1. ¹Departments of Medicine and Surgery, Mount Sinai Hospital IBD Centre, University of Toronto, Toronto, Ontario, Canada
2. ²Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
3. ³Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
4. ⁴Department of Medicine, Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University, Johns Hopkins University School of Medicine, Baltimore, MD, USA
5. ⁵Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
6. ⁶University of Chicago, Chicago, IL, USA
7. ⁷Medical Genetics Institute, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA
8. ⁸Department of Health Studies, University of Chicago, Chicago, IL, USA
9. ⁹Department of Medicine, Université de Montréal, Montréal Heart Institute, Montréal, Québec, Canada
10. ¹⁰Centre for Human Genetic Research, Massachusetts General Hospital, Simches Research Center, Boston, MA, USA

Correspondence: Dr MJ Daly, Massachusetts General Hospital, Simches Research Center, CPZN-6818, 185 Cambridge St, Boston, MA 02114, USA. Tel: +1 617 643 3290; Fax: +1 617 643 3293; E-mail: mjdaly@chgr.mgh.harvard.edu

¹¹These authors contributed equally to this work.

Received 16 May 2006; Revised 7 September 2006; Accepted 8 September 2006; Published online 10 January 2007.

Abstract

Although the general association of the inflammatory bowel disease (IBD) 5 region on chromosome 5q31 to Crohn's disease (CD) has been replicated repeatedly, the identity of the precise causal variant within the region remains unknown. A recent report proposed polymorphisms in solute carrier family 22, member 4 (SLC22A4) organic cation transporter 1(OCTN1) and solute carrier family 22, member 5 (SLC22A5) (OCTN2) as responsible for the IBD5 association, but definitive, large-sample comparison of those polymorphisms with others known to be in strong linkage disequilibrium was not performed. We evaluated 1879 affected offspring and parents ascertained by a North American IBD Genetics Consortium for six IBD5 tag single nucleotide polymorphisms (SNPs) to evaluate association localization and ethnic and subphenotypic specificity. We confirm association to the IBD5 region (best SNP IGR2096a_1/rs12521868, P<0.0005) and show this association to be exclusive to the non-Jewish (NJ) population (P=0.00005) (risk allele undertransmitted in Ashkenazi Jews). Using Phase II HapMap data, we demonstrate that there are a set of polymorphisms, spanning genes from prolyl 4-hydroxylase (P4HA2) through interferon regulatory factor 1 (IRF1) with equivalent statistical evidence of association to the reported SLC22A4 variant and that each, by itself, could entirely explain the IBD5 association to CD. Additionally, the previously reported SLC22A5 SNP is rejected as the potential causal variant. No specificity of association was seen with respect to disease type and location, and a modest association to ulcerative colitis is also observed. We confirm the importance of IBD5 to CD susceptibility, demonstrate that the locus may play a role in NJ individuals only, and establish that IRF1, PDLIM, and P4HA2 may be equally as likely to contain the IBD5 causal variant as the OCTN genes.