Loss-of-function variants in both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) 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 CFTR 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 CFTR 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 CFTR 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 CFTR variants on separate alleles and these subjects were enriched for COPD cases (p=0.010).

Cigarette smokers who carry one deleterious CFTR variant have higher rates of chronic bronchitis, while presence of two CFTR 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 ( CFTR ) 基因的两个拷贝的功能丧失变异会导致囊性纤维化 (CF)；然而，有证据表明，由于一种有害变异的存在而导致的 CFTR 功能降低可能会产生临床后果。在这里，我们假设有吸烟史的个体的CFTR变异与慢性阻塞性肺疾病 (COPD) 和相关表型相关。

通过国家心肺血液研究所 TOPMed（精准医学 TransOmics）计划，对来自 COPDGene（慢性阻塞性肺病遗传流行病学）研究的 8597 名受试者进行了全基因组测序，该研究是一项针对当前和以前吸烟者的观察性研究。我们提取了临床注释的CFTR变异，并对 COPD 和相关表型进行了单变异和变异组测试。在 ECLIPSE（慢性阻塞性肺病纵向评估以识别预测替代终点）研究的 2118 名受试者中进行了复制。

我们在CFTR基因边界内鉴定了 301 个编码变异：其中 147 个已在 CF 个体中报告，其中包括 36 个导致 CF 的变异。我们在 COPDGene 的变异集测试（单侧 p=0.0025；OR 1.53）以及 COPDGene 和 ECLIPSE 的荟萃分析（单侧 p=0.0060；OR 1.52）中发现，导致 CF 的变异与慢性支气管炎相关。 。单变体测试显示，COPDGene 中 F508del 变体与慢性支气管炎相关（单侧 p=0.015；OR 1.47）。此外，我们还确定了 32 名受试者在不同的等位基因上具有两个或多个CFTR变异，这些受试者的 COPD 病例丰富（p=0.010）。

携带一种有害CFTR变异的吸烟者患慢性支气管炎的几率较高，而携带两种CFTR变异的吸烟者可能与慢性阻塞性肺病有关。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。