Recently, a North American genome-wide association study identified three novel gene variants inPHOX2B, NCF4,andFAM92Bas well as one single nucleotide polymorphisms (SNP; rs224136) in the intergenic region on chromosome 10q21.1 as being associated with Crohn's disease (CD). However, their influence on European CD patients as well as ulcerative colitis (UC) is unknown. Therefore we aimed to replicate these novel CD susceptibility variants in a large European cohort with inflammatory bowel disease and analyzed potential gene-gene interactions with variants in theNOD2/CARD15, IL23R,andATG16L1genes.
Genomic DNA from 2,833 Caucasian individuals including 854 patients with CD, 476 patients with UC, and 1,503 healthy unrelated controls was analyzed for SNPs inPHOX2B(rs16853571),NCF4(rs4821544), andFAM92B(rs8050910), including rs224136 on chromosome 10q21.1.
In our study population, no association ofPHOX2B(P=0.563),NCF4(P=0.506),FAM92B(P=0.401), and rs224136 (P=0.363) with CD was found. Similarly, none of these SNPs was associated with UC. In contrast, all analyzed SNPs inNOD2/CARD15, IL23R,andATG16L1were strongly associated with CD withPvalues ranging from 5.0×10−3 to 1.6×10−22, but there was no epistasis with polymorphisms inPHOX2B, NCF4, FAM92B,and rs224136.
In contrast to the North American population,PHOX2B, NCF4, FAM92B,and rs224136 are not associated with CD in the European population, whereasNOD2/CARD15, IL23R,andATG16L1are strongly associated with CD in both the North American and European populations, confirming these three genes as major CD susceptibility genes in Caucasian populations.
1Department of Medicine II, Grosshadern, University of Munich, Munich, Germany; 2Clinic for Preventive Dentistry and Parodontology, University of Munich, Munich, Germany; 3Department of Pediatrics, Hannover Medical School, Hannover, Germany; 4Department of Internal Medicine, Knappschaftskrankenhaus Dortmund, Dortmund, Germany; 5Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany; 6Department of General Internal Medicine, Inselspital Bern, Bern, Switzerland; 7Department of Surgery, University of Munich (Innenstadt), Munich, Germany; 8Institute of Clinical Chemistry, Grosshadern, University of Munich, Munich, Germany; 9Max Planck Institute of Psychiatry, Munich, Germany. 10These authors contributed equally to this work.
Correspondence: Stephan Brand, MD, Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, D-81377 Munich, Germany.
Received 26 April 2008; accepted 10 September 2008
published online 3 February 2009