1. ¹The Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
2. ²Complex Genetics Section, DBG-Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
3. ³Université de Montreal and the Montreal Heart Institute/Institut de Cardiologie de Montreal, Montreal, Quebec, Canada

Correspondence: Professor C Wijmenga, Complex Genetics Section, Stratenum 2.117, DBG-Department of Biomedical Genetics, University Medical Centre Utrecht, PO Box 85060, 3508 AB Utrecht, The Netherlands. Tel: +31 30 253 8427; Fax: +31 30 253 8479; E-mail: t.n.wijmenga@med.uu.nl

⁴These authors have contributed equally to this work.

Received 14 December 2005; Revised 18 May 2006; Accepted 30 May 2006; Published online 12 July 2006.

Abstract

It is increasingly evident that different inflammatory disorders show some overlap in their pathological features, concurrence in families and individuals, and shared genetic factors. This might also be true for coeliac disease, a chronic inflammatory disorder of the gastrointestinal system, which shares two linkage regions with inflammatory bowel disease: on chromosome 5q31 (CELIAC2 and IBD5) and 19p13 (CELIAC4 and IBD6). We hypothesised that these regions contain genes that contribute to susceptibility to both disorders. The overlapping 5q31 region contains only five positional candidate genes, whereas the overlapping 19p13 region has 141 genes. As the common disease gene probably plays a role in inflammation, we selected five functional candidate genes from the 19p13 region. We studied these 10 positional and functional candidate genes in our Dutch coeliac disease cohort using 44 haplotype tagging single-nucleotide polymorphisms. Two genes from 19p13 showed a small effect on familial clustering: the cytochrome P450 F3 gene CYP4F3 (P_nominal 0.0375, odds ratio (OR) 1.77) and CYP4F2 (P_nominal 0.013, OR 1.33). CYP4F3 and CYP4F2 catalyse the inactivation of leukotriene B4 (LTB4), a potent mediator of inflammation responsible for recruitment and activation of neutrophils. The genetic association of LTB4-regulating gene variants connects the innate immune response of neutrophil mobilisation with that of the established Th1 adaptive immunity present in coeliac disease patients. The findings in coeliac disease need to be replicated. Expanding genetic association studies of these cytochrome genes to other inflammatory conditions should reveal whether their causative influence extends beyond coeliac disease.