Inflammatory Bowel Disease
Subject Category: Inflammatory Bowel Disease
Am J Gastroenterol 2009; 104: 630–638; doi:10.1038/ajg.2008.112; published online 27 January 2009
Confirmation of Multiple Crohn's Disease Susceptibility Loci in a Large Dutch–Belgian Cohort
Rinse K Weersma MD, PhD1, Pieter C F Stokkers MD, PhD2, Isabelle Cleynen MD, PhD3, Simone C S Wolfkamp MD2, Liesbet Henckaerts MD, PhD3, Stefan Schreiber MD, PhD4, Gerard Dijkstra MD, PhD1, Andre Franke PhD4, Ilja M Nolte PhD5, Paul Rutgeerts MD, PhD3, Cisca Wijmenga PhD6 and Séverine Vermeire MD, PhD3
- 1Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- 2Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands
- 3Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
- 4Institute for Clinical Molecular Biology, Christian-Albrechts University Kiel, Kiel, Germany
- 5Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- 6Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Correspondence: Rinse K. Weersma, MD, PhD, Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO Box 30001, Groningen 9700 RB, the Netherlands. E-mail: R.K.Weersma@int.umcg.nl
Received 24 June 2008; Accepted 1 October 2008; Published online 27 January 2009.
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.
