Abstract
Evidence from four independent linkage studies and two meta-analyses of genome-wide data support the existence of a locus conferring susceptibility to inflammatory bowel diseases (IBD) in chromosomal region 19p. Identification of a susceptibility allele in this ∼28.5 Mb region with over 600 genes is a formidable task. To tackle this problem, we undertook two approaches: (1) haplotype-based candidate-gene screen, and (2) evaluation of previously reported associations. For the former, we selected genes with potential implication in IBD pathogenesis based on published functional and expression data, typed SNPs, constructed haplotypes, screened for association in 180 IBD trios, and followed up preliminary associations in 343 IBD patients and 207 control individuals. Overall, we analyzed 465 SNPs, and 260 haplotypes distributed across 56 candidate genes. We found suggestive evidence of association (nominal P<0.01) with four genes (C3, FCER2, IL12RB1, and CRLF1) in a screening stage, but were unable to confirm these preliminary observations at follow-up. In the second approach, we typed four nonsynonymous polymorphisms in genes C3 (R102G and L314P) and ICAM1 (G241R and K469E) in four independent cohorts totaling 2178 IBD cases. We evaluated these data together with previously published reports for three of these variants (C3-Gly102, ICAM1-Arg241, and ICAM1-Glu469), in a meta-analysis. Our pooled meta-analysis provides compelling evidence against association of these variants with disease. Overall, we performed the most comprehensive candidate-gene association study for IBD to date. The information hereby generated constitutes a valuable resource to investigate other common genetic immune diseases, such as celiac disease.
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Acknowledgements
We thank the IBD patients and their families for their collaboration. We also extend our thanks to Tanja Wesse (Christian-Albrechts-University, Kiel, Germany) for technical assistance, and members of the Inflammatory Disease Research Group (The Broad Institute, Cambridge, USA) for helpful discussions. This study was supported by a research fellowship from the Crohn's and Colitis Foundation of America to MKT, the German Federal Department of Research and Education through the German National Genome Research Network (NGFN2) and the German Research Council (research group polygenic diseases; DFGFOR423) to SS, the Italian Health Minister (RC0503GA22) to VA, and grants from the NIH/NIDDK and The Broad Foundation to JDR.
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Tello-Ruiz, M., Curley, C., DelMonte, T. et al. Haplotype-based association analysis of 56 functional candidate genes in the IBD6 locus on chromosome 19. Eur J Hum Genet 14, 780–790 (2006). https://doi.org/10.1038/sj.ejhg.5201612
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DOI: https://doi.org/10.1038/sj.ejhg.5201612
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