Alcohol intake and cause-specific mortality: conventional and genetic evidence in a prospective cohort study of 512 000 adults in China

Abstract

Background Genetic variants that affect alcohol use in East Asian populations could help assess the causal effects of alcohol consumption on cause-specific mortality. We aimed to investigate the associations between alcohol intake and cause-specific mortality using conventional and genetic epidemiological methods among more than 512 000 adults in China.Methods The prospective China Kadoorie Biobank cohort study enrolled 512 724 adults (210 205 men and 302 519 women) aged 30-79 years, during 2004-08. Residents with no major disabilities from ten diverse urban and rural areas of China were invited to participate, and alcohol use was self-reported. During 12 years of follow-up, 56 550 deaths were recorded through linkage to death registries, including 23 457 deaths among 168 050 participants genotyped for ALDH2-rs671 and ADH1B-rs1229984. Adjusted hazard ratios (HRs) for cause-specific mortality by self-reported and genotype-predicted alcohol intake were estimated using Cox regression.Findings 33% of men drank alcohol most weeks. In conventional observational analyses, ex-drinkers, non-drinkers, and heavy drinkers had higher risks of death from most major causes than moderate drinkers. Among current drinkers, each 100 g/week higher alcohol intake was associated with higher mortality risks from cancers (HR 1<middle dot>18 [95% CI 1<middle dot>14-1<middle dot>22]), cardiovascular disease (CVD; HR 1<middle dot>19 [1<middle dot>15-1<middle dot>24]), liver diseases (HR 1<middle dot>51 [1<middle dot>27-1<middle dot>78]), non -medical causes (HR 1<middle dot>15 [1<middle dot>08-1<middle dot>23]), and all causes (HR 1<middle dot>18 [1<middle dot>15-1<middle dot>20]). In men, ALDH2-rs671 and ADH1B- rs1229984 genotypes predicted 60-fold differences in mean alcohol intake (4 g/week in the lowest group vs 255 g/week in the highest). Genotype-predicted alcohol intake was uniformly and positively associated with risks of death from all causes (n=12 939; HR 1<middle dot>07 [95% CI 1<middle dot>05-1<middle dot>10]) and from pre-defined alcohol-related cancers (n=1274; 1<middle dot>12 [1<middle dot>04-1<middle dot>21]), liver diseases (n=110; 1<middle dot>31 [1<middle dot>02-1<middle dot>69]), and CVD (n=6109; 1<middle dot>15 [1<middle dot>10-1<middle dot>19]), chiefly due to stroke (n=3285; 1<middle dot>18 [1<middle dot>12-1<middle dot>24]) rather than ischaemic heart disease (n=2363; 1<middle dot>06 [0<middle dot>99-1<middle dot>14]). Results were largely consistent using a polygenic score to predict alcohol intake, with higher intakes associated with higher risks of death from alcohol-related cancers, CVD, and all causes. Approximately 2% of women were current drinkers, and although power was low to assess observational associations of alcohol with mortality, the genetic evidence suggested that the excess risks in men were due to alcohol, not pleiotropy..Interpretation Higher alcohol intake increased the risks of death overall and from major diseases for men in China. There was no genetic evidence of protection from moderate drinking for all-cause and cause-specific mortality, including CVD.