X 染色体与慢性阻塞性肺疾病及相关表型的关联：一项全 X 染色体关联研究。
X chromosome associations with chronic obstructive pulmonary disease and related phenotypes: an X chromosome-wide association study.
机构信息
Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Ave, Boston, MA, 02115, USA.
出版信息
Respir Res. 2023 Feb 1;24(1):38. doi: 10.1186/s12931-023-02337-1.
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 FEV/FVC ([Formula: see text] 0.020, SE 0.004, p 4.97 × 10), with suggestive evidence of association with FEV ([Formula: see text] 0.092, SE 0.018, p 3.40 × 10). 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.
背景
X 染色体上的遗传变异与 COPD 风险之间的关联尚未得到充分探讨。我们假设 X 染色体上存在着对 COPD 相关表型的风险有重要影响的变异，并且可能导致 COPD 表现中的性别差异。
方法
我们使用来自三个 COPD 富集的成年吸烟者队列的 X 染色体数据，进行了 X 染色体特异性的质量控制、单倍型推断和与 COPD 病例对照状态、肺功能和定量肺气肿的关联分析。在所有受试者中进行了分析，然后按性别分层，最后在荟萃分析中进行了合并。
结果
在 10193 名非西班牙裔白人或欧洲血统的受试者中，一个位于 TMSB4X 附近的变体 rs5979771 与通过 FEV/FVC 测量的肺功能显著相关（[Formula: see text]0.020，SE 0.004，p 4.97 × 10），与 FEV 也有显著的关联趋势（[Formula: see text]0.092，SE 0.018，p 3.40 × 10）。按性别分层的分析显示，X 染色体上的变异在一个性别中呈不同的趋势，其效应大小或方向有显著差异。
结论
这项研究通过对来自多个 COPD 相关数据集的 X 染色体遗传标记进行综合遗传关联荟萃分析，鉴定了影响肺功能、COPD 和肺气肿的基因座。性别差异在复杂肺部疾病的病理生理学中起着重要作用，包括表现出性别差异效应的 X 染色体变异和可能通过 X 染色体失活逃逸而相关的变异。全面研究 X 染色体，以更好地了解 COPD 和肺功能的遗传控制，对于进一步了解疾病病理机制非常重要。
试验注册
COPDGene（慢性阻塞性肺病遗传研究）是在 ClinicalTrials.gov 上注册的，注册号为 NCT00608764（自 2008 年 1 月 28 日起生效）。ECLIPSE（COPD 纵向评估以确定预测替代终点研究）是 GlaxoSmithKline 的研究代码 SCO104960，在 ClinicalTrials.gov 上注册，注册号为 NCT00292552（自 2006 年 2 月 16 日起生效）。挪威 COPD 基因研究（GenKOLS）是由 GlaxoSmithKline 资助的，研究代码为 RES11080，Genetics of Chronic Obstructive Lung Disease。
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