Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, China.
Department of Preventive Medicine, Bin Hai Wan Central Hospital of Dongguan, Dongguan, China.
Cancer Med. 2023 Oct;12(20):20437-20449. doi: 10.1002/cam4.6610. Epub 2023 Oct 5.
Previous studies have shown that ALDH2 and ADH1B genes may be associated with alcohol metabolism and the risk of esophageal squamous cell carcinoma (ESCC), with inconsistent results. This meta-analysis aimed at comprehensively assessing the associations between ALDH2 and ADH1B polymorphisms and the risk of ESCC to synthesize and clarify the evidence.
We calculated summary estimates of the associations between four genetic variants (rs671 and rs674 in ALDH2, and rs1229984 and rs1042026 in ADH1B) and the ESCC risk across 23 publications in the additive model and allelic model. Venice criteria, Bayesian false discovery probability (BFDP), and false-positive reporting probability (FPRP) were used to assess the strength of epidemiological evidence. Heterogeneity among studies was evaluated by using the Higgin's I statistic, and publication bias was assessed by using funnel plots and Begg's test. A Mendelian randomization (MR) analysis was performed to determine the causal association between alcohol intake and esophageal cancer risk. Data from the HaploReg v4.1 and PolyPhen-2 were analyzed for functional annotations.
Of the four genetic variants, rs671 of ALDH2 was associated with a significantly reduced risk of ESCC (OR: 0.60, 95% CI: 0.50-0.73), whereas rs1229984 of ADH1B was associated with a significantly increased risk (2.50, 95% CI: 1.70-3.69) in the additive model. In the allelic model, the variant rs1229984 of ADH1B also increased the risk of ESCC (OR: 1.50; 95% CI: 1.21-1.87). The result for the variant rs671 was considered as strong epidemiological evidence. Functional annotations identified that the four variants were related to the enhancer histone marks and motif changes. The other two variants were not associated with the ESCC risk (rs674 of ALDH2 OR: 1.22, 95% CI: 0.71-2.12; rs1042026 of ADH1B OR: 1.28, 95% CI: 0.52-3.14) in the additive model. The MR analysis did not find a causal effect of alcohol on the esophageal cancer risk.
The results showed that ADH1B rs1229984 was significantly associated with an increased the risk of ESCC.
先前的研究表明，ALDH2 和 ADH1B 基因可能与酒精代谢和食管鳞状细胞癌（ESCC）的风险相关，但结果并不一致。本荟萃分析旨在综合评估 ALDH2 和 ADH1B 多态性与 ESCC 风险之间的关联，以综合和阐明证据。
我们在加性模型和等位基因模型中，计算了 rs671 和 rs674 在内的 4 个遗传变异（ALDH2 中的 rs671 和 rs674，以及 ADH1B 中的 rs1229984 和 rs1042026）与 ESCC 风险之间关联的综合估计值。威尼斯标准、贝叶斯假阳性发现概率（BFDP）和假阳性报告概率（FPRP）用于评估流行病学证据的强度。使用 Higgins I 统计量评估研究之间的异质性，并使用漏斗图和 Begg 检验评估发表偏倚。进行孟德尔随机化（MR）分析以确定饮酒与食管癌风险之间的因果关系。对 HaploReg v4.1 和 PolyPhen-2 的数据进行功能注释分析。
在这四个遗传变异中，ALDH2 的 rs671 与 ESCC 的风险显著降低相关（OR：0.60，95%CI：0.50-0.73），而 ADH1B 的 rs1229984 与风险显著增加相关（OR：2.50，95%CI：1.70-3.69）在加性模型中。在等位基因模型中，ADH1B 的变异 rs1229984 也增加了 ESCC 的风险（OR：1.50；95%CI：1.21-1.87）。变异 rs671 的结果被认为是强有力的流行病学证据。功能注释确定了这四个变体与增强子组蛋白标记和基序变化有关。另外两个变体与 ESCC 风险无关（ALDH2 的 rs674 OR：1.22，95%CI：0.71-2.12；ADH1B 的 rs1042026 OR：1.28，95%CI：0.52-3.14）在加性模型中。MR 分析未发现酒精对食管癌风险的因果作用。
结果表明，ADH1B 的 rs1229984 与 ESCC 风险显著增加相关。
