Confirmation of multiple Crohn's disease susceptibility loci in a large Dutch-Belgian cohort.
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.
Weersma
Rinse K
RK
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands. R.K.Weersma@int.umcg.nl
Stokkers
Pieter C F
PC
Cleynen
Isabelle
I
Wolfkamp
Simone C S
SC
Henckaerts
Liesbet
L
Schreiber
Stefan
S
Dijkstra
Gerard
G
Franke
Andre
A
Nolte
Ilja M
IM
Rutgeerts
Paul
P
Wijmenga
Cisca
C
Vermeire
Séverine
S
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
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