Open AccessNew insights into the genetic contribution of ALDH2 rs671 in pancreatic carcinogenesis: Evaluation by mediation analysis
Author(s) -
Koyanagi Yuriko N.,
Oze Isao,
Kasugai Yumiko,
Kawakatsu Yukino,
Taniyama Yukari,
Hara Kazuo,
Shimizu Yasuhiro,
Imoto Issei,
Ito Hidemi,
Matsuo Keitaro
Publication year - 2022
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15286
Subject(s) - aldh2 , odds ratio , alcohol , allele , mediation , confidence interval , pancreatic cancer , medicine , genetics , biology , cancer , biochemistry , gene , political science , law
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.