Su1761 A Baz1a Haplotype With Ancient American Ancestry Contributes to IBD in Puerto Ricans

Abstract

Background: Over 160 genomic regions contribute to Inflammatory Bowel Disease (IBD) in populations with ancestry from continental Europe. Of these regions, we have reported the association of NOD2 and IL23R with Crohn's Disease (CD) in Puerto Rico. However, the Puerto Rican population also has genomic contribution from Sub-Saharan Africa and Ancient America, and thus further study of IBD in Puerto Rico provides the opportunity for locating susceptibility variants by trans-ethnic mapping and for finding new genes contributing to IBD susceptibility. Aim: To study the association between immune-related genes and CD and Ulcerative Colitis (UC) in Puerto Ricans Methods: 1159 Puerto Ricans (CD 406, UC 244, Indeterminate Colitis 5, controls 504) were recruited from the University of Puerto Rico IBD Center and community gastroenterology practices. Blood samples were obtained from each subject and DNA genotyped with the ImmunoChip (Illumina, San Diego, CA). 892 subjects from the Human Genome Diversity Panel (HGDP) were genotyped for estimation of global and local continental ancestry. Global continental ancestry of each subject from Puerto Rico was estimated using Admixture 1.2 and locus continental ancestry was estimated using Local Ancestry in adMixed Populations (LAMPLD). Both Admixture and LAMPLD analyses were trained using the HGDP. Association was tested using GWAF. Results: Mean global continental ancestry of the Puerto Rican subjects was found to be 12% Ancient American, 14% Sub-Saharan African, and 74% European. We estimated that the continental ancestry at the NOD2 locus was completely European in both cases and controls. Estimated ancestry at the IL23R locus was both Ancient American and European at the 5'-end of the gene but was completely European in both cases and controls in the 3'-region containing the R381Q SNP (rs11209026). We also observed suggestive evidence for the association of a haplotype in BAZ1A promoter with CD (rs1200332, MAF 0.45 in CD, 0.35 in controls, OR 1.5, p=2 x 10-6). The ancestry of this haplotype was Ancient American. Discussion: In Puerto Rico, haplotypes of NOD2 and IL23R are predominantly of European ancestry. Trans-ethnic mapping of IL23R may have localized susceptibility to the region surrounding R381Q. We also observed suggestive evidence for the association of a novel gene with CD, BAZ1A. This gene association may have been observed here because of its Ancient American ancestry. Available data have demonstrated altered expression of BAZ1A due to cellular response to lipopolysaccharide. Our observations show that the promise of genetic studies in non-European populations may be realized. This study was supported by NIDDK U01DK062413 and 8U54MD007587-03.