背景:摄入的酒精主要被乙醇脱氢酶1B(ADH1B)氧化为乙醛,乙醛主要被醛脱氢酶2(ALDH2)进一步氧化为乙酸盐。尽管饮酒是食管癌的一个令人信服的危险因素,ADH1Brs1229984(His48Arg)的作用,与酒精代谢缓慢相关的单核苷酸多态性,在食管癌的发展尚不清楚。因为这种单核苷酸多态性与食道癌风险增加和饮酒强度有关,它与食道癌的关联可能通过独立于饮酒强度的直接途径起作用,通过饮酒强度介导的间接途径,或者两者兼而有之。
方法:为了解开这些不同的途径,我们通过将ADH1BArg等位基因和饮酒定义为暴露和介质,将中介分析应用于食管癌病例对照研究(600例和865例对照)。分别,并将ADH1BArg等位基因的总效应比值比分解为直接效应和间接效应比值比。
结果:ADH1BArg等位基因通过饮酒强度变化以外的途径与食道癌风险相关(直接效应比值比,2.03;95%置信区间,1.41-2.92),除了饮酒强度介导的间接途径(间接效应比值比,1.27;95%置信区间,1.05-1.53)。通过对ALDH2rs671(Glu504Lys)的基因型进行分层进一步分析,强烈减弱酶活性的功能性单核苷酸多态性,在每个层内显示出显著的直接效应优势比。
结论:这些结果表明,ADH1BArg等位基因通过减缓酒精分解而导致食道癌风险,除了它对酒精消耗量的影响。
BACKGROUND: Ingested alcohol is predominantly oxidized to acetaldehyde by alcohol dehydrogenase 1B (ADH1B), and acetaldehyde is further oxidized to acetate mainly by aldehyde dehydrogenase 2 (ALDH2). Although alcohol consumption is a convincing risk factor for oesophageal cancer, the role of ADH1B rs1229984 (His48Arg), the single-nucleotide polymorphism associated with slow alcohol metabolism, in oesophageal cancer development is unclear. Because this single-nucleotide polymorphism is associated with both increased risk of oesophageal cancer and drinking intensity, its association with oesophageal cancer might operate either through a direct pathway independently of drinking intensity, via an indirect pathway mediated by drinking intensity, or both.
METHODS: To disentangle these different pathways, we applied a mediation analysis to an oesophageal cancer
case-control study (600 cases and 865 controls) by defining the ADH1B Arg allele and alcohol consumption as exposure and mediator, respectively, and decomposed the total-effect odds ratio of the ADH1B Arg allele into direct- and indirect-effect odds ratio.
RESULTS: The ADH1B Arg allele was associated with oesophageal cancer risk through pathways other than change in drinking intensity (direct-effect odds ratio, 2.03; 95% confidence interval, 1.41-2.92), in addition to the indirect pathway mediated by drinking intensity (indirect-effect odds ratio, 1.27; 95% confidence interval, 1.05-1.53). Further analyses by stratifying genotypes of ALDH2 rs671 (Glu504Lys), the functional single-nucleotide polymorphism that strongly attenuates the enzymatic activity, showed significant direct-effect odds ratio within each stratum.
CONCLUSIONS: These results indicate that ADH1B Arg allele contributes to oesophageal cancer risk by slowing alcohol breakdown, in addition to its effect on the amount of alcohol consumed.