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      Novel Crohn Disease Locus Identified by Genome-Wide Association Maps to a Gene Desert on 5p13.1 and Modulates Expression of PTGER4

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          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 < 4 × 10 −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.

          Author Summary

          Individual susceptibility to many common diseases is determined by a combination of environmental and genetic factors. Identifying these genetic risk factors is one of the most important objectives of modern medical genetics, as it paves the way towards personalized medicine and drug target identification. Recent advances in SNP genotyping technology allows systematic association scanning of the entire genome for the detection of novel susceptibility loci. We herein apply this approach to Crohn disease, which afflicts an estimated 0.15% of the people in the developed world and identify a novel susceptibility locus on Chromosome 5. A unique feature of the novel 5p13.1 locus is that it coincides with a 1.25-Mb gene desert. We present evidence that genetic variants at this locus influence the expression levels of the closest gene, PTGER4, located 270 kb away, in the direction of the centromere. PTGER4 encodes the prostaglandin receptor EP4 and is a strong candidate susceptibility gene for Crohn disease as PTGER4 knock-out mice have increased susceptibility to colitis.

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          Most cited references13

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          Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

          Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
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            Interspersed repeats and other mementos of transposable elements in mammalian genomes.

            Arian Smit (1999)
            The bulk of the human genome is ultimately derived from transposable elements. Observations in the past year lead to some new and surprising ideas on functions and consequences of these elements and their remnants in our genome. The many new examples of human genes derived from single transposon insertions highlight the large contribution of selfish DNA to genomic evolution.
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              Oligonucleotide probe arrays have enabled massively parallel analysis of gene expression levels from a single cDNA sample. Application of microarray technology to analyzing genomic DNA has been stymied by the sequence complexity of the entire human genome. A robust, single base-resolution direct genomic assay would extend the reach of microarray technology. We developed an array-based whole-genome genotyping assay that does not require PCR and enables effectively unlimited multiplexing. The assay achieves a high signal-to-noise ratio by combining specific hybridization of picomolar concentrations of whole genome-amplified DNA to arrayed probes with allele-specific primer extension and signal amplification. As proof of principle, we genotyped several hundred previously characterized SNPs. The conversion rate, call rate and accuracy were comparable to those of high-performance PCR-based genotyping assays.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                pgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                April 2007
                20 April 2007
                5 March 2007
                : 3
                : 4
                : e58
                Affiliations
                [1 ] Unit of Animal Genomics, GIGA-R and Faculty of Veterinary Medicine, University of Liège, Liège, Belgium
                [2 ] Unit of Hepatology and Gastroenterology, Department of Clinical Sciences, GIGA-R, Faculty of Medicine, and CHU de Liège, University of Liège, Liège, Belgium
                [3 ] Department of Gastroenterology, Erasmus Hospital, Free University of Brussels, Brussels, Belgium
                [4 ] Department of Gastroenterology, University Hospital Leuven, Leuven, Belgium
                [5 ] Department of Gastroenterology, Clinique Universitaire St Luc, UCL, Brussels, Belgium
                [6 ] Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium
                [7 ] National Heart and Lung Institute, Imperial College London, England
                [8 ] Unit of Bioinformatics, GIGA-R and Institut Montefiore, University of Liège, Liège, Belgium
                [9 ] Centre National de Génotypage, Evry, France
                [10 ] Centre for Statistical Genetics, Department of Biostatistics, Ann Arbor, Michigan, United States
                University of Oxford, United Kingdom
                Author notes
                * To whom correspondence should be addressed. E-mail: michel.georges@ 123456ulg.ac.be
                Article
                07-PLGE-RA-0108R2 plge-03-04-10
                10.1371/journal.pgen.0030058
                1853118
                17447842
                31bf6bb6-999e-4cfc-9080-01c350ec3d5a
                Copyright: © 2007 Libioulle et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 15 February 2007
                : 27 February 2007
                Page count
                Pages: 6
                Categories
                Research Article
                Genetics and Genomics
                Homo (Human)
                Custom metadata
                Libioulle C, Louis E, Hansoul S, Sandor C, Farnir F, et al. (2007) Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet 3(4): e58. doi: 10.1371/journal.pgen.0030058

                Genetics
                Genetics

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