Jessica R Golbus1, Nathan O Stitziel2, Wei Zhao2, Chenyi Xue2, Martin Farrall2, Ruth McPherson2, Jeanette Erdmann2, Panos Deloukas2, Hugh Watkins2, Heribert Schunkert2, Nilesh J Samani2, Danish Saleheen2, Sekar Kathiresan2, Muredach P Reilly1. 1. From the Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia (J.R.G.); Cardiovascular Division, Department of Medicine (N.O.S.), Department of Genetics and McDonnell Genome Institute (N.O.S.), Washington University School of Medicine, St. Louis, MO; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia (W.Z., C.X., D.S.); Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F., H.W.); Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.M.); Medizinische Klinik II, University of Lübeck, Lübeck, Germany (J.E.); William Harvey Research Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (P.D.); Deutsches Herzzentrum München, Technische Universität München, DZHK, Munich Heart Alliance, München, Germany (H.S.); Department of Cardiovascular Sciences, University of Leicester & NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); Center for Human Genetic Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.K.); Department of Medicine, Harvard Medical School, Boston, MA (S.K.); Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (S.K.); and Department of Medicine, Columbia University, New York, NY (M.P.R.). jessica.golbus@uphs.upenn.edu mpr2144@cumc.columbia.edu. 2. From the Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia (J.R.G.); Cardiovascular Division, Department of Medicine (N.O.S.), Department of Genetics and McDonnell Genome Institute (N.O.S.), Washington University School of Medicine, St. Louis, MO; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia (W.Z., C.X., D.S.); Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F., H.W.); Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.M.); Medizinische Klinik II, University of Lübeck, Lübeck, Germany (J.E.); William Harvey Research Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (P.D.); Deutsches Herzzentrum München, Technische Universität München, DZHK, Munich Heart Alliance, München, Germany (H.S.); Department of Cardiovascular Sciences, University of Leicester & NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); Center for Human Genetic Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.K.); Department of Medicine, Harvard Medical School, Boston, MA (S.K.); Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (S.K.); and Department of Medicine, Columbia University, New York, NY (M.P.R.).
Abstract
BACKGROUND: The chemokine receptors CCR2, CCR5, and CX3CR1 coordinate monocyte trafficking in homeostatic and inflammatory states. Multiple small human genetic studies have variably linked single nucleotide polymorphisms in these genes to cardiometabolic disease. We interrogated genome-wide association, exome sequencing, and exome array genotyping studies to ascertain the relationship between variation in these genes and coronary artery disease (CAD), myocardial infarction (MI), and glucometabolic traits. METHODS AND RESULTS: We interrogated the CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) (60 801 cases and 123 504 controls), the MIGen and CARDIoGRAM Exome consortia (42 335 cases and 78 240 controls), and Exome Sequencing Project and Early-Onset Myocardial Infarction (ESP EOMI; 4703 cases and 5090 controls) data sets to ascertain the relationship between common, low frequency, and rare variation in CCR2, CCR5, or CX3CR1 with CAD and MI. We did not identify any variant associated with CAD or MI. We then explored common and low-frequency variation in South Asians through Pakistan Risk of Myocardial Infarction Study (PROMIS; 9058 cases and 8379 controls), identifying 6 variants associated with MI including CX3CR1 V249I. Finally, reanalysis of the European HapMap imputed Diabetes Genetics Replication and Meta-Analysis (DIAGRAM), Global Lipids Genetics Consortium (GLGC), Genetic Investigation of Anthropometric Traits (GIANT), and Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC) data sets revealed no association with glucometabolic traits although 3 single nucleotide polymorphisms in PROMIS were associated with type II diabetes mellitus. CONCLUSIONS: No chemokine receptor variant was associated with CAD, MI, or glucometabolic traits in large European ancestry cohorts. In a South Asian cohort, we identified single nucleotide polymorphism associations with MI and type II diabetes mellitus but these did not meet significance in cohorts of European ancestry. These findings suggest the need for larger studies in South Asians but exclude clinically meaningful associations with CAD and glucometabolic traits in Europeans.
BACKGROUND: The chemokine receptors CCR2, CCR5, and CX3CR1 coordinate monocyte trafficking in homeostatic and inflammatory states. Multiple small human genetic studies have variably linked single nucleotide polymorphisms in these genes to cardiometabolic disease. We interrogated genome-wide association, exome sequencing, and exome array genotyping studies to ascertain the relationship between variation in these genes and coronary artery disease (CAD), myocardial infarction (MI), and glucometabolic traits. METHODS AND RESULTS: We interrogated the CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) (60 801 cases and 123 504 controls), the MIGen and CARDIoGRAM Exome consortia (42 335 cases and 78 240 controls), and Exome Sequencing Project and Early-Onset Myocardial Infarction (ESP EOMI; 4703 cases and 5090 controls) data sets to ascertain the relationship between common, low frequency, and rare variation in CCR2, CCR5, or CX3CR1 with CAD and MI. We did not identify any variant associated with CAD or MI. We then explored common and low-frequency variation in South Asians through Pakistan Risk of Myocardial Infarction Study (PROMIS; 9058 cases and 8379 controls), identifying 6 variants associated with MI including CX3CR1 V249I. Finally, reanalysis of the European HapMap imputed Diabetes Genetics Replication and Meta-Analysis (DIAGRAM), Global Lipids Genetics Consortium (GLGC), Genetic Investigation of Anthropometric Traits (GIANT), and Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC) data sets revealed no association with glucometabolic traits although 3 single nucleotide polymorphisms in PROMIS were associated with type II diabetes mellitus. CONCLUSIONS: No chemokine receptor variant was associated with CAD, MI, or glucometabolic traits in large European ancestry cohorts. In a South Asian cohort, we identified single nucleotide polymorphism associations with MI and type II diabetes mellitus but these did not meet significance in cohorts of European ancestry. These findings suggest the need for larger studies in South Asians but exclude clinically meaningful associations with CAD and glucometabolic traits in Europeans.
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