期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 186, 期 7, 页码 622-632出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.201202-0366OC
关键词
chronic obstructive pulmonary disease; single-nucleotide polymorphism; genes
资金
- Flight Attendant Medical Research Institute
- NHLBI's Framingham Heart Study [N01-HC-25195]
- Affymetrix, Inc. [N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center
- National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]
- National Human Genome Research Institute [U01HG004402]
- National Institutes of Health [HHSN268200625226C, UL1RR025005]
- NIH Roadmap for Medical Research
- Division of Intramural Research, National Institute of Environmental Health [ZO1 ES43012]
- NHLBI [N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HL080295, HL075366, HL087652, HL105756, N01HR76101, N01HR76102]
- National Institute of Neurological Disorders and Stroke
- National Institute on Aging (NIA) [AG-023629, AG-15928, AG-20098, AG-027058]
- Cedars-Sinai Board of Govemors' Chair in Medical Genetics
- National Center for Research Resources CTSI grant [UL 1RR033176]
- National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]
- European Union [201379]
- Medical Research Council [G0000934]
- Wellcome Trust [068545/Z/02, 076113/B104/Z]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development
- Juvenile Diabetes Research Foundation International (IDRFI)
- JDRFI
- National Institute for Health Research Cambridge Biomedical Research Centre
- European Commission Framework Program 6 [018996]
- French Ministry of Research
- Cancer Research UK
- Medical Research Council
- NIH [N01-AG-12100]
- NIA Intramural Research Program
- Hjartavernd (the Icelandic Heart Association),
- Althingi (the Icelandic Parliament)
- Swiss National Science Foundation [33CS30-134276/1, 33CSCO-108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099, 3233-054996, PDFMP3-12317I]
- Federal Office for Forest, Environment, and Landscape
- Federal Office of Public Health
- Federal Office of Roads and Transport
- canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern
- Ticino, Valais, Zurich, the Swiss Lung League, the canton's Lung League of Basel Stadt/Basel Landschaft, Geneva, Ticin
- Valais and Zurich, Schweizerische Unfallversicherungsanstalt (SUVA), Freiwillige Akademische Gesellschaft, UBS Wealth Foundation
- Talecris Biotherapeutics GmbH
- Abbott Diagnostics
- Healthways, Western Australia
- Great Wine Estates of the Margaret River region of Western Australia
- AXA Research Fund
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/F019394/1]
- Research Into Ageing [LBC1936]
- Age UK (Disconnected Mind
- cross council Lifelong Health and Wellbeing Initiative [G0700704/84698]
- BBSRC
- Engineering and Physical Sciences Research Council
- Economic and Social Research Council
- Medical Research Council (MRC)
- U.S. NIH [R01 HL075478, R01 HL084323, P01 HL083069, 1101 HL089856, K12HL089990, K08 HL097029, U01 HL089897]
- Centers for Medicare and Medicaid Services
- Agency for Healthcare Research and Quality
- Cooperative Studies Program/ERIC of the U.S. Department of Veterans Affairs
- GlaxoSmithKline
- COPD Foundation
- Intramural Research Programs of the NIH, the National Institute of Environmental Health Sciences [Z01ES043012]
- CHARGE Consortium
- U.K. MRC Senior Clinical Fellowship [G0902313]
- MRC [G1000861]
- [U01 DK062418]
- [N01HR76103]
- [N01HR76104]
- [N01HR76105]
- [N01HR76106]
- [N01HR76107]
- [N01HR76108]
- [N01HR76109]
- [N01 HR76110]
- [N01HR76111]
- [N01HR76112]
- [N01HR76113]
- [N01HR76114]
- [N01HR76115]
- [N01HR76116]
- [N01HR76118]
- [N01HR76119]
- Swiss National Science Foundation (SNF) [33CS30_134276] Funding Source: Swiss National Science Foundation (SNF)
- BBSRC [BB/F019394/1] Funding Source: UKRI
- MRC [G0902313, G1000861, G0700704, G0000934, G0901786] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F019394/1] Funding Source: researchfish
- Medical Research Council [G0902313, G0700704B, G0901786, G1000861, MC_U106179471, G0000934, G0700704, G0401527, G1000143] Funding Source: researchfish
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.
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