New insights into the genetic contribution of ALDH2 rs671 in pancreatic carcinogenesis: Evaluation by mediation analysis

Cancer Sci. 2022 Apr;113(4):1441-1450. doi: 10.1111/cas.15286. Epub 2022 Feb 16.

Abstract

A functional variant on ALDH2 rs671 (G>A) confers a protective effect against alcohol-induced carcinogenesis through an indirect pathway mediated by decreased alcohol consumption. Conversely, this variant also contributes to the accumulation of carcinogenic agents, resulting in a direct carcinogenic effect. This study aimed to separately quantify these two opposing effects of the rs671 A allele on pancreatic cancer risk and explore the impact of the rs671 A allele and alcohol consumption on pancreatic carcinogenesis. We included 426 cases and 1456 age- and sex-matched controls. Odds ratio (OR) and 95% confidence interval (CI) for alcohol consumption were estimated using a conditional logistic regression model. By defining rs671 A allele and alcohol consumption as exposure and mediator, respectively, we used mediation analysis to decompose the total-effect OR of the rs671 A allele into direct- and indirect-effect ORs. Alcohol consumption (10 g/d) was associated with pancreatic cancer risk (OR, 1.05; 95% CI, 1.01-1.10), but tests for interaction between the rs671 A allele and alcohol consumption were nonsignificant, indicating that the effect of alcohol consumption did not vary by genotype. Mediation analysis showed that the nonsignificant total effect (OR, 1.15; 95% CI, 0.92-1.44) can be decomposed into the carcinogenic direct (OR, 1.34; 95% CI, 1.04-1.72) and protective indirect effect (OR, 0.86; 95% CI, 0.77-0.95). This study supports the association between alcohol consumption and pancreatic cancer risk and indicates the potential contribution of the rs671 A allele to pancreatic carcinogenesis through impaired metabolism of known or unknown ALDH2 substrates.

Keywords: alcohol consumption; aldehyde dehydrogenase 2; case-control study; mediation analysis; pancreatic cancer.

MeSH terms

  • Alcohol Drinking / adverse effects
  • Alcohol Drinking / genetics
  • Aldehyde Dehydrogenase, Mitochondrial / genetics
  • Carcinogenesis / genetics
  • Case-Control Studies
  • Genetic Predisposition to Disease
  • Humans
  • Logistic Models
  • Mediation Analysis*
  • Pancreatic Neoplasms* / genetics
  • Polymorphism, Single Nucleotide
  • Risk Factors

Substances

  • ALDH2 protein, human
  • Aldehyde Dehydrogenase, Mitochondrial