Amit V Khera1, Hong-Hee Won2, Gina M Peloso3, Colm O'Dushlaine4, Dajiang Liu5, Nathan O Stitziel6, Pradeep Natarajan1, Akihiro Nomura1, Connor A Emdin1, Namrata Gupta7, Ingrid B Borecki4, Rosanna Asselta8, Stefano Duga8, Piera Angelica Merlini9, Adolfo Correa10, Thorsten Kessler11, James G Wilson12, Matthew J Bown13, Alistair S Hall14, Peter S Braund13, David J Carey15, Michael F Murray15, H Lester Kirchner15, Joseph B Leader15, Daniel R Lavage15, J Neil Manus15, Dustin N Hartzel15, Nilesh J Samani13, Heribert Schunkert16, Jaume Marrugat17, Roberto Elosua17, Ruth McPherson18, Martin Farrall19, Hugh Watkins19, Eric S Lander7, Daniel J Rader20, John Danesh21, Diego Ardissino22, Stacey Gabriel7, Cristen Willer23, Gonçalo R Abecasis24, Danish Saleheen25, Frederick E Dewey4, Sekar Kathiresan1. 1. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts2Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston3Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston. 2. Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea. 3. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts5Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts. 4. Regeneron Genetics Center, Tarrytown, New Jersey. 5. Department of Public Health Sciences, Institute for Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania. 6. Department of Medicine, Washington University School of Medicine, St Louis, Missouri9Department of Genetics, Washington University School of Medicine, St Louis, Missouri10McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri. 7. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. 8. Department of Biomedical Sciences, Humanitas University, Milan, Italy12Humanitas Clinical and Research Center, Milan, Italy. 9. Ospedale Niguarda, Milano, Italy. 10. Department of Medicine, University of Mississippi Medical Center, Jackson. 11. Munich Heart Alliance, München, Germany16Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany. 12. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson. 13. NIHR Leicester Cardiovascular Biomedical Research Unit, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom. 14. Leeds Institute of Cardiovascular and Metabolic Medicine, Leeds University, Leeds, United Kingdom. 15. Geisinger Health System, Danville, Pennsylvania. 16. Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany. 17. Cardiovascular Epidemiology and Genetics, Hospital del Mar Research Institute, Barcelona, Spain. 18. University of Ottawa Heart Institute, Ottawa, Ontario, Canada. 19. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom24Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. 20. Department of Genetics, University of Pennsylvania, Philadelphia. 21. Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom27Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom28NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom29Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia. 22. Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy31Associazione per lo Studio Della Trombosi in Cardiologia, Pavia, Italy. 23. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor33Department of Human Genetics, University of Michigan, Ann Arbor34Department of Internal Medicine, University of Michigan, Ann Arbor. 24. Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor. 25. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Abstract
Importance: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. Objective: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). Design, Setting, and Participants: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. Exposures: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. Main Outcomes and Measures: Circulating lipid levels and CAD. Results: Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides. Conclusions and Relevance: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.
Importance: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. Objective: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). Design, Setting, and Participants: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. Exposures: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. Main Outcomes and Measures: Circulating lipid levels and CAD. Results: Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides. Conclusions and Relevance: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
Authors: G Miesenböck; B Hölzl; B Föger; E Brandstätter; B Paulweber; F Sandhofer; J R Patsch Journal: J Clin Invest Date: 1993-02 Impact factor: 14.808
Authors: Paul Nioi; Asgeir Sigurdsson; Gudmar Thorleifsson; Hannes Helgason; Arna B Agustsdottir; Gudmundur L Norddahl; Anna Helgadottir; Audur Magnusdottir; Aslaug Jonasdottir; Solveig Gretarsdottir; Ingileif Jonsdottir; Valgerdur Steinthorsdottir; Thorunn Rafnar; Dorine W Swinkels; Tessel E Galesloot; Niels Grarup; Torben Jørgensen; Henrik Vestergaard; Torben Hansen; Torsten Lauritzen; Allan Linneberg; Nele Friedrich; Nikolaj T Krarup; Mogens Fenger; Ulrik Abildgaard; Peter R Hansen; Anders M Galløe; Peter S Braund; Christopher P Nelson; Alistair S Hall; Michael J A Williams; Andre M van Rij; Gregory T Jones; Riyaz S Patel; Allan I Levey; Salim Hayek; Svati H Shah; Muredach Reilly; Gudmundur I Eyjolfsson; Olof Sigurdardottir; Isleifur Olafsson; Lambertus A Kiemeney; Arshed A Quyyumi; Daniel J Rader; William E Kraus; Nilesh J Samani; Oluf Pedersen; Gudmundur Thorgeirsson; Gisli Masson; Hilma Holm; Daniel Gudbjartsson; Patrick Sulem; Unnur Thorsteinsdottir; Kari Stefansson Journal: N Engl J Med Date: 2016-05-18 Impact factor: 91.245
Authors: Nathan O Stitziel; Hong-Hee Won; Alanna C Morrison; Gina M Peloso; Ron Do; Leslie A Lange; Pierre Fontanillas; Namrata Gupta; Stefano Duga; Anuj Goel; Martin Farrall; Danish Saleheen; Paola Ferrario; Inke König; Rosanna Asselta; Piera A Merlini; Nicola Marziliano; Maria Francesca Notarangelo; Ursula Schick; Paul Auer; Themistocles L Assimes; Muredach Reilly; Robert Wilensky; Daniel J Rader; G Kees Hovingh; Thomas Meitinger; Thorsten Kessler; Adnan Kastrati; Karl-Ludwig Laugwitz; David Siscovick; Jerome I Rotter; Stanely L Hazen; Russell Tracy; Sharon Cresci; John Spertus; Rebecca Jackson; Stephen M Schwartz; Pradeep Natarajan; Jacy Crosby; Donna Muzny; Christie Ballantyne; Stephen S Rich; Christopher J O'Donnell; Goncalo Abecasis; Shamil Sunaev; Deborah A Nickerson; Julie E Buring; Paul M Ridker; Daniel I Chasman; Erin Austin; Iftikhar J Kullo; Peter E Weeke; Christian M Shaffer; Lisa A Bastarache; Joshua C Denny; Dan M Roden; Colin Palmer; Panos Deloukas; Dan-Yu Lin; Zheng-zheng Tang; Jeanette Erdmann; Heribert Schunkert; John Danesh; Jaume Marrugat; Roberto Elosua; Diego Ardissino; Ruth McPherson; Hugh Watkins; Alex P Reiner; James G Wilson; David Altshuler; Richard A Gibbs; Eric S Lander; Eric Boerwinkle; Stacey Gabriel; Sekar Kathiresan Journal: N Engl J Med Date: 2014-11-12 Impact factor: 91.245
Authors: Melissa J Landrum; Jennifer M Lee; George R Riley; Wonhee Jang; Wendy S Rubinstein; Deanna M Church; Donna R Maglott Journal: Nucleic Acids Res Date: 2013-11-14 Impact factor: 16.971
Authors: Padhraig Gormley; Mitja I Kurki; Marjo Eveliina Hiekkala; Kumar Veerapen; Paavo Häppölä; Adele A Mitchell; Dennis Lal; Priit Palta; Ida Surakka; Mari Anneli Kaunisto; Eija Hämäläinen; Salli Vepsäläinen; Hannele Havanka; Hanna Harno; Matti Ilmavirta; Markku Nissilä; Erkki Säkö; Marja-Liisa Sumelahti; Jarmo Liukkonen; Matti Sillanpää; Liisa Metsähonkala; Seppo Koskinen; Terho Lehtimäki; Olli Raitakari; Minna Männikkö; Caroline Ran; Andrea Carmine Belin; Pekka Jousilahti; Verneri Anttila; Veikko Salomaa; Ville Artto; Markus Färkkilä; Heiko Runz; Mark J Daly; Benjamin M Neale; Samuli Ripatti; Mikko Kallela; Maija Wessman; Aarno Palotie Journal: Neuron Date: 2018-05-03 Impact factor: 17.173
Authors: Frederick E Dewey; Viktoria Gusarova; Richard L Dunbar; Colm O'Dushlaine; Claudia Schurmann; Omri Gottesman; Shane McCarthy; Cristopher V Van Hout; Shannon Bruse; Hayes M Dansky; Joseph B Leader; Michael F Murray; Marylyn D Ritchie; H Lester Kirchner; Lukas Habegger; Alex Lopez; John Penn; An Zhao; Weiping Shao; Neil Stahl; Andrew J Murphy; Sara Hamon; Aurelie Bouzelmat; Rick Zhang; Brad Shumel; Robert Pordy; Daniel Gipe; Gary A Herman; Wayne H H Sheu; I-Te Lee; Kae-Woei Liang; Xiuqing Guo; Jerome I Rotter; Yii-Der I Chen; William E Kraus; Svati H Shah; Scott Damrauer; Aeron Small; Daniel J Rader; Anders Berg Wulff; Børge G Nordestgaard; Anne Tybjærg-Hansen; Anita M van den Hoek; Hans M G Princen; David H Ledbetter; David J Carey; John D Overton; Jeffrey G Reid; William J Sasiela; Poulabi Banerjee; Alan R Shuldiner; Ingrid B Borecki; Tanya M Teslovich; George D Yancopoulos; Scott J Mellis; Jesper Gromada; Aris Baras Journal: N Engl J Med Date: 2017-05-24 Impact factor: 91.245
Authors: Jian V Huang; Andres Cardenas; Elena Colicino; C Mary Schooling; Sheryl L Rifas-Shiman; Golareh Agha; Yinan Zheng; Lifang Hou; Allan C Just; Augusto A Litonjua; Dawn L DeMeo; Xihong Lin; Emily Oken; Marie-France Hivert; Andrea A Baccarelli Journal: Epigenetics Date: 2018-11-13 Impact factor: 4.528
Authors: Yao Yu; Hao Hu; Ryan J Bohlender; Fulan Hu; Jiun-Sheng Chen; Carson Holt; Jerry Fowler; Stephen L Guthery; Paul Scheet; Michelle A T Hildebrandt; Mark Yandell; Chad D Huff Journal: Nucleic Acids Res Date: 2018-04-06 Impact factor: 16.971
Authors: Chuchun L Chang; Itsaso Garcia-Arcos; Rakel Nyrén; Gunilla Olivecrona; Ji Young Kim; Yunying Hu; Rishi R Agrawal; Andrew J Murphy; Ira J Goldberg; Richard J Deckelbaum Journal: Arterioscler Thromb Vasc Biol Date: 2018-01-25 Impact factor: 8.311