Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study.
Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study.
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DOI：
10.1016/s2213-2600(22)00251-x
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发表时间：
2023-01
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特发性肺纤维化（IPF）是一种无法治愈的肺部疾病，其特征是进行性疤痕形成，导致肺泡僵硬、肺活量减少和气体输送受阻。我们的目的是确定 IPF 诊断后与肺活量下降或气体转移下降相关的遗传变异。我们对诊断为 IPF 的个体的用力肺活量 (FVC) 和肺一氧化碳弥散能力 (DLCO) 的纵向测量进行了全基因组荟萃分析。 1996 年 6 月至 2017 年 8 月期间，来自美国、英国和西班牙各个中心的三项研究招募了个人。另一项独立研究 (CleanUP-IPF) 进一步研究了具有暗示意义的变异。所有四项研究均按照美国胸科学会/欧洲呼吸学会的指南诊断病例。如果在对所有发现和后续研究进行荟萃分析时，变异体的荟萃分析 p<5 × 10−⁸ 被定义为显着相关，在所有四项研究中具有一致的影响方向，并且在每项研究中名义上显着（p<0∙05）。 FVC 分析中纳入了 1329 名个体，总共 5216 项措施。 DLCO 分析包含 975 名个人，总共 3361 项措施。对于发现的全基因组分析，FVC 分析中包含 7 611 174 个遗传变异，DLCO 分析中包含 7 536 843 个遗传变异。位于蛋白激酶 N2 (PKN2) 反义 RNA 基因中的一个变异 (rs115982800) 显示出与 FVC 下降在全基因组范围内显着相关（每个风险等位基因 -140 mL/年 [95% CI –180 至 –100]；p=9∙14 × 10−12）。我们的分析确定了与疾病进展相关的遗传变异，这可能突显了 IPF 的新生物学机制。我们发现 PKN2（一种 Rho 和 Rac 效应蛋白）是本次分析中最有可能感兴趣的基因。 PKN2 抑制剂目前正在开发中，这标志着 IPF 的一种潜在的新型治疗方法。
Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease characterised by progressive scarring leading to alveolar stiffness, reduced lung capacity, and impeded gas transfer. We aimed to identify genetic variants associated with declining lung capacity or declining gas transfer after diagnosis of IPF. We did a genome-wide meta-analysis of longitudinal measures of forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) in individuals diagnosed with IPF. Individuals were recruited to three studies between June, 1996, and August, 2017, from across centres in the US, UK, and Spain. Suggestively significant variants were investigated further in an additional independent study (CleanUP-IPF). All four studies diagnosed cases following American Thoracic Society/European Respiratory Society guidelines. Variants were defined as significantly associated if they had a meta-analysis p<5 × 10−⁸ when meta-analysing across all discovery and follow-up studies, had consistent direction of effects across all four studies, and were nominally significant (p<0∙05) in each study. 1329 individuals with a total of 5216 measures were included in the FVC analysis. 975 individuals with a total of 3361 measures were included in the DLCO analysis. For the discovery genome-wide analyses, 7 611 174 genetic variants were included in the FVC analysis and 7 536 843 in the DLCO analysis. One variant (rs115982800) located in an antisense RNA gene for protein kinase N2 (PKN2) showed a genome-wide significant association with FVC decline (−140 mL/year per risk allele [95% CI –180 to –100]; p=9∙14 × 10−¹²). Our analysis identifies a genetic variant associated with disease progression, which might highlight a new biological mechanism for IPF. We found that PKN2, a Rho and Rac effector protein, is the most likely gene of interest from this analysis. PKN2 inhibitors are currently in development and signify a potential novel therapeutic approach for IPF.