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

Cancer Lett. 2018 May 1;421:43-50. doi: 10.1016/j.canlet.2017.12.020. Epub 2017 Dec 15.

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.

Keywords: Alcohol drink; Esophageal cancer; Polymorphism; eQTL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

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