reported drinking about 100 g of alcohol per week (one to two drinks per day) had lower risks of all three diseases than non-drinkers or heavier drinkers. 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 drinkers and genotype-predicted alcohol intake in all men had similarly strong positive associations with systolic blood pressure (each p<0·0001). Among women, few drank and the studied genotypes did not predict high mean alcohol intake and were not positively associated with blood pressure, stroke, or myocardial infarction.

Interpretation: 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.

Funding: 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.

Figure 1

Mean alcohol intake in men from ten study areas in China, subdivided by nine possible genotypes of two common variants that alter alcohol metabolism For each genotype, the A allele discourages alcohol consumption. Within each area, mean alcohol intake was plotted according to the nine possible ALDH2-rs671 and ADH1B-rs1229984 genotypes (each AA, AG, or GG) from AA/AA homozygosity for both variants to GG/GG homozygosity for both variants. Alcohol intake thresholds were defined at 10, 25, 50, 100, and 150 g per week to assign individuals into six categories of mean male alcohol intake on the basis of their genotype and area.

Figure 2

Patterns of alcohol use in six categories of genotype and study area Prevalence of ever drinking, defined as some alcohol in most weeks (A), and mean weekly alcohol intake (B) in six categories of genotype and study area.

Figure 3

Associations of physiological factors with drinking patterns and with genotypic determinants of mean alcohol intake, in men Conventional epidemiological analyses (A–C) relate self-reported drinking patterns at baseline to mean systolic blood pressure (A), HDL cholesterol (B), and γ-glutamyl transferase (C). Results are adjusted for age, area, education, income, and smoking. The means for current drinkers are plotted against usual alcohol intake, with a fitted line giving the slope (95% CI) per 280 g alcohol per week. Genetic epidemiological analyses (D–F) ignore individual drinking patterns, and for all men relate mean alcohol intake in six categories of genotype and study area to genotypic effects on mean systolic blood pressure (D), HDL cholesterol (E), and γ-glutamyl transferase (F). Results are adjusted for age and area. The slope of the fitted line is the inverse-variance-weighted mean of the slopes of the fitted lines in each study area. The area of each square in A–F is inversely proportional to the variance of the result. Error bars show 95% CIs.

Figure 4

Associations of stroke incidence with drinking patterns and with genotypic determinants of alcohol intake, in men Conventional epidemiological analyses (A–C) relate self-reported drinking patterns at baseline to the incidence of ischaemic stroke (A), intracerebral haemorrhage (B), and total stroke (C). Current drinkers with the lowest mean alcohol intake are the reference group (RR=1), and results are adjusted for age, area, education, income, and smoking. The RRs for current drinkers are plotted against usual alcohol intake, with a fitted line giving the RR (95% CI) per 280 g intake per week. Genetic epidemiological analyses (D–F) ignore individual drinking patterns, and for all men relate mean alcohol intake in six categories of genotype and study area to genotypic effects on the incidence of ischaemic stroke (D), intracerebral haemorrhage (E), and total stroke (F). The category with the lowest mean alcohol intake is the reference group (RR=1), and results are adjusted for age and area. The slope of the fitted line is the inverse-variance-weighted mean of the slopes of the lines of best fit within the ten study areas. The RR is plotted on a log scale and the area of each square is inversely proportional to the variance of the log risk. The group-specific 95% CIs, calculated from this variance, are shown by error bars. RR=relative risk.

Figure 5

Associations of coronary heart disease incidence with drinking patterns and with genotypic determinants of alcohol intake, in men Conventional epidemiological analyses (A–B) relate self-reported drinking patterns at baseline to the incidence of acute myocardial infarction (A) and total coronary heart disease (B). Current drinkers with the lowest mean alcohol intake are the reference group (RR=1), and results are adjusted for age, area, education, income, and smoking. The RRs for current drinkers are plotted against usual alcohol intake, with a fitted line giving the RR (95% CI) per 280 g intake per week. Genetic epidemiological analyses (C–D) ignore individual drinking patterns, and for all men relate mean alcohol intake in six categories of genotype and area to genotypic effects on the incidence of acute myocardial infarction (C) and total coronary heart disease (D). The category with the lowest mean alcohol intake is the reference group (RR=1), and results are adjusted for age and area. The slope of the fitted line is the inverse-variance-weighted mean of the slopes of the lines of best fit within the ten study areas. The RR is plotted on a log scale and the area of each square is inversely proportional to the variance of the log risk. The group-specific 95% CIs, calculated from this variance, are shown by error bars. RR=relative risk.