Genomic regions associated with susceptibility to Barrett's esophagus and esophageal adenocarcinoma in African Americans: The cross BETRNet admixture study.

Xianzhong Sun ,Xiaofeng Zhu,Sanford D Markowitz,Nicholas J Shaheen,Gary W Falk,David G Beer,Prasad G Iyer,Alexander Miron,Kishore Guda,Medha Venkat-Ramani,Deepa T Patil,Apoorva K Chandar,Jean S Wang,Julian A Abrams,Ilke Nalbantoglu,Prashanthi N Thota,Amitabh Chak,Joseph E Willis ,Robert C Elston ,Marcia Irene Canto ,Marty L Veigl ,Malcom V Brock

doi:10.1371/journal.pone.0184962

Abstract

BackgroundBarrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) are far more prevalent in European Americans than in African Americans. Hypothesizing that this racial disparity in prevalence might represent a genetic susceptibility, we used an admixture mapping approach to interrogate disease association with genomic differences between European and African ancestry.MethodsFormalin fixed paraffin embedded samples were identified from 54 African Americans with BE or EAC through review of surgical pathology databases at participating Barrett’s Esophagus Translational Research Network (BETRNet) institutions. DNA was extracted from normal tissue, and genotyped on the Illumina OmniQuad SNP chip. Case-only admixture mapping analysis was performed on the data from both all 54 cases and also on a subset of 28 cases with high genotyping quality. Haplotype phases were inferred with Beagle 3.3.2, and local African and European ancestries were inferred with SABER plus. Disease association was tested by estimating and testing excess European ancestry and contrasting it to excess African ancestry.ResultsBoth datasets, the 54 cases and the 28 cases, identified two admixture regions. An association of excess European ancestry on chromosome 11p reached a 5% genome-wide significance threshold, corresponding to -log10(P) = 4.28. A second peak on chromosome 8q reached -log10(P) = 2.73. The converse analysis examining excess African ancestry found no genetic regions with significant excess African ancestry associated with BE and EAC. On average, the regions on chromosomes 8q and 11p showed excess European ancestry of 15% and 20%, respectively.ConclusionsChromosomal regions on 11p15 and 8q22-24 are associated with excess European ancestry in African Americans with BE and EAC. Because GWAS have not reported any variants in these two regions, low frequency and/or rare disease associated variants that confer susceptibility to developing BE and EAC may be driving the observed European ancestry association evidence.

Highlights

Esophageal adenocarcinoma (EAC) is the seventh leading cause of death in U.S males [1] and one of the deadliest cancers worldwide, with 5-year survival rates lower than 20% [2], and in the United States the incidence rate has increased dramatically up to 7-fold over the past three decades [3,4]
The converse analysis examining excess African ancestry found no genetic regions with significant excess African ancestry associated with Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC)
Because GWAS have not reported any variants in these two regions, low frequency and/or rare disease associated variants that confer susceptibility to developing BE and EAC may be driving the observed European ancestry association evidence

Summary

Introduction

Esophageal adenocarcinoma (EAC) is the seventh leading cause of death in U.S males [1] and one of the deadliest cancers worldwide, with 5-year survival rates lower than 20% [2], and in the United States the incidence rate has increased dramatically up to 7-fold over the past three decades [3,4]. EAC occurs at least five-fold more frequently in EAs than AAs [13], the distribution of known risk factors for BE and EAC (e.g. GERD [14], obesity [15,16], etc) are at least as common in AA as EA, suggesting another basis for the racial differences Hypothesizing that this racial/ethnical difference in prevalence might represent a genetic susceptibility, we used an admixture mapping approach to interrogate disease association with genetic differences in European and African ancestry using a multi-institutional sample of AA patients with EAC or BE. Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) are far more prevalent in European Americans than in African Americans Hypothesizing that this racial disparity in prevalence might represent a genetic susceptibility, we used an admixture mapping approach to interrogate disease association with genomic differences between European and African ancestry

Methods

Results

Conclusion