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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI067068-11
Application #
8707311
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Rice, Jeffrey S
Project Start
2005-09-20
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
Clerc, Florent; Novokmet, Mislav; Dotz, Viktoria et al. (2018) Plasma N-Glycan Signatures Are Associated With Features of Inflammatory Bowel Diseases. Gastroenterology 155:829-843
Šimurina, Mirna; de Haan, Noortje; Vu?kovi?, Frano et al. (2018) Glycosylation of Immunoglobulin G Associates With Clinical Features of Inflammatory Bowel Diseases. Gastroenterology 154:1320-1333.e10
Mack, Steven J; Udell, Julia; Cohen, Franziska et al. (2018) High resolution HLA analysis reveals independent class I haplotypes and amino-acid motifs protective for multiple sclerosis. Genes Immun :
Pappas, D J; Lizee, A; Paunic, V et al. (2018) Significant variation between SNP-based HLA imputations in diverse populations: the last mile is the hardest. Pharmacogenomics J 18:367-376
Hui, Ken Y; Fernandez-Hernandez, Heriberto; Hu, Jianzhong et al. (2018) Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Sci Transl Med 10:
Misra, Ravi; Arebi, Naila (2017) Re: Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease. Gastroenterology 152:2082-2083
Gonsky, Rivkah; Fleshner, Phillip; Deem, Richard L et al. (2017) Association of Ribonuclease T2 Gene Polymorphisms With Decreased Expression and Clinical Characteristics of Severity in Crohn's Disease. Gastroenterology 153:219-232
Huang, Hailiang; Fang, Ming; Jostins, Luke et al. (2017) Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 547:173-178
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

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