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Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 × 10−8 and 6.95 × 10−8, respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 × 10−8; OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.

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Figure 1: Linkage disequilibrium (D) between SNPs at the 20q13 locus in the control cohort together with the corresponding Haploview gene track.
Figure 2: Colonic TNFRSF6B expression and serum DCR3 concentration.

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Acknowledgements

We would like to thank all participating subjects and families. We thank M. Garris, K. Thomas, A. Albano, E. Dabaghyan, K. Fain, W. Glaberson, K. Harden, A. Hill, C. Johnson-Honesty, L. McCleery, K. Lake, R. Bezold, A. Ryan, A. Thomas, A. Latiano and R. Skraban for their expert assistance with DNA processing, genotyping, RNA preparation, DCR3 ELISA, data collection or study management. We thank A. Rutherford and J. Nebel for study coordination. We also thank S. Kristinsson, L. Arni Hermannsson and A. Krisbjörnsson of Raförninn ehf for their extensive software design and informatics contribution. This research was financially supported by US National Institutes of Health grant (K23RR016111), Crohn's & Colitis Foundation of America (CCFA), The Koss foundation, the NIH General Clinical Research Center of the Medical College of Wisconsin (S.K.), NIH grant R01 DK058259, the CCFA (L.D.), the Primary Children's Medical Center Foundation, K23DK069513, M01-RR00064, C06-RR11234 from the National Center for Research Resources (S.L.G.), the Edmunds Fund, the Heineman Foundation, the IBD Family Research Council (R.B.), a Research Development Award from the Cotswold Foundation (H.H. and S.F.A.G.) and a CTSA award, UL1-RR024134-03 (H.H.). Colon microarray experiments were performed and analyzed in the Microarray and Bioinformatics Cores of the NIH-supported Cincinnati Children's Hospital Research Foundation Digestive Health Center (1P30DK078392-01). H. Xu of the Bioinformatics Core assisted with analysis of the microarray experiments. All genotyping and other aspects of the study were funded by an Institute Development Award (H.H., S.F.A.G.) from the Children's Hospital of Philadelphia. We thank the members of the International HapMap and Wellcome Trust Case Control Consortiums for publicly providing valuable data, which were crucial for part of our analyses.

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Contributions

S.K., R.N.B. and H.H. designed the study and H.H. supervised the genotyping data analysis and interpretation. L.A.D. designed and supervised the microarray and ELISA experiments, data analysis and interpretation. J.P.B., P.M.A.S. and S.F.A.G. conducted the statistical analyses. S.K., R.N.B., S.L.G., S.C., G.T., V.A. and L.A.D recruited the individuals with IBD and performed all phenotyping. C.E.K. and E.C.F. directed the genotyping in a team consisting of J.T.G., J.L.S., R.M.S. and F.G.O. J.P.B., M.I., K.A., J.T.G., A.W.E. and E.S. provided bioinformatics support. The remaining authors coordinated the studies. S.K., R.N.B., S.L.G., L.A.D., S.F.A.G. and H.H. wrote the manuscript.

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Correspondence to Hakon Hakonarson.

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Supplementary Methods, Supplementary Tables 1–3, Supplementary Figures 1 and 2 (PDF 366 kb)

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Kugathasan, S., Baldassano, R., Bradfield, J. et al. Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat Genet 40, 1211–1215 (2008). https://doi.org/10.1038/ng.203

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