Montse Guardiola1, Holly J Exeter2, Claire Perret2, Lasse Folkersen2, Ferdinand Van't Hooft2, Per Eriksson2, Anders Franco-Cereceda2, Gabrielle Paulsson-Berne2, Jutta Palmen2, KaWah Li2, Jackie A Cooper2, Kay-Tee Khaw2, Ziad Mallat2, Ewa Ninio2, Sonia-Athina Karabina2, Steve E Humphries2, S Matthijs Boekholdt2, Michael V Holmes2, Philippa J Talmud2. 1. From the Center for Cardiovascular Genetics, Institute of Cardiovascular Science (M.G., H.J.E., J.P., K.W.L., J.A.C., S.E.H., P.J.T.), and Genetic Epidemiology Group, Department of Epidemiology and Public Health (M.V.H.), University College London, London, UK; Unitat de Recerca en Lípids i Arteriosclerosi, Universitat Rovira i Virgili, CIBERDEM, IISPV, Reus, Spain (M.G.); Genomics and Pathophysiology of Cardiovascular Diseases Team, ICAN, Sorbonne Universités, UPMC University Paris 06, INSERM UMR_S 1166, Paris, France (C.P., E.N.); Molecular Genetics Department, Novo Nordisk A/S, Copenhagen, Denmark (L.F.); Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital Solna, Stockholm, Sweden (L.F., F.v.H., P.E., G.P.-B.); Atherosclerosis Research Unit, Department of Medicine Solna (F.v.H., P.E.), and Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge (K.-T.K.); Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, England, UK (Z.M.); Sorbonne Universités, UPMC Univ Paris 06 (S.-A.K.), and Physiopathology of Genetic Diseases With Pediatric Expression, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 933, Paris, France (S.-A.K.); Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands (S.M.B.); and Department of Surgery and Clinical Epidemiology Unit, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (M.V.H.). montse.guardiola@urv.cat. 2. From the Center for Cardiovascular Genetics, Institute of Cardiovascular Science (M.G., H.J.E., J.P., K.W.L., J.A.C., S.E.H., P.J.T.), and Genetic Epidemiology Group, Department of Epidemiology and Public Health (M.V.H.), University College London, London, UK; Unitat de Recerca en Lípids i Arteriosclerosi, Universitat Rovira i Virgili, CIBERDEM, IISPV, Reus, Spain (M.G.); Genomics and Pathophysiology of Cardiovascular Diseases Team, ICAN, Sorbonne Universités, UPMC University Paris 06, INSERM UMR_S 1166, Paris, France (C.P., E.N.); Molecular Genetics Department, Novo Nordisk A/S, Copenhagen, Denmark (L.F.); Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital Solna, Stockholm, Sweden (L.F., F.v.H., P.E., G.P.-B.); Atherosclerosis Research Unit, Department of Medicine Solna (F.v.H., P.E.), and Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge (K.-T.K.); Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, England, UK (Z.M.); Sorbonne Universités, UPMC Univ Paris 06 (S.-A.K.), and Physiopathology of Genetic Diseases With Pediatric Expression, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 933, Paris, France (S.-A.K.); Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands (S.M.B.); and Department of Surgery and Clinical Epidemiology Unit, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (M.V.H.).
Abstract
BACKGROUND: Observational studies report that secretory phospholipase A2 (sPLA2) activity is a marker for coronary heart disease (CHD) risk, and activity measures are thought to represent the composite activity of sPLA2-IIA, -V, and -X. The aim of this study was to use genetic variants of PLA2G10, encoding sPLA2-X, to investigate the contribution of sPLA2-X to the measure of sPLA2 activity and coronary heart disease (CHD) risk traits and outcome. METHODS AND RESULTS: Three PLA2G10 tagging single-nucleotide polymorphisms (rs72546339, rs72546340, and rs4003232) and a previously studied PLA2G10 coding single-nucleotide polymorphism rs4003228, R38C, were genotyped in a nested case: control cohort drawn from the prospective EPIC-Norfolk Study (2175 cases and 2175 controls). Meta-analysis of rs4003228 (R38C) and CHD was performed using data from the Northwick Park Heart Study II and 2 published cohorts AtheroGene and SIPLAC, providing in total an additional 1884 cases and 3119 controls. EPIC-Norfolk subjects in the highest tertile of sPLA2 activity were older and had higher inflammatory markers compared with those in the lowest tertile for sPLA2 activity. None of the PLA2G10 tagging single-nucleotide polymorphism nor R38C, a functional variant, were significantly associated with sPLA2 activity, intermediate CHD risk traits, or CHD risk. In meta-analysis, the summary odds ratio for R38C was odds ratio=0.97 (95% confidence interval, 0.77-1.22). CONCLUSIONS: PLA2G10 variants are not significantly associated with plasma sPLA2 activity or with CHD risk.
BACKGROUND: Observational studies report that secretory phospholipase A2 (sPLA2) activity is a marker for coronary heart disease (CHD) risk, and activity measures are thought to represent the composite activity of sPLA2-IIA, -V, and -X. The aim of this study was to use genetic variants of PLA2G10, encoding sPLA2-X, to investigate the contribution of sPLA2-X to the measure of sPLA2 activity and coronary heart disease (CHD) risk traits and outcome. METHODS AND RESULTS: Three PLA2G10 tagging single-nucleotide polymorphisms (rs72546339, rs72546340, and rs4003232) and a previously studied PLA2G10 coding single-nucleotide polymorphism rs4003228, R38C, were genotyped in a nested case: control cohort drawn from the prospective EPIC-Norfolk Study (2175 cases and 2175 controls). Meta-analysis of rs4003228 (R38C) and CHD was performed using data from the Northwick Park Heart Study II and 2 published cohorts AtheroGene and SIPLAC, providing in total an additional 1884 cases and 3119 controls. EPIC-Norfolk subjects in the highest tertile of sPLA2 activity were older and had higher inflammatory markers compared with those in the lowest tertile for sPLA2 activity. None of the PLA2G10 tagging single-nucleotide polymorphism nor R38C, a functional variant, were significantly associated with sPLA2 activity, intermediate CHD risk traits, or CHD risk. In meta-analysis, the summary odds ratio for R38C was odds ratio=0.97 (95% confidence interval, 0.77-1.22). CONCLUSIONS: PLA2G10 variants are not significantly associated with plasma sPLA2 activity or with CHD risk.
Authors: Fabrizio Giordanetto; Laurent Knerr; Peter Nordberg; Daniel Pettersen; Nidhal Selmi; Hans-Georg Beisel; Hannah de la Motte; Åsa Månsson; Mikael Dahlström; Johan Broddefalk; Gabrielle Saarinen; Fredrik Klingegård; Eva Hurt-Camejo; Birgitta Rosengren; Johannes Wikström; Maria Wågberg; Johan Brengdahl; Mattias Rohman; Jenny Sandmark; Tomas Åkerud; Robert G Roth; Frank Jansen; Marie Ahlqvist Journal: ACS Med Chem Lett Date: 2018-06-23 Impact factor: 4.345
Authors: Timothy A McCaffrey; Ian Toma; Zhaoquing Yang; Richard Katz; Jonathan Reiner; Ramesh Mazhari; Palak Shah; Michael Tackett; Dan Jones; Tisha Jepson; Zachary Falk; Richard Wargodsky; Dmitry Shtakalo; Denis Antonets; Justin Ertle; Ju H Kim; Yinglei Lai; Zeynep Arslan; Emily Aledort; Maha Alfaraidy; Georges St Laurent Journal: BMC Med Genomics Date: 2021-09-03 Impact factor: 3.063