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Gastroenterology. 2018 Dec 12. pii: S0016-5085(18)35401-5. doi: 10.1053/j.gastro.2018.12.004. [Epub ahead of print]

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

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Department of Surgery, Section of Thoracic Surgery, University of Michigan, Ann Arbor, MI 48109.
Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109.
Departments of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109.
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109.
Department of Medicine, Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD 21287.
Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill NC 27599.
Department of Medicine, Gastroenterology, Case Western Reserve University, Cleveland, OH 44106.
Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor MI 48109.
Department of Surgery, Section of Thoracic Surgery, University of Michigan, Ann Arbor, MI 48109. Electronic address:



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


We performed transcriptional profile analysis of esophageal squamous mucosa tissues from 20 African American and 20 European Americans (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 were 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 mRNA.


We found significantly higher levels of glutathione S-transferase theta 2 (GSTT2) mRNA in squamous mucosa from African Americans compared with European Americans and associated these with variants within the GSTT2 locus in African Americans. 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 Americans. The non-duplicated 17-bp promoter was more common in tissue samples from African descendant populations. 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.


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 Americans might protect them from GERD-induced damage and contribute to the low incidence of EAC in this population.


BE; cranberry proanthocyanidins; glutathione transferase; racial disparities

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