Confirmation of Multiple Crohn's Disease Susceptibility Loci in a Large Dutch–Belgian Cohort View Full Text


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Article Info

DATE

2009-01-27

AUTHORS

Rinse K Weersma, Pieter C F Stokkers, Isabelle Cleynen, Simone C S Wolfkamp, Liesbet Henckaerts, Stefan Schreiber, Gerard Dijkstra, Andre Franke, Ilja M Nolte, Paul Rutgeerts, Cisca Wijmenga, Séverine Vermeire

ABSTRACT

OBJECTIVES: Inflammatory bowel diseases (IBD)-Crohn's disease (CD) and ulcerative colitis (UC)-are chronic gastrointestinal inflammatory disorders with a complex genetic background. A genome-wide association scan by the Wellcome Trust Case Control Consortium (WTCCC) recently identified several novel susceptibility loci. METHODS: We performed a large replication study in 2,731 Dutch and Belgian IBD patients (1,656 CD and 1,075 UC) and 1,086 controls. In total, 40 single nucleotide polymorphisms (SNPs) that showed moderate or strong association in the WTCCC study, along with SNPs in the previously identified genes IL23R, ATG16L1, and NELL1, were studied. RESULTS: We confirmed the associations with IL23R (rs11209026, P=2.69E-12), ATG16L1 (rs2241880, P=4.82E-07), IRGM (rs4958847, P=2.26E-05), NKX2-3 (rs10883365, P=5.91E-06), 1q24 (rs12035082, P=1.51E-05), 5p13 (rs17234657, P=2.62E-05), and 10q21 (rs10761659, P=8.95E-04). We also identified associations with cyclin Y (CCNY; rs3936503, P=2.09 E-04) and Hect domain and RCC1-like domain 2 (HERC2; rs916977, P=1.12E-04). Pooling our data with the original WTCCC data substantiated these associations. Several SNPs were also moderately associated with UC. Two genetic risk profiles based on the number of risk alleles and based on a weighted score were created. On the basis of these results, we calculated sensitivities, specificities, positive and negative predictive values, and likelihood ratios for CD. CONCLUSIONS: We replicated genetic associations for CD with IL23R, ATG16L1, IRGM, NKX2-3, 1q24, 10q21, 5p13, and PTPN2 and report evidence for associations with HERC2 and CCNY. Pooling our data with the results of the WTCCC strengthened the results, suggesting genuine genetic associations. We show that a genetic risk profile can be constructed that is clinically useful and that can aid in making treatment decisions. More... »

PAGES

ajg2008112

References to SciGraph publications

  • 2007-06. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls in NATURE
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  • 2008-06-29. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease in NATURE GENETICS
  • 2004-04-11. Genetic variation in DLG5 is associated with inflammatory bowel disease in NATURE GENETICS
  • 1996-02. Mapping of a susceptibility locus for Crohn's disease on chromosome 16 in NATURE
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  • 2006-12-31. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1 in NATURE GENETICS
  • 2007-06-06. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility in NATURE GENETICS
  • 2007-04-15. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis in NATURE GENETICS
  • 2004-04-11. Functional variants of OCTN cation transporter genes are associated with Crohn disease in NATURE GENETICS
  • 2008-04-27. Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis in NATURE GENETICS
  • 2006-01-15. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies in NATURE GENETICS
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    http://scigraph.springernature.com/pub.10.1038/ajg.2008.112

    DOI

    http://dx.doi.org/10.1038/ajg.2008.112

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1014606926

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/19174780


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