Abstract
Two genetic variants that alter alcohol metabolism, ALDH2‐rs671 and ADH1B‐rs1229984, can modify oesophageal cancer risk associated with alcohol consumption in East Asians, but their associations with other cancers remain uncertain. ALDH2‐rs671 G>A and ADH1B‐rs1229984 G>A were genotyped in 150 722 adults, enrolled from 10 areas in China during 2004 to 2008. After 11 years' follow‐up, 9339 individuals developed cancer. Cox regression was used to estimate hazard ratios (HRs) for site‐specific cancers associated with these genotypes, and their potential interactions with alcohol consumption. Overall, the A‐allele frequency was 0.21 for ALDH2‐rs671 and 0.69 for ADH1B‐rs1229984, with A‐alleles strongly associated with lower alcohol consumption. Among men, ALDH2‐rs671 AA genotype was associated with HR of 0.69 (95% confidence interval: 0.53‐0.90) for IARC alcohol‐related cancers (n = 1900), compared to GG genotype. For ADH1B‐rs1229984, the HRs of AG and AA vs GG genotype were 0.80 (0.69‐0.93) and 0.75 (0.64‐0.87) for IARC alcohol‐related cancers, 0.61 (0.39‐0.96) and 0.61 (0.39‐0.94) for head and neck cancer (n = 196) and 0.68 (0.53‐0.88) and 0.60 (0.46‐0.78) for oesophageal cancer (n = 546). There were no significant associations of these genotypes with risks of liver (n = 651), colorectal (n = 556), stomach (n = 725) or lung (n = 1135) cancers. Among male drinkers, the risks associated with higher alcohol consumption were greater among ALDH2‐rs671 AG than GG carriers for head and neck, oesophageal and lung cancers (P interaction < .02). Among women, only 2% drank alcohol regularly, with no comparable associations observed between genotype and cancer. These findings support the causal effects of alcohol consumption on upper aerodigestive tract cancers, with ALDH2‐rs671 AG genotype further exacerbating the risks.
Highlights
Cancer is a leading cause of premature mortality and disability globally, accounting for an estimated 19.3 million new cancer cases and 10 million deaths in 2020.1 Worldwide, 24%of total cancer cases, including 37% of lung cancer and 47% of digestive tract cancers, occurred in China.[1]
Using data from the prospective China Kadoorie Biobank (CKB), we investigated the associations of aldehyde dehydrogenase 2 (ALDH2)-rs[671] and alcohol dehydrogenase 1B (ADH1B)-rs1229984 with total and common site-specific cancers in 151,000 Chinese adults
Previous case-control studies and meta-analyses in East Asian populations have reported associations of ALDH2-rs[671] genotypes with risks of oesophageal cancer[10,12,32] and head and neck cancer,[33] and that the relationships may be modified by alcohol consumption
Summary
Cancer is a leading cause of premature mortality and disability globally, accounting for an estimated 19.3 million new cancer cases and 10 million deaths in 2020.1 Worldwide, 24%. Of total cancer cases, including 37% of lung cancer and 47% of digestive tract (oesophagus, stomach, liver) cancers, occurred in China.[1] Based mainly on observational studies, the International Agency for Research on Cancer (IARC) reported that there is sufficient evidence that alcohol consumption is causally related to development of cancers in the head and neck, oesophagus, liver, colon-rectum, and female breast, but causal evidence remains inconclusive for other cancer sites including lung and stomach due to other possible confounders (e.g. smoking, diet).[2] Worldwide, it was estimated that 3 million deaths could be attributed to alcohol consumption, including >0.4 million from cancer.[3]. An East Asianspecific loss-of-function variant in the aldehyde dehydrogenase 2 (ALDH2) gene
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