Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions
Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions
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DOI：
10.1038/ng.2411
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发表时间：
2012-10-01
期刊：
影响因子：
30.8
通讯作者：
Lin, Dongxin
中科院分区：
文献类型：
--
作者：
Wu, Chen;Kraft, Peter;Lin, Dongxin
我们在2，031例受影响个体（病例）和2，044例对照中进行了食管鳞状细胞癌（ESCC）的全基因组关联研究（GWAS）和全基因组基因-环境相互作用分析，并在8，092例病例和8，620例对照中进行了独立验证。我们发现了9个新的ESCC易感基因座，其中7个位于染色体4 q23、16q12.1、17 q21、22 q12、3q 27、17 p13和18 p11，具有显著的边缘效应（P = 1.78 x 10（-39）至P = 2.49 x 10（-11）），其中两个，在2 q22和13 q33，仅在基因-饮酒相互作用中有显著关联（基因-环境互作P（P-G × E）= 4.39 × 10 ~（-11）和P-G × E = 4.80 × 10 ~（-8））。4 q23基因座的变异，包括ADH簇，每个都与饮酒在ESCC风险中有显著的相互作用（P-G x E = 2.54 x 10（-7）至P-G x E = 3.23 x 10（-2））。我们证实了12 q24上ALDH 2基因座与ESCC的已知关联，联合分析显示，与没有这些风险等位基因的饮酒者相比，同时具有ADH 1B和ALDH 2风险等位基因的饮酒者患ESCC的风险增加了4倍。我们的研究结果强调了ESCC风险的直接遗传贡献，以及通过与饮酒的相互作用对ESCC的遗传贡献。
We conducted a genome-wide association study (GWAS) and a genome-wide gene-environment interaction analysis of esophageal squamous-cell carcinoma (ESCC) in 2,031 affected individuals (cases) and 2,044 controls with independent validation in 8,092 cases and 8,620 controls. We identified nine new ESCC susceptibility loci, of which seven, at chromosomes 4q23, 16q12.1, 17q21, 22q12, 3q27, 17p13 and 18p11, had a significant marginal effect (P = 1.78 x 10(-39) to P = 2.49 x 10(-11)) and two of which, at 2q22 and 13q33, had a significant association only in the gene-alcohol drinking interaction (gene-environment interaction P (P-G x E) = 4.39 x 10(-11) and P-G x E = 4.80 x 10(-8), respectively). Variants at the 4q23 locus, which includes the ADH cluster, each had a significant interaction with alcohol drinking in their association with ESCC risk (P-G x E = 2.54 x 10(-7) to P-G x E = 3.23 x 10(-2)). We confirmed the known association of the ALDH2 locus on 12q24 to ESCC, and a joint analysis showed that drinkers with both of the ADH1B and ALDH2 risk alleles had a fourfold increased risk for ESCC compared to drinkers without these risk alleles. Our results underscore the direct genetic contribution to ESCC risk, as well as the genetic contribution to ESCC through interaction with alcohol consumption.