Exploring the genetics of airflow limitation in lung function across the lifespan - a polygenic risk score study.

IF 9.6 1区医学 Q1 MEDICINE, GENERAL & INTERNAL

EClinicalMedicine Pub Date : 2024-08-12 eCollection Date: 2024-09-01 DOI:10.1016/j.eclinm.2024.102731

Natalia Hernandez-Pacheco, Anna Kilanowski, Ashish Kumar, John A Curtin, Núria Olvera, Sara Kress, Xander Bertels, Lies Lahousse, Laxmi Bhatta, Raquel Granell, Sergi Marí, Jose Ramon Bilbao, Yidan Sun, Casper-Emil Tingskov Pedersen, Tarik Karramass, Elisabeth Thiering, Christina Dardani, Simon Kebede Merid, Gang Wang, Jenny Hallberg, Sarah Koch, Judith Garcia-Aymerich, Ana Esplugues, Maties Torrent, Jesus Ibarluzea, Lesley Lowe, Angela Simpson, Ulrike Gehring, Roel C H Vermeulen, Graham Roberts, Anna Bergström, Judith M Vonk, Janine F Felix, Liesbeth Duijts, Klaus Bønnelykke, Nic Timpson, Guy Brusselle, Ben M Brumpton, Arnulf Langhammer, Stephen Turner, John W Holloway, Syed Hasan Arshad, Anhar Ullah, Adnan Custovic, Paul Cullinan, Clare S Murray, Maarten van den Berge, Inger Kull, Tamara Schikowski, Jadwiga A Wedzicha, Gerard Koppelman, Rosa Faner, Àlvar Agustí, Marie Standl, Erik Melén

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引用次数: 0

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is caused by interactions between many factors across the life course, including genetics. A proportion of COPD may be due to reduced lung growth in childhood. We hypothesized that a polygenic risk score (PRS) for COPD is associated with lower lung function already in childhood and up to adulthood.

Methods: A weighted PRS was calculated based on the 82 association signals (p ≤ 5 × 10^-8) revealed by the largest GWAS of airflow limitation (defined as COPD) to date. This PRS was tested in association with lung function measures (FEV₁, FVC, and FEV₁/FVC) in subjects aged 4-50 years from 16 independent cohorts participating in the Chronic Airway Diseases Early Stratification (CADSET) Clinical Research Collaboration. Age-stratified meta-analyses were conducted combining the results from each cohort (n = 45,406). These findings were validated in subjects >50 years old.

Findings: We found significant associations between the PRS for airflow limitation and: (1) lower pre-bronchodilator FEV₁/FVC from school age (7-10 years; β: -0.13 z-scores per one PRS z-score increase [-0.15, -0.11], q-value = 7.04 × 10^-53) to adulthood (41-50 years; β: -0.16 [-0.19, -0.13], q-value = 1.31 × 10^-24); and (2) lower FEV₁ (from school age: 7-10 years; β: -0.07 [-0.09, -0.05], q-value = 1.65 × 10^-9, to adulthood: 41-50 years; β: -0.17 [-0.20, -0.13], q-value = 4.48 x 10^-20). No effect modification by smoking, sex, or a diagnosis of asthma was observed.

Interpretation: We provide evidence that a higher genetic risk for COPD is linked to lower lung function from childhood onwards.

Funding: This study was supported by CADSET, a Clinical Research Collaboration of the European Respiratory Society.

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探索肺功能气流受限的遗传学--多基因风险评分研究。

背景：慢性阻塞性肺病（COPD）是由整个生命过程中包括遗传在内的多种因素相互作用造成的。一部分慢性阻塞性肺病可能是由于儿童时期肺部发育不良造成的。我们假设，慢性阻塞性肺病的多基因风险评分（PRS）与儿童期直至成年期较低的肺功能有关：方法：根据迄今为止最大的气流受限（定义为慢性阻塞性肺病）GWAS 发现的 82 个关联信号（p ≤ 5 × 10-8）计算出加权 PRS。该 PRS 与肺功能指标（FEV1、FVC 和 FEV1/FVC）进行了关联测试，测试对象来自参与慢性气道疾病早期分层（CADSET）临床研究合作的 16 个独立队列中的 4-50 岁受试者。结合每个队列的结果进行了年龄分层荟萃分析（n = 45,406）。这些结果在年龄大于 50 岁的受试者中得到了验证：我们发现气流受限的 PRS 与以下因素有明显的关联(1) 从学龄期（7-10 岁；β：PRS z 分数每增加 1 分，气流受限 PRS z 分数降低 -0.13 [-0.15, -0.11], q 值 = 7.04 × 10-53）到成年期（41-50 岁；β：-0.16 [-0.19, -0.13]，q 值 = 1.31 × 10-24）；以及 (2) FEV1 降低（从学龄期：7-10 岁；β：-0.07 [-0.09, -0.05]，q 值 = 1.65 × 10-9，到成年期：41-50 岁；β：-0.17 [-0.20, -0.13]，q 值 = 4.48 x 10-20）。没有观察到吸烟、性别或哮喘诊断的影响：我们提供的证据表明，慢性阻塞性肺病较高的遗传风险与儿童时期较低的肺功能有关：本研究得到了欧洲呼吸学会临床研究合作组织 CADSET 的支持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EClinicalMedicine Medicine-Medicine (all)

CiteScore

18.90

自引率

1.30%

发文量

506

审稿时长

22 days

期刊介绍： eClinicalMedicine is a gold open-access clinical journal designed to support frontline health professionals in addressing the complex and rapid health transitions affecting societies globally. The journal aims to assist practitioners in overcoming healthcare challenges across diverse communities, spanning diagnosis, treatment, prevention, and health promotion. Integrating disciplines from various specialties and life stages, it seeks to enhance health systems as fundamental institutions within societies. With a forward-thinking approach, eClinicalMedicine aims to redefine the future of healthcare.