Journal article

Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

Gian Andri Thun, Medea Imboden, Ilaria Ferrarotti, Ashish Kumar, Ma'en Obeidat, Michele Zorzetto, Margot Haun, Ivan Curjuric, Alexessander Couto Alves, Victoria E Jackson, Eva Albrecht, Janina S Ried, Alexander Teumer, Lorna M Lopez, Jennifer E Huffman, Stefan Enroth, Yohan Bosse, Ke Hao, Wim Timens, Ulf Gyllensten Show all

PLOS GENETICS | PUBLIC LIBRARY SCIENCE | Published : 2013

Abstract

Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SN..

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University of Melbourne Researchers

Grants

Awarded by Swiss National Science Foundation


Awarded by European Commission


Awarded by Wellcome Trust


Awarded by Medical Research Council


Awarded by Wellcome Trust Strategic Award


Awarded by European Commission Framework Programme 6


Awarded by European Union framework program 6 European Special Populations Research Network project


Awarded by Competence Network ASCONET, subnetwork COSYCONET


Awarded by Research Into Ageing


Awarded by cross council Lifelong Health and Wellbeing Initiative


Awarded by Biotechnology and Biological Sciences Research Council (BBSRC)


Awarded by Division of Lung Diseases of the National Heart, Lung, and Blood Institute


Awarded by Academy of Finland


Awarded by University of Oulu, Finland


Awarded by NHLBI


Awarded by NIH/NIMH


Awarded by ENGAGE project


Awarded by Medical Research Council, UK


Awarded by Swedish Medical Research Council


Awarded by European Commission Sixth Framework Programme Specific Targeted Research Projects


Awarded by European Union Framework Programme 6 EUROSPAN project


Awarded by Federal Ministry of Education and Research


Awarded by networks 'Greifswald Approach to Individualized Medicine'


Awarded by COSYCONET


Awarded by Biotechnology and Biological Sciences Research Council


Awarded by Chief Scientist Office


Awarded by DIVISION OF LUNG DISEASES


Awarded by NATIONAL HEART, LUNG, AND BLOOD INSTITUTE


Awarded by NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES


Awarded by NATIONAL INSTITUTE OF MENTAL HEALTH


Funding Acknowledgements

This SAPALDIA project was supported by the Swiss National Science Foundation (grants: 33CS30_134276/1, 33CSCO-108796, 3247BO-104283, 3247BO104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099, 3233-054996, PDFMP3-123171); the Federal Office for Forest, Environment and Landscape; the Federal Office of Public Health; the Federal Office of Roads and Transport; the canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais and Zurich; the Swiss Lung League; the canton's Lung League of Basel Stadt, Basel Landschaft, Geneva, Ticino, Valais and Zurich; Schweizerische Unfallversicherungsanstalt (SUVA); Freiwillige Akademische Gesellschaft; UBS Wealth Foundation; Talecris Biotherapeutics GmbH; Grifols; Abbott Diagnostics; Kedrion S.p.A.; IRCCS (Istituto di ricovero e cura a carattere scientifico) Foundation San Matteo Hospital; and Cariplo Foundation 2006 projects. Genotyping in the GABRIEL framework was supported by European Commission (018996) and Wellcome Trust (WT 084703MA). Individual studies: The British 1958 Birth Cohort DNA collection was 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. The 1994-95 Busselton Health Study is funded by Healthway. The Copenhagen City Heart Study is funded by the Danish Heart Foundation and the Danish Lung Foundation. The CROATIA-Korcula, CROATIA-Vis and CROATIA-Split studies in the Croatian islands of Korcula and Vis and mainland city of Split were supported by grants from the Medical Research Council (UK); the Ministry of Science, Education, and Sport of the Republic of Croatia (grant number 108-1080315-0302); and the European Union framework program 6 European Special Populations Research Network project (contract LSHG-CT-2006-018947). The eQTL-Study, including for this project the University of British Columbia and the University of Groningen, was funded by Merck Research Laboratories. The KORA research platform (KORA, Cooperative Health Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum Munchen-German Research Center for Environmental Health which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ.Further support was provided by the Competence Network ASCONET, subnetwork COSYCONET (FKZ 01GI0882). The Lothian Birth Cohort 1936 data collection was funded by Research Into Ageing (Ref. 251). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (Ref. G0700704/84698). The whole genome association study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) (Ref. BB/F019394/1). Funding from the BBSRC, Engineering and Physical Sciences Research Council (EPSRC), Economic and Social Research Council (ESRC) and Medical Research Council (MRC) is gratefully acknowledged. The Lung Health Study was supported by contract N01-HR-46002 from the Division of Lung Diseases of the National Heart, Lung, and Blood Institute. The rs4905179 data were from Gene-Environment Association Studies (GENEVA). The Northern Finland Birth Cohort 1966 received financial support from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/NIMH (5R01MH63706: 02), ENGAGE project and grant agreement HEALTH-F4-2007-201413, and the Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE). The DNA extractions, sample quality controls, biobank up-keeping and aliquotting was performed in the National Public Health Institute, Biomedicum Helsinki, Finland and supported financially by the Academy of Finland and Biocentrum Helsinki. The Northern Swedish Population Health Study was funded by the Swedish Medical Research Council (Project K2007-66X-20270-01-3), and the Foundation for Strategic Research. NSPHS, as part of European Special Populations Research Network, was also supported by European Commission Sixth Framework Programme Specific Targeted Research Projects Grant 01947 (LSHG-CT-2006-01947). The Orkney Complex Disease Study was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, and the European Union Framework Programme 6 EUROSPAN project (contract LSHG-CT-2006-018947). The Study of Health in Pomerania is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the networks 'Greifswald Approach to Individualized Medicine' (GANI_MED, grant no. 03IS2061A) and COSYCONET (grant no. 01GI0883), both funded by the Federal Ministry of Education and Research. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG and the Cache 'Campus program of the InterSystems GmbH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.