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Stratification by CARD15 variant genotype in a genome-wide search for inflammatory bowel disease susceptibility loci

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Abstract

Previously we have conducted a genome-wide search for inflammatory bowel disease susceptibility loci in a large European cohort. Results from this study demonstrated suggestive evidence of linkage to loci at chromosomes 1q, 6p, and 10p and replicated linkages on chromosomes 12 and 16. Recently, NOD2/CARD15 on chromosome 16q12 has been found to be strongly associated with Crohn's disease. In order to determine if there are other loci in the genome that interact with the three associated functional variants in CARD15 (R702W, G908R, 1007fs), we have stratified our large inflammatory bowel disease genome scan cohort by dividing pedigrees into two groups stratified by CARD15 variant genotype. The two pedigree groups were analysed using non-parametric allele sharing methods. The group of pedigrees that contained one of the three CARD15 variants had two suggestive linkage results occurring in 6p (lod = 3.06 at D6S197, IBD phenotype) and 10p (lod=2.29 at D10S197, CD phenotype). In addition, at 16q12 where CARD15 is located, the original genome scan had a peak lod score of 2.18 at D16S415 (CD phenotype). The stratified pedigree cohort containing one of three CARD15 variants had a peak lod score of 0.90 at D16S415 (CD phenotype), accounting for approximately less than half of the genetic evidence for linkage at this locus. This result is in agreement with the existence of a substantial number of private variants at the NOD2/CARD15 locus. Interaction with NOD2/CARD15 needs to be considered in future gene identification efforts on chromosomes 6 and 10.

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Acknowledgements

The authors thank the physicians, IBD patients and their families for participating in this study. The lead clinical investigators from the UK contributing to the patient collection: John Lennard-Jones, John Lee, Andrew MacPherson and Stephen Bridger are gratefully acknowledged. The cooperation of the German Crohn's and colits foundation (DCCV e. V.), Prof. Raedler (Hamburg), Prof. Kruis (Köln), Dr. Theuer (Heilbronn), Dr. Meckler (Gedern), Prof. Lochs, Dr. Wedel, T. Herrmann (Berlin), Dr. Herchenbach (Recklinghausen), Prof. Scheurlen (Würzburg), Dr. Demharter (Augsburg), Dr. Simon (Munich), Dr. Purrmann (Moers), Dr. Jessen (Kiel), Dr. Zehnter (Dortmund), Dr. Lübke, Dr. Weismüller (Koblenz), Dr. Eiche (Denkendorf, Dr. Schönfelder (Aachen), Prof. Fleig (Halle) (all in Germany), Dr. Wewalka (Linz), Dr. Knofloch (Wels) (both in Austria) and Dr. Hodgson, Dr. Sanderson, Dr. Pounder, Dr. Forbes, Dr. Forgacs (London), Dr. Bird (Maidstone), Dr. Hines (Haywards-Heath), Dr. Cairns, Dr. Ireland (Brighton), Dr. Barrison (St Albans) and Dr. Smith-Lang (Sidcup) (all in the UK) is gratefully acknowledged. The authors appreciate the many stimulating discussions and gracious support offered by Drs. Emtage, Daniels, Joslyn and further acknowledge the expert technical efforts of Jonalyn Matusalem, Larenia Pedriguez, Hye Jin Yang and Nancy Leysens. This work was supported by Axys Pharmaceuticals, DNA Sciences, the National Association for Colitis and Crohn's disease (UK), Crohn's in Childhood Research Association (UK), the Sir Halley Stewart Trust, the Deutsche Forschungsgemeinschaft, a competence network for inflammatory bowel disease, the German Human Genome project and the German National Genome Network.

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Author notes

  1. Sarah H. Shaw

    Present address: Illumina, 9885 Towne Centre Drive, San Diego, CA, 92121-1975, USA

  2. Ray White

    Present address: Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA, 94608, USA

Authors and Affiliations

  1. DNA Sciences, Fremont, California, USA

    Sarah H. Shaw, Ray White & Mark E. Curran

  2. First Medical Department, Christian-Albrechts-University, Kiel, Germany

    Jochen Hampe & Stefan Schreiber

  3. Division of Genetics and Development, Guy's, King's and St. Thomas' School of Medicine, London, UK

    Christopher G. Mathew

  4. Department of General Internal Medicine, Christian-Albrechts-University, Schittenhelmstrasse 12, 24105, Kiel, Germany

    Stefan Schreiber

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  1. Sarah H. Shaw
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Correspondence to Stefan Schreiber.

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Shaw, S.H., Hampe, J., White, R. et al. Stratification by CARD15 variant genotype in a genome-wide search for inflammatory bowel disease susceptibility loci. Hum Genet 113, 514–521 (2003). https://doi.org/10.1007/s00439-003-1020-7

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