Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Eur Respir J. 2022 Aug 10;60(2). doi: 10.1183/13993003.01994-2021. Print 2022 Aug.
Loss-of-function variants in both copies of the cystic fibrosis transmembrane conductance regulator () gene cause cystic fibrosis (CF); however, there is evidence that reduction in CFTR function due to the presence of one deleterious variant can have clinical consequences. Here, we hypothesise that variants in individuals with a history of smoking are associated with chronic obstructive pulmonary disease (COPD) and related phenotypes.
Whole-genome sequencing was performed through the National Heart, Lung, and Blood Institute TOPMed (TransOmics in Precision Medicine) programme in 8597 subjects from the COPDGene (Genetic Epidemiology of COPD) study, an observational study of current and former smokers. We extracted clinically annotated variants and performed single-variant and variant-set testing for COPD and related phenotypes. Replication was performed in 2118 subjects from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study.
We identified 301 coding variants within the gene boundary: 147 of these have been reported in individuals with CF, including 36 CF-causing variants. We found that CF-causing variants were associated with chronic bronchitis in variant-set testing in COPDGene (one-sided p=0.0025; OR 1.53) and in meta-analysis of COPDGene and ECLIPSE (one-sided p=0.0060; OR 1.52). Single-variant testing revealed that the F508del variant was associated with chronic bronchitis in COPDGene (one-sided p=0.015; OR 1.47). In addition, we identified 32 subjects with two or more variants on separate alleles and these subjects were enriched for COPD cases (p=0.010).
Cigarette smokers who carry one deleterious variant have higher rates of chronic bronchitis, while presence of two variants may be associated with COPD. These results indicate that genetically mediated reduction in CFTR function contributes to COPD related phenotypes, in particular chronic bronchitis.
囊性纤维化跨膜电导调节因子 () 基因的两个拷贝中的功能丧失变异导致囊性纤维化 (CF)；然而，有证据表明，由于存在一个有害变异，CFTR 功能的降低可能会产生临床后果。在这里，我们假设在有吸烟史的个体中， 变体与慢性阻塞性肺疾病 (COPD) 和相关表型有关。
通过国家心肺血液研究所 TOPMed（精准医学中的转录组学）计划在 COPDGene（COPD 的遗传流行病学）研究中的 8597 名受试者中进行全基因组测序，这是一项对当前和以前吸烟者进行的观察性研究。我们提取了临床注释的 变体，并对 COPD 和相关表型进行了单变体和变体集检测。在 ECLIPSE（评估 COPD 以确定预测替代终点的纵向研究）研究中的 2118 名受试者中进行了复制。
我们在 基因边界内发现了 301 个编码变异：其中 147 个已在 CF 个体中报道，包括 36 个 CF 致病变异。我们发现，在 COPDGene 中的变体集检测中，CF 致病变体与慢性支气管炎有关（单侧 p=0.0025；OR 1.53），在 COPDGene 和 ECLIPSE 的荟萃分析中也是如此（单侧 p=0.0060；OR 1.52）。单变体测试表明，F508del 变体与 COPDGene 中的慢性支气管炎有关（单侧 p=0.015；OR 1.47）。此外，我们在 COPDGene 中发现了 32 名受试者在不同等位基因上携带两个或更多的 变体，这些受试者中 COPD 病例较多（p=0.010）。
携带一个有害 变体的吸烟的人患有慢性支气管炎的比率较高，而存在两个 变体可能与 COPD 有关。这些结果表明，遗传介导的 CFTR 功能降低导致 COPD 相关表型，特别是慢性支气管炎。
