Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Slomškov Trg 15, 2000 Maribor, Slovenia.
J Gastroenterol. 2011 Sep;46(9):1081-91. doi: 10.1007/s00535-011-0426-6. Epub 2011 Jun 22.
The IBD5 locus (OMIM ID 606348) on chromosome 5 was suggested to be one of the most important genetic factors involved in the pathogenesis of inflammatory bowel diseases (IBDs). However the main contributor from this region is still unknown.
We investigated the possible association of the IBD5 locus with IBD in Slovenian patients and correlation between disease-associated single nucleotide polymorphisms (SNPs) and quantitative gene expression (eQTL) of candidate genes from the IBD5 locus in peripheral blood lymphocytes and colon tissue biopsies from IBD patients. We genotyped SNPs from the IBD5 locus in 312 healthy controls and 632 IBD patients.
We found statistically significant association of polymorphisms rs1050152 in gene SLC22A4 (p = 0.005, OR = 2.177, 95% CI = 1.270-3.526) and rs2631372 in gene SLC22A5 (p = 0.001, OR = 0.473, 95% CI = 0.307-0.731) and TC haplotype of both polymorphisms (p = 0.006, OR = 1,541, 95% CI = 1.130-2.100) with refractory Crohn's disease (CD) in Slovenian patients who do not respond to standard therapy, including patients who develop fistulas. We found decreased expression of SLC22A4 and SLC22A5 genes in peripheral blood lymphocytes from IBD patients compared to control group and decreased expression of SLC22A5 gene in inflamed tissue biopsies compared to noninflamed colon (p = 0.009). We found lower expression of SLC22A5 gene in IBD patients with disease-susceptible genotypes for both disease-associated SNPs.
Our data suggest that SNPs and haplotype in the IBD5 SLC22A4/SLC22A5 region contribute to the development of particularly refractory Crohn's disease in the Slovenian population, and expression studies in blood lymphocytes and colon tissue biopsies and eQTL analysis suggest that SLC22A5 is the main gene in the IBD5 region contributing to the IBD pathogenesis.
染色体 5 上的 IBD5 基因座（OMIM ID 606348）被认为是参与炎症性肠病（IBD）发病机制的最重要遗传因素之一。然而，该区域的主要贡献者仍不清楚。
我们研究了斯洛文尼亚患者中 IBD5 基因座与 IBD 的可能关联，以及疾病相关单核苷酸多态性（SNP）与来自 IBD5 基因座的候选基因在外周血淋巴细胞和 IBD 患者的结肠组织活检中的定量基因表达（eQTL）之间的相关性。我们对 312 名健康对照和 632 名 IBD 患者的 IBD5 基因座 SNP 进行了基因分型。
我们发现基因 SLC22A4 中的多态性 rs1050152（p=0.005，OR=2.177，95%CI=1.270-3.526）和基因 SLC22A5 中的多态性 rs2631372（p=0.001，OR=0.473，95%CI=0.307-0.731）以及这两个多态性的 TC 单倍型与斯洛文尼亚患者难治性克罗恩病（CD）之间存在统计学显著关联，这些患者对标准治疗无反应，包括发生瘘管的患者。我们发现与对照组相比，IBD 患者外周血淋巴细胞中 SLC22A4 和 SLC22A5 基因的表达降低，与非炎症结肠相比，炎症组织活检中 SLC22A5 基因的表达降低（p=0.009）。我们发现 SLC22A5 基因在易患两种疾病相关 SNP 的 IBD 患者中的表达较低。
我们的数据表明，IBD5 SLC22A4/SLC22A5 区域的 SNP 和单倍型有助于斯洛文尼亚人群中特定难治性 CD 的发展，并且血液淋巴细胞和结肠组织活检中的表达研究和 eQTL 分析表明 SLC22A5 是导致 IBD 发病机制的 IBD5 区域的主要基因。
