Genetic variant repressing ADH1A expression confers susceptibility to esophageal squamous-cell carcinoma.

Abstract

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 the GWAS data, gene-drinking interaction, expression quantitative trait locus (eQTL) analysis and biochemical experiments to clarify the specific mechanism of the polymorphisms in ADH loci. By imputation and eQTL analysis, we identified rs1154402C>G in intron 1 of ADH5 substantially associated with the expression levels of ADH1A. Association analysis showed that the rs1154402[G] allele was significantly associated with ESCC risk in drinkers (OR = 1.44, 95% CI = 1.20-1.73; P = 7.74 × 10-5) but not in nondrinkers (OR = 1.14, 95% CI = 0.93-1.37; P = .220). Furthermore, the ADH5 variant showed a significant interaction with drinking and the genetic variant near ALDH2 encoding the enzyme oxidizing acetaldehyde, a carcinogenic product resulted from alcohol oxidation catalyzed by ADHs. We demonstrated for the first time that rs1154402C>G change might create a silencer, repressing ADH1A transcription via long-range interaction with ADH1A promoter. These results suggest that genetic variant in ADH5 might confer alcohol drinkers susceptible to ESCC by down-regulation of ADH1A, which weakens alcohol catabolism.

• Authors: Qionghua Cui, Linna Peng, Lixuan Wei, Jiang Chang, Wenle Tan, Yingying Luo, Xudong Huang, Yanjie Zhao, Jun Li, Jiahui Chu, Mingming Shao, Chao Zhang, Cheng Li, Wen Tan, Dongxin Lin, Chen Wu
• Journal: Cancer letters (Cancer Lett) Vol. 421 Pg. 43-50 (05 01 2018) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 29248712 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017. Published by Elsevier B.V.

Chemical References

• AVP protein, human
• Neurophysins
• Protein Precursors
• Vasopressins

Topics

• Esophageal Neoplasms (genetics)
• Esophageal Squamous Cell Carcinoma (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• Genetic Predisposition to Disease (genetics)
• Genome-Wide Association Study
• Genotype
• Humans
• Neurophysins (genetics)
• Polymorphism, Single Nucleotide
• Protein Precursors (genetics)
• Vasopressins (genetics)