Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study.
Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study.
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DOI：
10.1016/s2213-2600(13)70045-6
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发表时间：
2013-06
影响因子：
76.2
通讯作者：
Garcia, Joe G. N.
中科院分区：
文献类型：
--
作者：
Noth, Imre;Zhang, Yingze;Ma, Shwu-Fan;Flores, Carlos;Barber, Mathew;Huang, Yong;Broderick, Steven M.;Wade, Michael S.;Hysi, Pirro;Scuirba, Joseph;Richards, Thomas J.;Juan-Guardela, Brenda M.;Vij, Rekha;Han, MeiLan K.;Martinez, Fernando J.;Kossen, Karl;Seiwert, Scott D.;Christie, Jason D.;Nicolae, Dan;Kaminski, Naftali;Garcia, Joe G. N.
特发性肺纤维化(IPF)是一种可能涉及多个基因位点的破坏性疾病。MUC5B的几个罕见的遗传变异和一个常见的单核苷酸多态(SNP)与该病有关。我们的目的是确定与IPF易感性和最终死亡率相关的其他常见变异。首先，我们进行了三个阶段的全基因组关联研究：第一阶段是发现全基因组关联研究；第二阶段和第三阶段是独立的病例对照研究。每个阶段从几个美国中心获得符合标准的IPF患者的欧洲裔美国人的DNA样本。第一阶段的欧美对照个体的数据是从基因型和表型数据库中收集的；匹兹堡大学招募了额外的对照个体来增加这个数字。对于第二阶段和第三阶段的控制，我们收集了另外一些在另一项研究中招募的性别匹配的欧洲裔美国控制个体的数据。对患者和对照组的DNA样本进行基因分型，以确定与IPF相关的SNPs。在第一阶段确定的SNP被转移到第二阶段，而在荟萃分析中达到全基因组意义(p<；5×10−8)的SNP被转移到第三阶段。三个有随访数据的病例系列是从第一阶段和第二阶段的GWAS中选择的，使用的是有随访数据的样本。在这些病例系列中进行了死亡率分析，以评估与IPF相关的SNPs，这些SNPs在第一和第二阶段的荟萃分析中达到了全基因组意义。最后，我们从肺基因组研究联盟获得了IPF患者肺部的基因表达谱数据，并分析了与SNP基因型的相关性。在GWAS的第一阶段(542名IPF患者，542名对照个体通过遗传祖先估计与病例一一匹配)，我们确定了20个基因座。6个SNP在第二阶段(544名患者，687名对照个体)达到全基因组意义：3个TOLLIP SNP(rs111521887，rs5743894，rs5743890)和1个MUC5B SNP(Rs35705950)位于11p15.5，1个MDGA2 SNP(Rs7144383)位于14q21.3，1个SPPL2C SNP(Rs17690703)位于17q21.31。第三阶段(324名患者，702名对照个体)证实了除rs7144383外，所有这些SNPs的关联。MUC5B SNP(Rs35705950)和TOLLIP SNP(rs111521887[R2=0.07]、rs5743894[R2=0.16]和rs5743890[R2=0.01])之间的连锁不平衡较低。683名来自GWAS的患者进入了死亡率分析。尽管具有保护性TOLLIP微小等位基因rs5743890，但仍发生IPF的个体的死亡风险增加(固定效应模型的荟萃分析：危险比1.72[95%可信区间1.24-2.38]；p=0.0012)。与普通等位基因纯合子携带者相比，携带rs5743890次要等位基因的个体TOLLIP表达降低20%(p=0.097)，携带rs111521887次要等位基因的个体TOLLIP表达降低40%(p=3.0×10−4)，携带rs5743894次要等位基因的个体TOLLIP表达降低50%(p=2.93×10−5)。TOLLIP和SPPL2C的新变异与IPF易感性相关。TOLLIP的一个新的变种rs5743890也与死亡率有关。这些关联和携带TOLLIP SNPs的特发性肺纤维化患者中TOLLIP表达的减少强调了该基因在疾病中的重要性。国立卫生研究院、国家心肺和血液研究所、肺纤维化基金会、肺纤维化联盟和卡洛斯三世研究所。
Idiopathic pulmonary fibrosis (IPF) is a devastating disease that probably involves several genetic loci. Several rare genetic variants and one common single nucleotide polymorphism (SNP) of MUC5B have been associated with the disease. Our aim was to identify additional common variants associated with susceptibility and ultimately mortality in IPF. First, we did a three-stage genome-wide association study (GWAS): stage one was a discovery GWAS; and stages two and three were independent case-control studies. DNA samples from European-American patients with IPF meeting standard criteria were obtained from several US centres for each stage. Data for European-American control individuals for stage one were gathered from the database of genotypes and phenotypes; additional control individuals were recruited at the University of Pittsburgh to increase the number. For controls in stages two and three, we gathered data for additional sex-matched European-American control individuals who had been recruited in another study. DNA samples from patients and from control individuals were genotyped to identify SNPs associated with IPF. SNPs identified in stage one were carried forward to stage two, and those that achieved genome-wide significance (p<5 × 10−8) in a meta-analysis were carried forward to stage three. Three case series with follow-up data were selected from stages one and two of the GWAS using samples with follow-up data. Mortality analyses were done in these case series to assess the SNPs associated with IPF that had achieved genome-wide significance in the meta-analysis of stages one and two. Finally, we obtained gene-expression profiling data for lungs of patients with IPF from the Lung Genomics Research Consortium and analysed correlation with SNP genotypes. In stage one of the GWAS (542 patients with IPF, 542 control individuals matched one-by-one to cases by genetic ancestry estimates), we identified 20 loci. Six SNPs reached genome-wide significance in stage two (544 patients, 687 control individuals): three TOLLIP SNPs (rs111521887, rs5743894, rs5743890) and one MUC5B SNP (rs35705950) at 11p15.5; one MDGA2 SNP (rs7144383) at 14q21.3; and one SPPL2C SNP (rs17690703) at 17q21.31. Stage three (324 patients, 702 control individuals) confirmed the associations for all these SNPs, except for rs7144383. Linkage disequilibrium between the MUC5B SNP (rs35705950) and TOLLIP SNPs (rs111521887 [r2=0.07], rs5743894 [r2=0.16], and rs5743890 [r2=0.01]) was low. 683 patients from the GWAS were included in the mortality analysis. Individuals who developed IPF despite having the protective TOLLIP minor allele of rs5743890 carried an increased mortality risk (meta-analysis with fixed-effect model: hazard ratio 1.72 [95% CI 1.24–2.38]; p=0.0012). TOLLIP expression was decreased by 20% in individuals carrying the minor allele of rs5743890 (p=0.097), 40% in those with the minor allele of rs111521887 (p=3.0 × 10−4), and 50% in those with the minor allele of rs5743894 (p=2.93 × 10−5) compared with homozygous carriers of common alleles for these SNPs. Novel variants in TOLLIP and SPPL2C are associated with IPF susceptibility. One novel variant of TOLLIP, rs5743890, is also associated with mortality. These associations and the reduced expression of TOLLIP in patients with IPF who carry TOLLIP SNPs emphasise the importance of this gene in the disease. National Institutes of Health; National Heart, Lung, and Blood Institute; Pulmonary Fibrosis Foundation; Coalition for Pulmonary Fibrosis; and Instituto de Salud Carlos III.