Genetic variant repressing ADH1A expression confers susceptibility to esophageal squamous-cell carcinoma.
作者： Qionghua Cui , Linna Peng , Lixuan Wei , Jiang Chang , Wenle Tan
DOI: 10.1016/J.CANLET.2017.12.020
关键词:
摘要: Genome-wide association studies (GWAS) have discovered numerous genetic susceptibility loci including a cluster of alcohol dehydrogenase (ADH) gene family for esophageal squamous-cell carcinoma (ESCC). However, the underlying mechanism has not fully been elucidated. In this study, we integrated GWAS data, gene-drinking interaction, expression quantitative trait locus (eQTL) analysis and biochemical experiments to clarify specific polymorphisms in ADH loci. By imputation eQTL analysis, identified rs1154402C>G intron 1 ADH5 substantially associated with levels ADH1A. Association showed that rs1154402[G] allele was significantly ESCC risk drinkers (OR = 1.44, 95% CI 1.20-1.73; P 7.74 × 10-5) but nondrinkers 1.14, 0.93-1.37; .220). Furthermore, variant significant interaction drinking near ALDH2 encoding enzyme oxidizing acetaldehyde, carcinogenic product resulted from oxidation catalyzed by ADHs. We demonstrated first time change might create silencer, repressing ADH1A transcription via long-range promoter. These results suggest confer susceptible down-regulation ADH1A, which weakens catabolism.
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