2 research outputs found
Genetic Complexity of Crohn’s Disease in Two Large Ashkenazi Jewish Families
Background & Aims
Crohn’s disease (CD) is a highly heritable disease that is particularly common in the Ashkenazi Jewish population. We studied 2 large Ashkenazi Jewish families with a high prevalence of CD in an attempt to identify novel genetic risk variants.
Methods
Ashkenazi Jewish patients with CD and a positive family history were recruited from the University College London Hospital. We used genome-wide, single-nucleotide polymorphism data to assess the burden of common CD-associated risk variants and for linkage analysis. Exome sequencing was performed and rare variants that were predicted to be deleterious and were observed at a high frequency in cases were prioritized. We undertook within-family association analysis after imputation and assessed candidate variants for evidence of association with CD in an independent cohort of Ashkenazi Jewish individuals. We examined the effects of a variant in DUOX2 on hydrogen peroxide production in HEK293 cells.
Results
We identified 2 families (1 with >800 members and 1 with >200 members) containing 54 and 26 cases of CD or colitis, respectively. Both families had a significant enrichment of previously described common CD-associated risk variants. No genome-wide significant linkage was observed. Exome sequencing identified candidate variants, including a missense mutation in DUOX2 that impaired its function and a frameshift mutation in CSF2RB that was associated with CD in an independent cohort of Ashkenazi Jewish individuals.
Conclusions
In a study of 2 large Ashkenazi Jewish with multiple cases of CD, we found the genetic basis of the disease to be complex, with a role for common and rare genetic variants. We identified a frameshift mutation in CSF2RB that was replicated in an independent cohort. These findings show the value of family studies and the importance of the innate immune system in the pathogenesis of CD
Recommended from our members
High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis.
This is the author accepted manuscript. The final version is available from NPG at http://www.nature.com/ng/journal/v47/n2/full/ng.3176.html#acknowledgmentsGenome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.We would like to thank the International PSC study group (http://www.ipscsg.org/) for sharing data. We are grateful to B.A. Lie and K. Holm for helpful discussions. J.D.R. holds a Canada Research Chair, and this work was supported by a US National Institute of Diabetes and Digestive and Kidney Diseases grant (NIDDK; R01 DK064869 and U01 DK062432). The laboratory of A.F. is supported by the German Ministry of Education and Research (BMBF) grant program e:Med (sysINFLAME). A.F. receives infrastructure support from the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence 'Inflammation at Interfaces' and holds an endowment professorship (Peter Hans Hofschneider Professorship) of the Foundation for Experimental Biomedicine (Zurich, Switzerland). Grant support for T.H.K. and A.F. was received from the European Union Seventh Framework Programme (FP7/2007-2013, grant number 262055, ESGI). M.N.C. is supported by the Intramural Research Program of the US National Institutes of Health (NIH), Frederick National Laboratory, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. J.C.B. was supported by a Wellcome Trust grant (WT098051). D.M. and V.K. are supported by the NIHR Cambridge Biomedical Research Centre. L.P.S. is supported by an NIDDK grant (U01 DK062429-14). J.A.T. is supported by the UK Medical Research Council. D.P.B.M. is supported by the Leona M. and Harry B. Helmsley Charitable Trust, the European Union (305479) and by grants from the NIDDK (U01 DK062413, P01 DK046763-19, U54 DE023789-01), the National Institute of Allergy and Infectious Diseases (NIAID; U01 AI067068) and the Agency for Healthcare Research and Quality (AHRQ; HS021747). R.H.D. holds the Inflammatory Bowel Disease Genetic Research endowed chair at the University of Pittsburgh and was supported by an NIDDK grant (U01 DK062420) and a US National Cancer Institute grant (CA141743). S.L.H. and J.R.O. would like to also acknowledge the support of the US NIH (R01 NS049477 and 1U19 A1067152) and the National Multiple Sclerosis Society (RG 2899-D11). S.L. wishes to acknowledge support from the Australian National Health and Medical Research Council (R.D. Wright Career Development Fellowship, APP1053756)