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- Title
Novel Crohn Disease Locus Identified by Genome-Wide Association Maps to a Gene Desert on 5p13.1 and Modulates Expression of PTGER4.
- Authors
Libioulle, Cécile; Louis, Edouard; Hansoul, Sarah; Sandor, Cynthia; Farnir, Frédéric; Franchimont, Denis; Vermeire, Séverine; Dewit, Olivier; De Vos, Martine; Dixon, Anna; Demarche, Bruno; Gut, Ivo; Heath, Simon; Foglio, Mario; Liming Liang; Laukens, Debby; Mni, Myriam; Zelenika, Diana; Van Gossum, André; Rutgeerts, Paul
- Abstract
To identify novel susceptibility loci for Crohn disease (CD), we undertook a genome-wide association study with more than 300,000 SNPs characterized in 547 patients and 928 controls. We found three chromosome regions that provided evidence of disease association with p-values between 10-6 and 10-9. Two of these (IL23R on Chromosome 1 and CARD15 on Chromosome 16) correspond to genes previously reported to be associated with CD. In addition, a 250-kb region of Chromosome 5p13.1 was found to contain multiple markers with strongly suggestive evidence of disease association (including four markers with p < 10-7). We replicated the results for 5p13.1 by studying 1,266 additional CD patients, 559 additional controls, and 428 trios. Significant evidence of association (p < 4X10-4) was found in case/ control comparisons with the replication data, while associated alleles were over-transmitted to affected offspring (p < 0.05), thus confirming that the 5p13.1 locus contributes to CD susceptibility. The CD-associated 250-kb region was saturated with 111 SNP markers. Haplotype analysis supports a complex locus architecture with multiple variants contributing to disease susceptibility. The novel 5p13.1 CD locus is contained within a 1.25-Mb gene desert. We present evidence that disease-associated alleles correlate with quantitative expression levels of the prostaglandin receptor EP4, PTGER4, the gene that resides closest to the associated region. Our results identify a major new susceptibility locus for CD, and suggest that genetic variants associated with disease risk at this locus could modulate cis-acting regulatory elements of PTGER4.
- Subjects
DISEASE susceptibility; CROHN'S disease; CHROMOSOMES; PROSTAGLANDINS; DISEASE risk factors
- Publication
PLoS Genetics, 2007, Vol 3, Issue 4, pe58
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.0030058