During the last cycle of this Program Project (PPG), genome-wide association study (GWAS) technology has created a revolution in complex genetics. We have contributed to many of the collaborations that have identified lists of susceptibility genes for common genetic traits, including specifically Crohn's disease (CD) and ulcerative colitis (UC). As is now well-known, Identification of a susceptibility gene provides clues, not only to variation within the identified gene, but also to additional genes and gene-gene Interactions that are pathway-related. Thus, as the GWAS revolution moved forward during the last cycle, we expanded our study of the genetics of IBD-related Immuno-phenotypes into two directions using haplotype-based analyses: (1) testing the role of GWAS-identlfied genes, and (2) testing genes In the same pathway as GWAS-identified loci. Furthermore, we have laid a foundation for this present cycle by completing a GWAS on over 1000 CD and over 900 UC subjects, with well-characterized clinical phenotypes and antibody expression data for ANCA, ASCA, anti-CBir1, anti-I2, and anti-OmpC (i.e. IBD Immuno-phenotypes) (with Project 2, 3 and Core B). As this PPG has demonstrated, these immuno-phenotypes are heritable and associated with IBD severity. We therefore propose a GWAS-identified pathway approach for unraveling the genetic contribution to the immuno-phenotypes and thus for clinical course and response to therapies. Given our preliminary data, we hypothesize that combinations of genetic variation in multiple genes in the Tcell receptor activation pathway are related to differences in both immuno-phenotypes and in disease course (i.e. IBD severity), and that this can be established in a pathway-directed two-stage study design. With the goal of identifying genes that contribute to immuno-phenotypes and thus IBD severity, we propose 3 Specific Aims:
Aim 1 - genotyping 4608 haplotype tagged and functional SNPs in a 2600 member discovery cohort;
Aim 2 - genotyping 2304 SNPs in a 3400 member confirmation cohort along with trans-ethnic mapping;
and Aim 3 - testing association with clinical features. This project will interact with the other projects (Projects 2 - 5) of the PPG by collaborating in the genetic aspects of their Aims.

Public Health Relevance

It is becoming appreciated that realizing personalized medicine will include the development of models and tests that predict disease onset clinical course, disease natural history, and response to various therapies. Because of the relationship between immunophenotypes and IBD disease severity, unraveling the genetic contribution to immuno-phenotypes will reveal genetic variation related to clinical course and treatment and therefore contribute to the translational use of genetic information to IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK046763-21
Application #
8566146
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O1))
Project Start
1997-09-30
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
21
Fiscal Year
2012
Total Cost
$204,912
Indirect Cost
$6,838
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Brant, Steven R; Okou, David T; Simpson, Claire L et al. (2017) Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease. Gastroenterology 152:206-217.e2
Volkmann, Elizabeth R; Hoffmann-Vold, Anna-Maria; Chang, Yu-Ling et al. (2017) Systemic sclerosis is associated with specific alterations in gastrointestinal microbiota in two independent cohorts. BMJ Open Gastroenterol 4:e000134
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
Schwerd, T; Bryant, R V; Pandey, S et al. (2017) NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease. Mucosal Immunol :
Zhang, Hong; Zheng, Libo; McGovern, Dermot P B et al. (2017) Myeloid ATG16L1 Facilitates Host-Bacteria Interactions in Maintaining Intestinal Homeostasis. J Immunol 198:2133-2146
Xu, Chunlan; Ghali, Sally; Wang, Jiani et al. (2017) CSA13 inhibits colitis-associated intestinal fibrosis via a formyl peptide receptor like-1 mediated HMG-CoA reductase pathway. Sci Rep 7:16351
Zhang, Hong; Zheng, Libo; Chen, Jeremy et al. (2017) The protection role of Atg16l1 in CD11c+dendritic cells in murine colitis. Immunobiology 222:831-841
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
Hoang-Yen Tran, D; Hoang-Ngoc Tran, D; Mattai, S A et al. (2016) Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor. Int J Obes (Lond) 40:1424-34
van der Gracht, Esmé; Zahner, Sonja; Kronenberg, Mitchell (2016) When Insult Is Added to Injury: Cross Talk between ILCs and Intestinal Epithelium in IBD. Mediators Inflamm 2016:9765238

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