New genetic markers for COPD discovered

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States, yet there are no effective medicines that improve mortality from the disease. While smoking remains the single most important risk factor for COPD, genetics also play an important role. In a new Research Letter published in Nature Genetics on Feb. 6, 2017, investigators describe 13 new genetic regions associated with COPD, including four that have not previously been associated with any type of lung function. The researchers also found overlap of the genetic risk of COPD with two other lung diseases, asthma and pulmonary fibrosis. These findings create an improved understanding of the genetic basis for this deadly disease.

"We are excited about these findings because we have not only uncovered new genetic risk factors for COPD, but also shown overlap of COPD genetic risk with the risk to asthma and pulmonary fibrosis," said lead author Brian Hobbs, MD, MMSc a physician-researcher in the Channing Division of Network Medicine and Pulmonary and Critical Care Division of BWH. "This is the first step in a longer process in which we hope to better understand the genetic basis for COPD, or what may be several different diseases that present as COPD. Now that we know there are new regions of the genome associated with COPD, we can build on this research by probing new biological pathways with the ultimate goal of improving therapies for our patients with this disease."

Researchers conducted a genome-wide association study of risk for chronic obstructive pulmonary disease (COPD) in a large, multi-ancestry cohort (15,256 cases and 47,936 controls). This type of study allows investigators to look across a comprehensive set of genetic variants in different individuals to see if any variant is associated with disease. Top findings from this study were replicated in a second cohort. The authors also sought to understand more about their findings by examining overlap with other diseases and examining what was known about gene function in these regions. In addition to identifying 13 new genetic regions associated with COPD, they also discovered four genetic regions that were not previously associated with any lung function trait. Nine of the genetic regions have been identified as playing an important role in lung function. Two have previously shown an association with pulmonary fibrosis; however, the specific forms of these genetic variants that increase risk for COPD decrease risk for pulmonary fibrosis. All analyses accounted for the effects of age, gender, and cigarette smoking on disease risk.

"While it is extremely important that patients not smoke for many health reasons – including the prevention of COPD – we know that smoking cessation may not be enough to stave off the disease," said Michael Cho, MD, MPH, one of the senior authors of this manuscript and a physician-researcher in the Channing Division of Network Medicine and Pulmonary and Critical Care Division. "Many patients with COPD experience self-blame, but they may be comforted to know that genetics does play a role in who ultimately develops the disease."

The BWH group also co-authored a companion paper in the same issue of Nature Genetics, led by researchers from the University of Leicester and University of Nottingham. In this large study of lung function in the UK population, they almost doubled the number of genetic variants associated with lung function levels, and found a strong association between this combined genetic risk score and COPD.

This research was conducted by the International COPD Genetics Consortium, a collaborative research effort established in 2010 at a conference at BWH. Marike Boezen, PhD, of the University of Groningen, co-led the study with Cho. The consortium now involves more than 20 studies around the world.

"This work is representative of the importance of global collaboration and the shared goal of improving care for patients everywhere," said Cho. "We're grateful for the efforts of all of the authors, each of whom played a valuable role in this discovery."

"These findings would only be possible with the kind of large collaborative efforts that supports this study. Not only do the results build on our knowledge of COPD, but also reveal potential links with other lung diseases, like pulmonary fibrosis and asthma and can form the underpinnings of a precision medicine strategy for the treatment of more than one lung disease," said Dr. James Kiley, Director of the Division of Lung Diseases of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH).

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This research was funded by: NHLBI R01 HL084323, R01 HL113264, R01 HL089856, and P01 HL105339; K08 HL097029 and R01 HL113264, R01 HL089897 and P01 HL114501; the Alpha-1 Foundation and a VA Research Career Scientist award.

The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Nora Franceschini is supported by R21HL123677-01. This work was also supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.

We acknowledge use of phenotype and genotype data from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. Genotyping for the B58C-WTCCC subset was funded by the Wellcome Trust grant 076113/B/04/Z. The B58C-T1DGC genotyping utilized resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. B58C-T1DGC GWAS data were deposited by the Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research (CIMR), University of Cambridge, which is funded by Juvenile Diabetes Research Foundation International, the Wellcome Trust and the National Institute for Health Research Cambridge Biomedical Research Centre; the CIMR is in receipt of a Wellcome Trust Strategic Award (079895). The B58C-GABRIEL genotyping was supported by a contract from the European Commission Framework Programme 6 (018996) and grants from the French Ministry of Research.

This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL085251, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org.

The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center.

The COPACETIC study was supported by a European Union FP7 grant (201379, COPACETIC). NELSON was funded by 'Zorg Onderzoek Nederland-Medische Wetenschappen, KWF Kankerbestrijding, Stichting Centraal Fonds Reserves van Voormalig Vrijwillige Ziekenfondsverzekeringen, Siemens Germany, G. Ph. Verhagen Stichting, Rotterdam Oncologic Thoracic Steering Committee, Erasmus Trust Fund, Stichting tegen Kanker. Kim de Jong is supported by grant number 4.113.007 the Lung Foundation Netherlands.

The COPDGene project (NCT00608764) was supported by Award Number R01HL089897 and Award Number R01HL089856 from the National Heart, Lung, And Blood Institute. The COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Siemens, Sunovion, and GlaxoSmithKline.

The ECLIPSE study (NCT00292552; GSK code SCO104960) was funded by GSK.

This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract number N01?HC?25195) and its contract with Affymetrix, Inc for genotyping services (contract number N02?HL?6?4278). Also supported by NIH P01 AI050516.

KARE was funded by the Consortium for Large Scale Genome Wide Association Study III (2011E7300400), which was supported by the genotyping data (the Korean Genome Analysis Project, 4845-301) and the phenotype data (the Korean Genome Epidemiology Study, 4851-302). This was also supported by the National Project for Personalized Genomic Medicine (A111218-11-GM02), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2013R1A1A1057961) and the Ministry of Education, Science and Technology (NRF-355-2011-1-E00060, NRF-2012R1A6A3A01039450).

The Lung eQTL study at Laval University was supported by the Chaire de pneumologie de la Fondation JD Bégin de l'Université Laval, the Fondation de l'Institut universitaire de cardiologie et de pneumologie de Québec, the Respiratory Health Network of the FRQS, the Canadian Institutes of Health Research (MOP – 123369), and the Cancer Research Society and Read for the Cure. Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases.

The Norway GenKOLS study (Genetics of Chronic Obstructive Lung Disease, GSK code RES11080) was funded by GSK.

The ICGN study was funded by GSK.

The LifeLines cohort study was supported by the Dutch Ministry of Health, Welfare and Sport, the Ministry of Economic Affairs, Agriculture and Innovation, the province of Groningen, the European Union (regional development fund), the Northern Netherlands Provinces (SNN), the Netherlands Organisation for Scientific Research (NWO), University Medical Center Groningen (UMCG), University of Groningen, de Nierstichting (the Dutch Kidney Foundation), and the Diabetes Fonds (the Diabetic Foundation).

The Lovelace cohort and analysis was primarily supported by National Cancer Institute grant R01 CA097356 (SAB). The State of New Mexico as a direct appropriation from the Tobacco Settlement Fund to SAB. through collaboration with University of New Mexico provided initial support to establish the LSC. Additional support was provided by NIH/NCI P30 CA118100 (SAB), HL68111 (Y.T.), and HL107873-01 (YT and SB).

MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, and DK063491. MESA Family is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071258, and R01HL071259 by the National Center for Research Resources, Grant UL1RR033176, and the National Center for Advancing Translational Sciences, Grant UL1TR000124. The MESA Lung study was supported by grants R01 HL077612, R01 HL093081 and RC1 HL100543 from the NHLBI. This publication was developed under a STAR research assistance agreement, No. RD831697 (MESA Air), awarded by the U.S Environmental protection Agency. It has not been formally reviewed by the EPA. The views expressed in this document are solely those of the authors and the EPA does not endorse any products or commercial services mentioned in this publication. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0.

The National Emphysema Treatment Trial was supported by the NHLBI N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118 and N01HR76119, the Centers for Medicare and Medicaid Services and the Agency for Healthcare Research and Quality. The Normative Aging Study is supported by the Cooperative Studies Program/ERIC of the US Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). D.S. is supported by a VA Research Career Scientist award.

The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam.

The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050-060-810. The generation and management of spirometric data was supported by FWO project G035014N. Lies Lahousse is a Postdoctoral Fellow of the Fund for Scientific Research Foundation – Flanders (FWO).

SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C HHSN268200900019C, HHSN268200900020C), which were supplemented by contributions made through the Foundation for the NIH from AstraZeneca; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc; Chiesi Farmaceutici SpA; Forest Research Institute, Inc; GSK; Grifols Therapeutics, Inc; Ikaria, Inc; Nycomed GmbH; Takeda Pharmaceutical Company; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc; and Sanofi.

The UK BiLEVE study was funded by a Medical Research Council (MRC) strategic award to M.D.T., I.P.H., D.P.S. and L.V.W. (MC_PC_12010). The research undertaken by M.D.T., M.S.A., L.V.W. and N.S. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). This research used the ALICE High Performance Computing Facility at the University of Leicester. The Universities of Leicester and Nottingham acknowledge receipt of a Collaborative Research and Development grant from the Healthcare and Bioscience iNet, a project funded by the East Midlands Development Agency, part-financed by the European Regional Development Fund and delivered by Medilink East Midlands. I.P.H. holds a Medical Research Council programme grant (G1000861).

This research has been conducted using the UK Biobank Resource under Application Number 648. The research undertaken by M.D.T., M.S.A., L.V.W. and N.S. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, And Blood Institute or the National Institutes of Health.

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