Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4.
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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DOI：
10.1371/journal.pgen.0030058
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发表时间：
2007-04-20
期刊：
影响因子：
4.5
通讯作者：
Georges M
中科院分区：
文献类型：
--
作者：
Libioulle C;Louis E;Hansoul S;Sandor C;Farnir F;Franchimont D;Vermeire S;Dewit O;de Vos M;Dixon A;Demarche B;Gut I;Heath S;Foglio M;Liang L;Laukens D;Mni M;Zelenika D;Van Gossum A;Rutgeerts P;Belaiche J;Lathrop M;Georges M
为了确定克罗恩病（CD）的新型易感性位置，我们进行了一项全基因组关联研究，其中超过300,000个SNP在547例患者和928例中，我们发现了三个染色体区域。在10-6和10-9之间。与CD相关的是，发现250-KB的5p13.1染色体包含多个具有疾病关联的标记（包括四个标记，P <10-7）通过研究1,266名CD患者，559例其他对照和428个三重奏（P <4×10-4）。使用复制数据，相关的等位基因过度转移以影响后代（p <0.05），从而证实了5p13.1的基因座有助于CD敏感性分析支持具有多种疾病敏感性的多种变体。 1.25-MB基因沙漠。该基因座与疾病风险相关的遗传变异可以调节PTGER4的顺式作用调节元件。
对许多常见疾病的敏感性是由环境和遗传因素的组合确定的SNP基因分型技术允许对整个基因组进行系统的关联扫描，以检测新的敏感性局部。克罗恩病影响了发达国家中估计的0.15％的人，并在5号染色体上确定了新型的易感性基因座。新颖的5p13.1基因座的独特特征是它与1.25-MB的基因沙漠相吻合证据表明，该基因座的遗传变异会影响最接近的基因PTGER4，位于270 kb的范围内，ptger4编码了前列腺素受体EP4，是克罗恩病的强大候选易感基因，因为PTGER4敲除小鼠对结肠炎的敏感性增加。
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. 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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