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
Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States of America.
Division of Gastroenterology and Hepatology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America.
PLoS One. 2017 Oct 26;12(10):e0184962. doi: 10.1371/journal.pone.0184962. eCollection 2017.
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.
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.
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.
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.
巴雷特食管（BE）和食管腺癌（EAC）在欧裔美国人中的发病率远高于非裔美国人。假设这种患病率的种族差异可能代表一种遗传易感性，我们采用混合映射方法来探究疾病与欧洲和非洲血统之间基因组差异的关联。
通过查阅参与巴雷特食管转化研究网络（BETRNet）机构的外科病理数据库，从54名患有BE或EAC的非裔美国人中鉴定出福尔马林固定石蜡包埋样本。从正常组织中提取DNA，并在Illumina OmniQuad SNP芯片上进行基因分型。对所有54例病例的数据以及28例基因分型质量高的病例子集进行仅病例混合映射分析。使用Beagle 3.3.2推断单倍型相位，使用SABER plus推断局部非洲和欧洲血统。通过估计和测试欧洲血统过量并将其与非洲血统过量进行对比来检验疾病关联。
54例病例和28例病例这两个数据集均鉴定出两个混合区域。11号染色体短臂上欧洲血统过量的关联达到全基因组5%的显著性阈值，对应-log10（P）=4.28。8号染色体长臂上的第二个峰值达到-log10（P）=2.73。检查非洲血统过量的反向分析未发现与BE和EAC相关的具有显著过量非洲血统的遗传区域。平均而言，8号染色体长臂和11号染色体短臂上的区域分别显示欧洲血统过量15%和20%。
在患有BE和EAC的非裔美国人中，11号染色体短臂15区和8号染色体长臂22 - 24区与欧洲血统过量相关。由于全基因组关联研究（GWAS）尚未报道这两个区域的任何变异，可能是赋予BE和EAC易感性的低频和/或罕见疾病相关变异推动了观察到的欧洲血统关联证据。
