Genetic Analysis in A Dutch Study Sample Identifies More Ulcerative Colitis Susceptibility Loci and Shows Their Additive Role in Disease Risk
Genetic Analysis in A Dutch Study Sample Identifies More Ulcerative Colitis Susceptibility Loci and Shows Their Additive Role in Disease Risk
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DOI：
10.1038/ajg.2009.576
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发表时间：
2010-02-01
影响因子：
9.8
通讯作者：
Weersma, Rinse K.
中科院分区：
文献类型：
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作者：
Festen, Eleonora A. M.;Stokkers, Pieter C. F.;Weersma, Rinse K.
遗传易感性是溃疡性结肠炎（UC）发病机制的主要因素。最近，三项研究，包括全基因组关联研究（GWAS），报告新的UC risk locus.METHODS：从第一UC-GWAS的前20个单核苷酸多态性（SNP）进行基因分型，作为研究的复制阶段的一部分，在561例UC病例和728例对照，从我们的荷兰UC研究样本。我们在另外两项研究中对这些个体进行了8个SNP的基因分型，并在我们荷兰UC研究样本的另外894例UC病例和1，174例对照中复制了所有显著相关的SNP。对所有患者（n = 1，455）和对照组（n = 1，902）进行了综合分析。结果：共发现12个SNPs与UC的发病相关，包括HLA-B1、IL 10、IL 23 R、JAK 2、S100 Z、ARPC 2和ECM 1。我们确定了10 q26，由UC-GWAS标记，但在其复制阶段未得到证实，作为UC基因座，并发现了与GAS 7相关的趋势。剂量反应模型显示，携带11个或更多的风险等位基因的个人有一个比值比为8.2（置信区间3.0-22.8）UC susceptibility.CONCLUSIONS：我们证实了多个位点与UC在荷兰人口的关联，并发现证据10 q26和GAS 7的趋势表明关联。遗传模型显示，个体中的多个风险基因座增加了发生UC的风险。
OBJECTIVES: Genetic susceptibility is known to make a major contribution to the pathogenesis of ulcerative colitis (UC). Recently, three studies, including a genome-wide association study (GWAS), reported novel UC risk loci.METHODS: The top-20 single-nucleotide polymorphisms (SNPs) from the first UC-GWAS were genotyped, as part of the study's replication phase, in 561 UC cases and 728 controls from our Dutch UC study sample. We genotyped eight SNPs identified in two more studies, in these individuals, and replicated all significantly associated SNPs in an additional 894 UC cases and 1,174 controls from our Dutch UC study sample. A combined analysis for all patients (n = 1,455) and controls (n = 1,902) was performed. Dose-response models were constructed with the associated risk alleles.RESULTS: We found 12 SNPs tagging ten loci, including HLA-DRA, IL10, IL23R, JAK2, S100Z, ARPC2, and ECM1, to be associated with UC. We identified 10q26, flagged by the UC-GWAS but not confirmed in its replication phase, as a UC locus and found a trend toward association for GAS7. No association with disease localization or severity was found. The dose-response models show that individuals carrying 11 or more risk alleles have an odds ratio of 8.2 (confidence interval 3.0-22.8) for UC susceptibility.CONCLUSIONS: We confirmed the association of multiple loci with UC in the Dutch population and found evidence for association of 10q26 and a trend suggesting association for GAS7. Genetic models show that multiple risk loci in an individual increase the risk for developing UC.