Alcohol drinking mediates the association between polymorphisms of ADH1B and ALDH2 and hepatitis B-related hepatocellular carcinoma

Background: The role of polymorphisms on ADH1B and ALDH2 in patients with chronic hepatitis B is unclear. This study aims to examine whether alcohol drinking mediates the association between two ADH1B and ALDH2 polymorphisms and the risk of hepatocellular carcinoma among chronic hepatitis B patients. Methods: A total of 3,824 individuals were enrolled in this study. Two SNPs, rs1229984 (ADH1B) and rs671 (ALDH2), were genotyped using the Affymetrix Axiom Genome-Wide CHB1 Array (Affymetrix, Inc). Multivariate unconditional logistic regression and mediation analyses were used, comparing CT or TT with CC for rs1229984 and GA and AA with GG for rs671. Results: There were 602 cases of hepatocellular carcinoma and 3,222 controls. Frequencies of the rs1229984 (ADH1B) T allele and rs671 (ALDH2) A allele were 72.9% and 28.8%, respectively. Individuals who carried at least one deficient allele for both SNPs were significantly less likely to become habitual alcohol drinkers, with an OR and 95% confidence interval (CI) of 0.24 (0.15-0.40). Alleles for rs1229984 (ADH1B) and rs671 (ALDH2) were not associated with hepatocellular carcinoma in multivariate analyses. However, mediation analyses showed that the rs1229984 T allele, rs671 A allele, and two SNPs combined were significantly associated with decreased hepatocellular carcinoma risk, mediated through alcohol drinking, with an OR (95% CI) of 0.87 (0.79-0.96), 0.70 (0.61-0.82), and 0.73 (0.58-0.88), respectively. Conclusions: Polymorphisms on ADH1B and ALDH2 had significant indirect effects on hepatocellular carcinoma risk, mediated through alcohol drinking. Impact: Future genetic studies of chronic hepatitis B and hepatocellular carcinoma must take mediation effects into consideration.