Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction
Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction
复制标题
DOI：
10.1164/rccm.201202-0366oc
复制
发表时间：
2012-10-01
影响因子：
24.7
通讯作者：
Stricker, Bruno H.
中科院分区：
文献类型：
--
作者：
Wilk, Jemma B.;Shrine, Nick R. G.;Stricker, Bruno H.
基本原理：全基因组关联研究（GWAS）已经确定了影响肺功能的基因座，但已知影响慢性阻塞性肺疾病（COPD）的基因较少。目的：对GWAS进行气流阻塞的荟萃分析，气流阻塞是通过肺量测定法评估的COPD的关键病理生理学特征，在基于人群的队列中检查所有参与者，包括曾经吸烟者，从不吸烟者，无哮喘参与者和更严重的病例。研究了15个队列（3，368例受影响; 29，507例未受影响），并使用基于人群的家庭研究和病例对照研究的荟萃分析进行复制和区域随访（3，837例; 4，479例对照受试者）。气流阻塞被定义为FEV 1和它的比率FVC（FEV 1/FVC）都低于各自的正常下限，确定由公布的参考equations.Measurements和主要结果：发现荟萃分析确定了一个区域染色体15q25.1会议全基因组的意义，在以往吸烟者，包括AGPHD 1，IREB 2，和CHRNA 5/CHRNA 3基因。该地区在从不吸烟者中也有适度的相关性。基因表达研究证实了CHRNA 5/3在肺、气道平滑肌和支气管上皮细胞中的存在。HTR 4（一个先前与FEV 1/FVC相关的基因）的单核苷酸多态性在联合荟萃分析中获得了全基因组的统计学显著性。顶部单核苷酸多态性在ADAM 19，RARB，PPAP 2B，和ADAMTS 19名义上复制在COPD荟萃analysis.Conclusions：这些结果表明一个重要的作用，CHRNA 5/3区域作为气流阻塞的遗传危险因素，可能是独立的吸烟和牵连的HTR 4基因在气流阻塞的病因。
Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV1 and its ratio to FVC (FEV1/FVC) both less than their respective lower limits of normal as determined by published reference equations.Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV1/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.