title: Confirmation of multiple Crohn's disease susceptibility loci in a large Dutch-Belgian cohort.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands. R.K.Weersma@int.umcg.nl
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.forename: Pieter C F
authors.initials: PC
authors.lastname: Stokkers
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cleynen
authors.forename: Simone C S
authors.initials: SC
authors.lastname: Wolfkamp
authors.forename: Liesbet
authors.initials: L
authors.lastname: Henckaerts
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Gerard
authors.initials: G
authors.lastname: Dijkstra
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Ilja M
authors.initials: IM
authors.lastname: Nolte
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Séverine
authors.initials: S
authors.lastname: Vermeire
mesh_terms: D000071183:Autophagy-Related Proteins; D001530:Belgium; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics; D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics; D009426:Netherlands; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D044767:Ubiquitin-Protein Ligases
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; D018398:Homeodomain Proteins; C515500:IL23R protein, human; C104144:NELL1 protein, human; C534957:NKX2-3 protein, human; C429018:NOD2 protein, human; D009419:Nerve Tissue Proteins; D053473:Nod2 Signaling Adaptor Protein; D018123:Receptors, Interleukin; D014157:Transcription Factors; C118566:HERC2 protein, human; D044767:Ubiquitin-Protein Ligases; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D019204:GTP-Binding Proteins; C513539:IRGM protein, human