Constitutively Higher Level of GSTT2 in Esophageal Tissues From African Americans Protects Cells Against DNA Damage

Gastroenterology. 2019 Apr;156(5):1404-1415. doi: 10.1053/j.gastro.2018.12.004. Epub 2018 Dec 19.

Abstract

Background & aims: African American and European American individuals have a similar prevalence of gastroesophageal reflux disease (GERD), yet esophageal adenocarcinoma (EAC) disproportionately affects European American individuals. We investigated whether the esophageal squamous mucosa of African American individuals has features that protect against GERD-induced damage, compared with European American individuals.

Methods: We performed transcriptional profile analysis of esophageal squamous mucosa tissues from 20 African American and 20 European American individuals (24 with no disease and 16 with Barrett's esophagus and/or EAC). We confirmed our findings in a cohort of 56 patients and analyzed DNA samples from patients to identify associated variants. Observations were validated using matched genomic sequence and expression data from lymphoblasts from the 1000 Genomes Project. A panel of esophageal samples from African American and European American subjects was used to confirm allele-related differences in protein levels. The esophageal squamous-derived cell line Het-1A and a rat esophagogastroduodenal anastomosis model for reflux-generated esophageal damage were used to investigate the effects of the DNA-damaging agent cumene-hydroperoxide (cum-OOH) and a chemopreventive cranberry proanthocyanidin (C-PAC) extract, respectively, on levels of protein and messenger RNA (mRNA).

Results: We found significantly higher levels of glutathione S-transferase theta 2 (GSTT2) mRNA in squamous mucosa from African American compared with European American individuals and associated these with variants within the GSTT2 locus in African American individuals. We confirmed that 2 previously identified genomic variants at the GSTT2 locus, a 37-kb deletion and a 17-bp promoter duplication, reduce expression of GSTT2 in tissues from European American individuals. The nonduplicated 17-bp promoter was more common in tissue samples from populations of African descendant. GSTT2 protected Het-1A esophageal squamous cells from cum-OOH-induced DNA damage. Addition of C-PAC increased GSTT2 expression in Het-1A cells incubated with cum-OOH and in rats with reflux-induced esophageal damage. C-PAC also reduced levels of DNA damage in reflux-exposed rat esophagi, as observed by reduced levels of phospho-H2A histone family member X.

Conclusions: We found GSTT2 to protect esophageal squamous cells against DNA damage from genotoxic stress and that GSTT2 expression can be induced by C-PAC. Increased levels of GSTT2 in esophageal tissues of African American individuals might protect them from GERD-induced damage and contribute to the low incidence of EAC in this population.

Keywords: BE; Cranberry Proanthocyanidins; Glutathione Transferase; Racial Disparities.

Publication types

  • Comparative Study
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / enzymology
  • Adenocarcinoma / ethnology
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • African Americans / genetics*
  • Animals
  • Barrett Esophagus / enzymology
  • Barrett Esophagus / ethnology
  • Barrett Esophagus / genetics*
  • Barrett Esophagus / pathology
  • DNA Damage*
  • Disease Models, Animal
  • Esophageal Mucosa / enzymology*
  • Esophageal Mucosa / pathology
  • Esophageal Neoplasms / enzymology
  • Esophageal Neoplasms / ethnology
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / pathology
  • European Continental Ancestry Group / genetics*
  • Female
  • Gastroesophageal Reflux / enzymology
  • Gastroesophageal Reflux / ethnology
  • Gastroesophageal Reflux / genetics*
  • Gastroesophageal Reflux / pathology
  • Glutathione Transferase / genetics*
  • Glutathione Transferase / metabolism
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protective Factors
  • Rats, Sprague-Dawley
  • Risk Factors
  • United States / epidemiology
  • Up-Regulation

Substances

  • Histones
  • Phosphoproteins
  • gamma-H2AX protein, rat
  • GSTT2 protein, human
  • Gstt2 protein, rat
  • Glutathione Transferase

Supplementary concepts

  • Adenocarcinoma Of Esophagus