AJHG - Genetic Associations for Activated Partial Thromboplastin Time and Prothrombin Time, their Gene Expression Profiles, and Risk of Coronary Artery Disease

AJHG - Genetic Associations for Activated Partial Thromboplastin Time and Prothrombin Time, their Gene Expression Profiles, and Risk of Coronary Artery Disease

Copyright © 2012 The American Society of Human Genetics All rights reserved.
The American Journal of Human Genetics, 14 June 2012

doi:10.1016/j.ajhg.2012.05.009

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Genetic Associations for Activated Partial Thromboplastin Time and Prothrombin Time, their Gene Expression Profiles, and Risk of Coronary Artery Disease

Weihong Tang^1, 30, ,  , Christine Schwienbacher^2, 3, 30, Lorna M. Lopez^4, 5, 30, Yoav Ben-Shlomo⁶, Tiphaine Oudot-Mellakh⁷, Andrew D. Johnson^8, 9, 10, Nilesh J. Samani^11, 12, 31, Saonli Basu¹³, Martin Gögele², Gail Davies⁵, Gordon D.O. Lowe¹⁴, David-Alexandre Tregouet⁷, Adrian Tan¹³, James S. Pankow¹, Albert Tenesa^15, 16, Daniel Levy⁹, Claudia B. Volpato², Ann Rumley¹⁴, Alan J. Gow^4, 5, Cosetta Minelli², John W.G. Yarnell¹⁷, David J. Porteous^4, 18, John M. Starr^4, 19, John Gallacher²⁰, Eric Boerwinkle²¹, Peter M. Visscher²², Peter P. Pramstaller^2, 23, 24, Mary Cushman²⁵, Valur Emilsson²⁶, Andrew S. Plump²⁷, Nena Matijevic²⁸, Pierre-Emmanuel Morange²⁹, Ian J. Deary^4, 5, 30, Andrew A. Hicks^2, 30 and Aaron R. Folsom^1, 30

¹ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55454, USA
² Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC); affiliated institute of the University of Lübeck, Lübeck, Germany), Viale Druso 1, 39100 Bolzano, Italy
³ Department of Experimental and Diagnostic Medicine, University of Ferrara, 44121 Ferrara, Italy
⁴ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK
⁵ Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK
⁶ School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK
⁷ INSERM UMR_S 937; Institute of Cardiometabolism and Nutrition (ICAN); Université Pierre et Marie Curie (UPMC, Paris 6); 75013 Paris, France
⁸ National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA
⁹ Center for Population Studies, National Heart, Lung and Blood Institute, Bethesda, MD 20824, USA
¹⁰ Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD 20824, USA
¹¹ Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester LE3 9QP, UK
¹² National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK
¹³ Division of Biostatistics, University of Minnesota, Minneapolis, MN 55455, USA
¹⁴ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK
¹⁵ Institute of Genetics and Molecular Medicine, Medical Research Council (MRC) Human Genetics Unit, Edinburgh EH4 2XU, UK
¹⁶ The Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9RG, UK
¹⁷ Epidemiology Research Group, Queen's University Belfast, Grosvenor Road, Belfast BT12 6BJ, UK
¹⁸ Medical Genetics Section, University of Edinburgh, Edinburgh EH4 2XU, UK
¹⁹ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK
²⁰ Department of Primary Care and Public Health, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
²¹ Human Genetics Center and Human Genome Sequencing Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
²² Queensland Statistical Genetics, Queensland Institute of Medical Research, Brisbane 4029, Australia
²³ Department of Neurology, General Central Hospital, 39100 Bolzano, Italy
²⁴ Department of Neurology, University of Lübeck, 23538 Lübeck, Germany
²⁵ Departments of Medicine and Pathology, University of Vermont, Burlington, VT 05405, USA
²⁶ Molecular Programming and Research Informatics, Merck & Co., Inc., Rahway, NJ 07065, USA
²⁷ Department of Cardiovascular Disease, Merck Research Laboratory, Rahway, NJ 07065, USA
²⁸ Hemostasis Laboratory, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
²⁹ INSERM, UMR_S 1062, Aix-Marseille Université, 13385 Marseille, France

Corresponding author

³⁰ These authors contributed equally to this work

³¹ On behalf of the CARDIoGRAM Consortium; a full list of CARDIoGRAM members can be found in the Supplemental Data

Abstract

Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonly used to screen for coagulation-factor deficiencies. One genome-wide association study (GWAS) has been reported previously for aPTT, but no GWAS has been reported for PT. We conducted a GWAS and meta-analysis to identify genetic loci for aPTT and PT. The GWAS for aPTT was conducted in 9,240 individuals of European ancestry from the Atherosclerosis Risk in Communities (ARIC) study, and the GWAS for PT was conducted in 2,583 participants from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS) and the Lothian Birth Cohorts (LBC) of 1921 and 1936. Replication was assessed in 1,041 to 3,467 individuals. For aPTT, previously reported associations with KNG1, HRG, F11, F12, and ABO were confirmed. A second independent association in ABO was identified and replicated (rs8176704, p = 4.26 × 10⁻²⁴). Pooling the ARIC and replication data yielded two additional loci in F5 (rs6028, p = 3.22 × 10⁻⁹) and AGBL1 (rs2469184, p = 3.61 × 10⁻⁸). For PT, significant associations were identified and confirmed in F7 (rs561241, p = 3.71 × 10⁻⁵⁶) and PROCR/EDEM2 (rs2295888, p = 5.25 × 10⁻¹³). Assessment of existing gene expression and coronary artery disease (CAD) databases identified associations of five of the GWAS loci with altered gene expression and two with CAD. In summary, eight genetic loci that account for ∼29% of the variance in aPTT and two loci that account for ∼14% of the variance in PT were detected and supported by functional data.