Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes.
Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes.
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DOI：
10.1371/journal.pgen.1004955
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发表时间：
2015-02
期刊：
影响因子：
4.5
通讯作者：
UK IBD Genetics Consortium
中科院分区：
文献类型：
--
作者：
Prescott NJ;Lehne B;Stone K;Lee JC;Taylor K;Knight J;Papouli E;Mirza MM;Simpson MA;Spain SL;Lu G;Fraternali F;Bumpstead SJ;Gray E;Amar A;Bye H;Green P;Chung-Faye G;Hayee B;Pollok R;Satsangi J;Parkes M;Barrett JC;Mansfield JC;Sanderson J;Lewis CM;Weale ME;Schlitt T;Mathew CG;UK IBD Genetics Consortium
罕见的编码序列变异对复杂疾病遗传易感性的贡献是一个重要但尚未解决的问题。到目前为止，大多数研究已经调查了来自包含常见疾病相关变异的区域的有限数量的基因。在这里，我们调查这在炎症性肠病的外显子和近端启动子的531个基因的测序选择从全基因组关联研究和途径分析在汇集的DNA面板从474例克罗恩病和480对照。在测序实验中有关联证据或具有潜在功能意义的80个变体被选择用于6，507例IBD病例和3，064例人群对照的随访基因分型。在3，662例IBD病例和3，639例对照的扩展组中对前5种疾病相关变体进行基因分型，并在10，147例IBD病例和7，008例对照的组合分析中测试相关性。主要组织相容性复合体中BTNL 2基因中的一种罕见编码变体p.G454C与IBD风险增加显著相关（p = 9.65x10−10，OR = 2.3[95%CI = 1.75-3.04]），但与该位点已知的常见相关CD和UC变体无关。另外3个基因的罕见（<1%）和低频率（1-5%）变异显示与IBD风险增加（ARIH 2 c.338-6C>T）或风险降低（IL 12 B p.V298F和NICN p.H191R）相关（p<0.005）。这些结果提供了额外的见解参与抑制T细胞活化的发展中的两个亚表型的炎症性肠病。我们认为，尽管罕见的编码变异可能对复杂疾病的易感性有一定的总体贡献，但它们可以帮助我们了解有助于发病机制的分子途径。克罗恩病和溃疡性结肠炎是两种形式的炎症性肠病，其引起胃肠道的慢性炎症。人类基因组160多个区域中的常见遗传变异与这些疾病的风险改变有关，但对疾病风险的估计遗传贡献大部分无法解释。我们试图确定改变基因编码蛋白质结构或功能的罕见遗传变异是否也有助于疾病易感性。我们使用高通量DNA测序在近500名患者和对照中筛选了500多个基因的此类变体，并在约10，000名患者和7，000名对照中验证了有趣的变体。我们检测到有限数量的编码区罕见变异与疾病的相关性，表明它们在遗传易感性中所占的比例并不高。然而，他们强调了在炎症性肠病发展中具有潜在重要性的基因的参与，包括参与免疫细胞激活，免疫应答基因调节和细胞中蛋白质降解的基因。
The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn’s disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10−10, OR = 2.3[95% CI = 1.75–3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1–5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis. Crohn’s disease and ulcerative colitis are two forms of inflammatory bowel disease which cause chronic inflammation of the gastrointestinal tract. Common genetic variants in more than 160 regions of the human genome have been associated with an altered risk of these disorders, but leave much of the estimated genetic contribution to disease risk unexplained. We sought to establish whether rare genetic variants which alter the structure or function of the proteins encoded by genes also contribute to disease susceptibility. We used high throughput DNA sequencing to screen over 500 genes for such variants in nearly 500 patients and controls, and validated interesting variants in about 10,000 patients and 7,000 controls. We detected association of a limited number of rare variants from coding regions with disease, suggesting that they do not account for a large proportion of genetic susceptibility. However, they highlight the involvement of genes of potential importance in the development of inflammatory bowel disease, including those involved in the activation of immune cells, the regulation of immune response genes, and the degradation of proteins in cells.
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