Common Genetic Determinants of Lung Function, Subclinical Atherosclerosis and Risk of Coronary Artery Disease Maria Sabater-Lleal 1 *, Anders Ma ¨ larstig 2 , Lasse Folkersen 1¤ , Marı ´a Soler Artigas 3,4 , Damiano Baldassarre 5,6 , Maryam Kavousi 7 , Peter Almgren 8 , Fabrizio Veglia 6 , Guy Brusselle 7,9,10 , Albert Hofman 7 , Gunnar Engstro ¨m 8 , Oscar H. Franco 7 , Olle Melander 8,11 , Gabrielle Paulsson-Berne 12 , Hugh Watkins 13 , Per Eriksson 1 , Steve E. Humphries 14 , Elena Tremoli 5,6 , Ulf de Faire 15 , Martin D. Tobin 3,4 , Anders Hamsten 1 1 Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden, 2 Pfizer Worldwide Research and Development, Cambridge, United Kingdom, 3 Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, United Kingdom, 4 National Institute for Health Research, Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom, 5 Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita ` di Milano, Milan, Italy, 6 Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Cattere Scientifico, Milan, Italy, 7 Department of Epidemiology, Erasmus Medical Center - University Medical Center Rotterdam, Rotterdam, the Netherlands, 8 Department of Clinical Sciences, Lunds University, Malmo ¨, Sweden, 9 Department of Internal Medicine, Erasmus Medical Center - University Medical Center Rotterdam, Rotterdam, the Netherlands, 10 Inspectorate for Health Care, The Hague, the Netherlands, 11 Department of Internal Medicine, Ska ˚ne University Hospital, Malmo ¨ , Sweden, 12 Cardiovascular Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden, 13 Department of Cardiovascular Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, 14 Center for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, United Kingdom, 15 Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden Abstract Chronic obstructive pulmonary disease (COPD) independently associates with an increased risk of coronary artery disease (CAD), but it has not been fully investigated whether this co-morbidity involves shared pathophysiological mechanisms. To identify potential common pathways across the two diseases, we tested all recently published single nucleotide polymorphisms (SNPs) associated with human lung function (spirometry) for association with carotid intima-media thickness (cIMT) in 3,378 subjects with multiple CAD risk factors, and for association with CAD in a case-control study of 5,775 CAD cases and 7,265 controls. SNPs rs2865531, located in the CFDP1 gene, and rs9978142, located in the KCNE2 gene, were significantly associated with CAD. In addition, SNP rs9978142 and SNP rs3995090 located in the HTR4 gene, were associated with average and maximal cIMT measures. Genetic risk scores combining the most robustly spirometry– associated SNPs from the literature were modestly associated with CAD, (odds ratio (OR) (95% confidence interval (CI 95 ) = 1.06 (1.03, 1.09); P-value = 1.5 6 10 24 , per allele). In conclusion, our study suggests that some genetic loci implicated in determining human lung function also influence cIMT and susceptibility to CAD. The present results should help elucidate the molecular underpinnings of the co-morbidity observed across COPD and CAD. Citation: Sabater-Lleal M, Ma ¨larstig A, Folkersen L, Soler Artigas M, Baldassarre D, et al. (2014) Common Genetic Determinants of Lung Function, Subclinical Atherosclerosis and Risk of Coronary Artery Disease. PLoS ONE 9(8): e104082. doi:10.1371/journal.pone.0104082 Editor: Giuseppe Novelli, Tor Vergata University of Rome, Italy Received April 3, 2014; Accepted July 6, 2014; Published August 5, 2014 Copyright: ß 2014 Sabater-Lleal et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that, for approved reasons, some access restrictions apply to the data underlying the findings. Because of restrictions based on privacy regulations and informed consent of the participants, we want to state that data cannot be made freely available in a public repository. Data can however be obtained upon request. Requests For RS data should be directed towards the management team for the Rotterdam Study (secretariat.epi@ erasmusmc.nl), which has a protocol for approving data requests; to Anders Hamsten (Anders.Hamsten@ki.se) for PROCARDIS data; to Fabrizio Veglia (Fabrizio. veglia@ccfm.it.) for IMPROVE data; to Olle Melander (olle.melander@med.lu.se) for MDC data; to Per Eriksson (per.eriksson@ki.se) for ASAP data; and to Gabrielle Paulsson-Berne (gabrielle.berne@ki.se) for BIKE data. Funding: On behalf of all the authors, Dr. Sabater-Lleal would like to state that the authors received no specific funding for this work, however Pfizer provided support in the form of salary for author Dr. Ma ¨larstig, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the ‘author contributions’ section. Competing Interests: With regards to conflicts of interest, the authors have the following interests. Anders Ma ¨larstig is employed by Pfizer Worldwide Research and Development and holds Pfizer stocks and options. Dr. Engstro ¨ m has disclosed being formerly employed by AstraZeneca R&D. Dr. Folkersen is currently employed at Novo Nordisk A/S, Denmark although all his contributions in this manuscript were done when employed at Karolinska Institutet. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. * Email: maria.sabater.lleal@ki.se ¤ Current address: PharmakoGenetics department, Novo Nordisk A/S, Bagsvaerd, Denmark PLOS ONE | www.plosone.org 1 August 2014 | Volume 9 | Issue 8 | e104082