Journal
GENES AND IMMUNITY
Volume 14, Issue 5, Pages 310-316Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gene.2013.19
Keywords
haplotype association; Ashkenazi Jewish; Crohn's disease; NF-kappa B signaling; synthetic association
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Funding
- National Institutes of Health [NIDDK U01 DK062429, U01 DK062422, R01 DK092235, RC1 DK086800, NIDDK F30 DK098927, NIGMS T32 GM007205, R01 DK77905]
- New York Crohn's Disease Foundation
- Crohn's and Colitis Foundation of America [KL2RR024138]
- Div Of Information & Intelligent Systems
- Direct For Computer & Info Scie & Enginr [845677] Funding Source: National Science Foundation
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The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn's disease (CD) compared with non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to CD etiology in this population, most notably at NOD2, in which three causal, uncommon and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes that showed significantly greater association to CD in the Ashkenazi Jewish population compared with a non-Jewish population (145 haplotypes and no haplotypes with P-value <10(-3), respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established CD loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-kappa B signaling. The BRD7 signal showed conditional dependence with only the downstream rare CD-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association.
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