Department of Pathology and Clinical Laboratories, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan.
Gastric Cancer. 2018 Nov;21(6):936-945. doi: 10.1007/s10120-018-0823-0. Epub 2018 Apr 3.
Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms have a strong impact on carcinogenic acetaldehyde accumulation after alcohol drinking. To date, however, evidence for a significant ALDH2-alcohol drinking interaction and a mediation effect of ALDH2/ADH1B through alcohol drinking on gastric cancer have remained unclear. We conducted two case-control studies to validate the interaction and to estimate the mediation effect on gastric cancer.
We calculated odds ratios (OR) and 95% confidence intervals (CI) for ALDH2/ADH1B genotypes and alcohol drinking using conditional logistic regression models after adjustment for potential confounding in the HERPACC-2 (697 cases and 1372 controls) and HERPACC-3 studies (678 cases and 678 controls). We also conducted a mediation analysis of the combination of the two studies to assess whether the effects of these polymorphisms operated through alcohol drinking or through other pathways.
ALDH2 Lys alleles had a higher risk with increased alcohol consumption compared with ALDH2 Glu/Glu (OR for heavy drinking, 3.57; 95% CI 2.04-6.27; P for trend = 0.007), indicating a significant ALDH2-alcohol drinking interaction (P = 0.024). The mediation analysis indicated a significant positive direct effect (OR 1.67; 95% CI 1.38-2.03) and a protective indirect effect (OR 0.84; 95% CI 0.76-0.92) of the ALDH2 Lys alleles with the ALDH2-alcohol drinking interaction. No significant association of ADH1B with gastric cancer was observed.
The observed ALDH2-alcohol drinking interaction and the direct effect of ALDH2 Lys alleles may suggest the involvement of acetaldehyde in the development of gastric cancer.
乙醛脱氢酶 2（ALDH2；rs671，Glu504Lys）和醇脱氢酶 1B（ADH1B；rs1229984，His47Arg）多态性对饮酒后致癌性乙醛的积累有很大影响。然而，迄今为止，关于 ALDH2-饮酒的相互作用以及 ALDH2/ADH1B 通过饮酒对胃癌的中介作用的证据仍不清楚。我们进行了两项病例对照研究，以验证相互作用，并估计通过饮酒对胃癌的中介作用。
我们使用条件逻辑回归模型计算了 HERPACC-2（697 例和 1372 例对照）和 HERPACC-3 研究（678 例和 678 例对照）中 ALDH2/ADH1B 基因型和饮酒的比值比（OR）和 95%置信区间（CI），并在调整了潜在混杂因素后进行了分析。我们还对两项研究的组合进行了中介分析，以评估这些多态性是否通过饮酒或通过其他途径发挥作用。
与 ALDH2Glu/Glu 相比，ALDH2Lys 等位基因在饮酒量增加时具有更高的风险（重度饮酒的 OR，3.57；95%CI，2.04-6.27；P 趋势=0.007），表明存在显著的 ALDH2-饮酒相互作用（P=0.024）。中介分析表明，ALDH2Lys 等位基因与 ALDH2-饮酒相互作用具有显著的正向直接作用（OR 1.67；95%CI，1.38-2.03）和保护间接作用（OR 0.84；95%CI，0.76-0.92）。未观察到 ADH1B 与胃癌之间存在显著关联。
观察到的 ALDH2-饮酒相互作用和 ALDH2Lys 等位基因的直接作用可能表明乙醛参与了胃癌的发生。
