The two common inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are chronic relapsing, remitting conditions of the gastrointestinal tract. Association studies have identified a number of susceptibility genes for both diseases, implicating both adaptive and innate immunity in response to intestinal microbes and, for CD, the autophagy pathway in disease susceptibility. As with virtually all autoimmune and inflammatory disease, allelic variation at the HLA class I and class II loci has been associated with both UC and CD. Based on our previous work, the association of specific HLA haplotypes (eg. DRB1*0103-DQB1*0301) is particularly strong and, based on our recent GWAS, the strongest SNP association is with particular clinical subtypes (eg. medically refractory UC). The contribution of the natural killer cells (NK) in innate immunity to the risk of IBD has not been as well examined. NK cells are controlled by several gene families that encode cell surface receptors. The stimulatory and/or inhibitory KIR receptors use polymorphic epitopes on HLA class I as their cognate ligands. In a recent study of CD, we found inhibitory KIR heterozygotes (KIR2DL2/KIR2DL3) significantly associated with protection in the absence of their HLA ligand (CI), and predisposing in the presence of CI ligand homozygosity. We propose to expand this work by examining the role of HLA and KIR alleles, haplotypes and KIR gene-HLA ligand pairs with clinically well-defined CD and UC cohorts of Caucasian and Hispanic-Puerto Rican ancestry. We will use our newly developed Roche 454 GS FLX sequencing system for allelic HLA resolution, and will finish development and validation on our KIR (16 gene) 454 assays to sequence both gene complexes in our cohorts. Caucasian (1300 patients/550 controls and 100 family trios) and Puerto Rican (300 patients/200 controls) CD cohorts, and Caucasian (300 patients with medically refractory disease/550 controls) and Puerto Rican (200 patients/200 controls) UC cohorts will be examined. We will also develop bioinformatic tools to deal with the complex analysis of the highly polymorphic HLA and KIR genes, and make these data management and analysis tools available through NIAID's ImmPort in partnership with BISC.

Public Health Relevance

Ulcerative colitis and Crohn's disease are serious and common inflammatory diseases, involving adaptive and innate immunity and requiring long term and expensive health care. A deeper understanding of the role of HLA and KIR polymorphism in these diseases and in specific clinical subtypes of UC and CD may prove clinically valuable in patient stratification for choice of therapy;patients whose genotype indicates a more severe and rapid disease course may benefit from more aggressive therapy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAI1-MFH-I (M3))
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Rice, Jeffrey S
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Children's Hospital & Res Ctr at Oakland
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Kopylov, Uri; Boucher, Gabrielle; Waterman, Matti et al. (2016) Genetic Predictors of Benign Course of Ulcerative Colitis-A North American Inflammatory Bowel Disease Genetics Consortium Study. Inflamm Bowel Dis 22:2311-6
Milius, Robert P; Heuer, Michael; George, Mike et al. (2016) The GL service: Web service to exchange GL string encoded HLA & KIR genotypes with complete and accurate allele and genotype ambiguity. Hum Immunol 77:249-56
Li, Dalin; Achkar, Jean-Paul; Haritunians, Talin et al. (2016) A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition. Gastroenterology 151:724-32
Rivas, Manuel A; Graham, Daniel; Sulem, Patrick et al. (2016) A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. Nat Commun 7:12342
Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke et al. (2016) Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study. Lancet 387:156-67
Pappas, Derek J; Marin, Wesley; Hollenbach, Jill A et al. (2016) Bridging ImmunoGenomic Data Analysis Workflow Gaps (BIGDAWG): An integrated case-control analysis pipeline. Hum Immunol 77:283-7
Chu, Hiutung; Khosravi, Arya; Kusumawardhani, Indah P et al. (2016) Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 352:1116-20
Osoegawa, Kazutoyo; Mack, Steven J; Udell, Julia et al. (2016) HLA Haplotype Validator for quality assessments of HLA typing. Hum Immunol 77:273-82
Guerrerio, Anthony L; Frischmeyer-Guerrerio, Pamela A; Huang, Chengrui et al. (2016) Increased Prevalence of Inflammatory Bowel Disease in Patients with Mutations in Genes Encoding the Receptor Subunits for TGFβ. Inflamm Bowel Dis 22:2058-62
Chuang, Ling-Shiang; Villaverde, Nicole; Hui, Ken Y et al. (2016) A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF. Gastroenterology 151:710-723.e2

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