Department of Medicine II-Grosshadern, University of Munich, Munich, Germany.
PLoS One. 2012;7(12):e52873. doi: 10.1371/journal.pone.0052873. Epub 2012 Dec 27.
Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes.
METHODOLOGY/PRINCIPAL FINDINGS: A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10⁻⁵; 0.76 [0.67-0.87]) and of rs7720838 (p = 6.91×10⁻⁴; 0.81 [0.71-0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10⁻⁷ for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD.
CONCLUSIONS/SIGNIFICANCE: We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility.
全基因组关联研究发现，5p13.1 上的一个 PTGER4 表达调节区域是克罗恩病（CD）易感区域。本研究旨在对炎症性肠病（IBD）的大样本患者进行此项关联研究，并阐明与其他 IBD 基因的基因型和表型相互作用。
方法/主要发现：共对 7073 例患者和对照者进行了基因分型：844 例 CD、471 例溃疡性结肠炎和 1488 例对照者分析了染色体 5p13.1 上的单核苷酸多态性（SNP）rs4495224 和 rs7720838。该研究包括北美（CD：n=684；对照者：n=1440）和德国来源（CD：n=1098；对照者：n=1048）的两个复制队列。进行了基因型-表型、上位性和转录因子结合分析。在发现队列中，rs4495224（p=4.10×10⁻⁵；0.76[0.67-0.87]）和 rs7720838（p=6.91×10⁻⁴；0.81[0.71-0.91]）与 CD 易感性相关。这些关联在两个复制队列中得到了证实。体内分析预测 rs4495224 和 rs7720838 是转录因子 NF-κB 和 XBP1 结合位点的重要组成部分，CD 风险等位基因携带者的结合评分更高，为这些 SNP 如何增加 PTGER4 表达提供了解释。PTGER4 SNP 与 IBD 表型无关联。在发现队列中，5p13.1 与 ATG16L1 之间的上位性检测到 CD 易感性（rs7720838 和 rs2241880 的 p=5.99×10⁻⁷），但在两个复制队列中均未得到复制，这表明该基因-基因相互作用在 CD 易感性中不起主要作用。
结论/意义：我们证实了 5p13.1 是 CD 的主要易感位点，并通过体内分析证实 rs4495224 和 rs7720838 是 NF-κB 和 XBP1 结合位点的一部分。需要进一步的功能研究来证实我们体内分析的结果，并分析 PTGER4 表达的变化是否调节 CD 的易感性。
