Association of IL23R, TNFRSF1A, and HLA-DRB1*0103 allele variants with inflammatory bowel disease phenotypes in the Finnish population
Association of IL23R, TNFRSF1A, and HLA-DRB1*0103 allele variants with inflammatory bowel disease phenotypes in the Finnish population
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DOI：
10.1002/ibd.20431
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发表时间：
2008-08-01
影响因子：
4.9
通讯作者：
Paavola-Sakki, Paulina
中科院分区：
文献类型：
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作者：
Lappalainen, Maarit;Halme, Leena;Paavola-Sakki, Paulina
背景：克罗恩病（CD）和溃疡性结肠炎（UC）是炎症性肠病（IBD）的两种主要形式，是具有显著遗传易感性的复杂疾病。第一个cd相关基因CARD15/NOD2最近被发现，此后出现了几篇关于新的IBD候选基因的报道。我们研究了芬兰IBD患者的IL23R、ATGI6L1、DLG5、ABCB1/MDR1、TLR4、TNFRSF1A、5号染色体风险单倍型（包括SLC22A4和SLC22A5）和HLA-DRB1*0103等位基因遗传变异与疾病表型的相关性。方法：采用聚合酶链反应（PCR）和限制性内切酶消化或Sequenom iPLEX方法对699例IBD患者进行疾病相关变异的基因分型。结果：跨越1L23R基因的5个标记与CD相关，SNP（单核苷酸多态性）rs2201841的相关性最强（P = 0.002）。罕见的HLA-DRB1*0103等位基因与UC相关（P = 0.008）， TNFRSF1A A36G变异与家族性UC相关（P = 0.007）。通过表型分析，我们发现家族性UC与罕见的TNFRSF1A等位基因36G和IVS6+10G之间存在关联（P分别= 0.001和P = 0.042）。此外，IL23R标记与狭窄性CD相关（P = 0.010-0.017），回肠结肠CD在相同2种TNFRSF1A变异的携带者中更为普遍（P = 0.021和P = 0.028）。TLR4和HLA变异的基因型-表型关联不太显著。结论：我们能够复制IL23R变体与CD以及HLA-DRB1*0103与UC的关联；确认TNFRSF1A与UC的关联需要进一步的研究。我们的研究结果还表明，IL23R和TNFRSF1A位点的多态性，可能还有HLA和TLR4位点的多态性，可能是IBD表型变异的原因。
Background: Crohn's disease (CD) and ulcerative colitis (UC), 2 major forms of inflammatory bowel disease (IBD), are complex disorders with significant genetic predisposition. The first CD-associated gene, CARD15/NOD2, was recently identified and since then several reports on novel IBD candidate genes have emerged. We investigated disease phenotype association to genetic variations in IL23R, ATGI6L1, DLG5, ABCB1/MDR1, TLR4, TNFRSF1A, chromosome 5 risk haplotype including SLC22A4 and SLC22A5, and HLA-DRB1*0103 allele among Finnish IBD patients.Methods: A total of 699 IBD patients were genotyped for disease-associated variants by polymerase chain reaction (PCR) and restriction enzyme digestion or Sequenom iPLEX method.Results: Five markers spanning the 1L23R gene were associated with CD. The SNP (single nucleotide polymorphism) rs2201841 gave the strongest association (P = 0.002). The rare HLA-DRB1*0103 allele was found to associate with UC (P = 0.008), and the TNFRSF1A A36G variant was associated with familial UC (P = 0.007). Upon phenotypic analysis we detected association between familial UC and rare TNFRSF1A alleles 36G and IVS6+10G (P = 0.001 and P = 0.042, respectively). In addition, IL23R markers were associated with stricturing CD (P = 0.010-0.017), and ileocolonic CD was more prevalent in the carriers of the same 2 TNFRSF1A variants (P = 0.021 and P = 0.028, respectively). Less significant genotype-phenotype associations were observed for the TLR4 and HLA variants.Conclusions: We were able to replicate the association of the IL23R variants with CD as well as HLA-DRB1*0103 with UC; confirmation of TNFRSF1A association with UC needs additional studies. Our findings also suggest that polymorphisms at IL23R and TNFRSF1A, and possibly HLA and TLR4, loci may account for phenotypic variation in IBD.