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Human Molecular Genetics Advance Access published online on July 5, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm169
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Investigation of NOD1/CARD4 variation in Inflammatory Bowel Disease using a haplotype-tagging strategy

Johan Van Limbergen1,2, Elaine R Nimmo1, Richard K Russell2, Hazel E Drummond1, Linda Smith1, Niall H Anderson3, Gail Davies1, Ian D Arnott1, David C Wilson2,4 and Jack Satsangi1,*

1 Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom 2 Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom 3 Public Health Sciences, University of Edinburgh, Edinburgh, United Kingdom 4 Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom

* Corresponding author: Professor Jack Satsangi, Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh - United Kingdom, EH4 2XU, Phone: 00 44 131 651 1807, Fax: 00 44 131 651 1085, E-mail: J.Satsangi{at}ed.ac.uk

Received April 6, 2007; Revised June 28, 2007; Accepted June 28, 2007

Both NOD1/CARD4 and NOD2/CARD15 are intracellular pattern-recognition receptors involved in the innate immune response. Germline NOD2/CARD15 variation has a definite effect on susceptibility to Crohn's disease (CD) and phenotype although this contribution is weak in Scotland and Scandinavia. The NOD1/CARD4 gene lies within the putative inflammatory bowel disease (IBD) locus at 7p14.3. We have assessed in detail the influence of germline NOD1/CARD4 variation on IBD susceptibility and phenotype in the Scottish population. 2296 subjects, including 356 children with IBD, were involved in parallel case-control and family-based association studies. Nine tagging Single Nucleotide Polymorphisms (SNPs) were selected based on HapMap data spanning the whole of the NOD1/CARD4 gene. Our case-control SNP analysis was powered to detect an effect size with OR 1.5 for IBD and OR 1.6 for CD. No significant associations were observed between any of nine NOD1/CARD4 SNPs studied and IBD, CD or Ulcerative Colitis (UC) (p>0.05 for all). Haplotype case-control analysis was also negative (p>0.05 in IBD, CD and UC). Multimarker TDT analysis was negative (p>0.05 in IBD, CD and UC). NOD2/CARD15 variant carriage had no influence on NOD1/CARD4 effect on IBD susceptibility. The present study represents the first application of a gene wide haplotype-tagging approach to assess in detail the contribution of NOD1/CARD4 in IBD. Common germline NOD1/CARD4 variation does not represent an important determinant of disease susceptibility in our high-incidence population.


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