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

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

Background:
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:
Formalin 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.

Results:
Both 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.

Conclusions:
Chromosomal 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.

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Academic Units
Medicine
Published Here
February 8, 2018
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