背景:尚未充分探索X染色体上的遗传变异与COPD风险之间的关联。我们假设X染色体具有在确定COPD相关表型风险方面重要的变异,并可能导致COPD表现的性别差异。
方法:使用来自三个富含COPD的成年吸烟者队列的X染色体数据,我们进行了X染色体特异性质量控制,imputation,并测试与COPD病例对照状态的相关性,肺功能,和定量肺气肿。在所有受试者中进行分析,然后按性别分层,随后进行荟萃分析。
结果:在10,193名非西班牙裔白人或欧洲血统的受试者中,TMSB4X附近的变种,rs5979771,通过FEV1/FVC([公式:见文本]0.020,SE0.004,第4.97×10-08页),与FEV1相关的暗示证据([公式:见正文]0.092,SE0.018,p3.40×10-07)。性别分层分析显示,X染色体变异在一种性别中具有不同的趋势,具有明显不同的效果大小或方向。
结论:这项研究确定了影响肺功能的基因座,COPD,对来自多个COPD相关数据集的X染色体遗传标记进行综合遗传关联meta分析。性别差异在复杂肺部疾病的病理生物学中起重要作用,包括X染色体变异体,这些变异体表现出不同的性别效应,以及可能通过逃避X染色体失活而相关的变异体。全面询问X染色体,以更好地了解COPD的遗传控制和肺功能,对于进一步了解疾病病理具有重要意义。试验注册COPD研究的遗传流行病学(COPDGene)在ClinicalTrials.gov上注册,NCT00608764(自2008年1月28日起活跃)。COPD纵向评估以确定预测性替代终点研究(ECLIPSE),葛兰素史克研究代码SCO104960,在ClinicalTrials.gov注册,NCT00292552(自2006年2月16日起活跃)。挪威COPD遗传学研究(GenKOLS)持有葛兰素史克研究代码RES11080,慢性阻塞性肺疾病的遗传学。
BACKGROUND: The association between genetic variants on the X chromosome to risk of COPD has not been fully explored. We hypothesize that the X chromosome harbors variants important in determining risk of COPD related phenotypes and may drive sex differences in COPD manifestations.
METHODS: Using X chromosome data from three COPD-enriched cohorts of adult smokers, we performed X chromosome specific quality control, imputation, and testing for association with COPD case-control status, lung function, and quantitative emphysema. Analyses were performed among all subjects, then stratified by sex, and subsequently combined in meta-analyses.
RESULTS: Among 10,193 subjects of non-Hispanic white or European ancestry, a variant near TMSB4X, rs5979771, reached genome-wide significance for association with lung function measured by FEV1/FVC ([Formula: see text] 0.020, SE 0.004, p 4.97 × 10-08), with suggestive evidence of association with FEV1 ([Formula: see text] 0.092, SE 0.018, p 3.40 × 10-07). Sex-stratified analyses revealed X chromosome variants that were differentially trending in one sex, with significantly different effect sizes or directions.
CONCLUSIONS: This investigation identified loci influencing lung function, COPD, and emphysema in a comprehensive genetic association meta-analysis of X chromosome genetic markers from multiple COPD-related datasets. Sex differences play an important role in the pathobiology of complex lung disease, including X chromosome variants that demonstrate differential effects by sex and variants that may be relevant through escape from X chromosome inactivation. Comprehensive interrogation of the X chromosome to better understand genetic control of COPD and lung function is important to further understanding of disease pathology.
Trial registration Genetic Epidemiology of COPD
Study (COPDGene) is registered at ClinicalTrials.gov, NCT00608764 (Active since January 28, 2008). Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints
Study (ECLIPSE), GlaxoSmithKline
study code SCO104960, is registered at ClinicalTrials.gov, NCT00292552 (Active since February 16, 2006). Genetics of COPD in Norway
Study (GenKOLS) holds GlaxoSmithKline
study code RES11080, Genetics of Chronic Obstructive Lung Disease.