Meta-Analysis

. 2020 Aug 11;142(6):546-555.

doi: 10.1161/CIRCULATIONAHA.119.045526. Epub 2020 Jul 13.

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data

Bakhtawar K Mahmoodi^{1

2}, Vinicius Tragante³, Marcus E Kleber⁴, Michael V Holmes^{5

6}, Amand F Schmidt^{3

7}, Raymond O McCubrey⁸, Laurence J Howe⁷, Kenan Direk⁷, Hooman Allayee⁹, Ekaterina V Baranova¹⁰, Peter S Braund^{11

12}, Graciela E Delgado⁴, Niclas Eriksson¹³, Crystel M Gijsberts¹⁴, Yan Gong¹⁵, Jaana Hartiala^{9

16}, Mahyar Heydarpour^{17

18}, Gerard Pasterkamp¹⁹, Salma Kotti²⁰, Pekka Kuukasjärvi²¹, Petra A Lenzini²², Daniel Levin²³, Leo-Pekka Lyytikäinen^{24

25}, Jochen D Muehlschlegel^{17

18}, Christopher P Nelson^{14

11}, Kjell Nikus^{26

27}, Anna P Pilbrow²⁸, W H Wilson Tang^{29

30}, Sander W van der Laan³¹, Jessica van Setten³, Ragnar O Vilmundarson³², John Deanfield⁷, Panos Deloukas³³, Frank Dudbridge³⁴, Stefan James^{13

35}, Ify R Mordi²³, Andrej Teren^{36

37}, Thomas O Bergmeijer¹, Simon C Body³⁸, Michiel Bots^{39

40}, Ralph Burkhardt³⁷, Rhonda M Cooper-DeHoff^{15

41}, Sharon Cresci^{22

42}, Nicolas Danchin⁴³, Robert N Doughty⁴⁴, Diederick E Grobbee³⁹, Emil Hagström^{35

45}, Stanley L Hazen^{29

46}, Claes Held^{13

35}, Imo E Hoefer⁴⁷, G Kees Hovingh⁴⁸, Julie A Johnson^{15

41}, Marcin P Kaczor⁴⁹, Mika Kähönen^{50

51}, Olaf H Klungel¹⁰, Jari O Laurikka^{21

52}, Terho Lehtimäki^{24

25}, Anke H Maitland-van der Zee^{10

53}, Ruth McPherson⁵⁴, Colin N Palmer⁵⁵, Adriaan O Kraaijeveld³, Carl J Pepine⁴¹, Marek Sanak⁴⁹, Naveed Sattar⁵⁶, Markus Scholz^{37

57}, Tabassome Simon^{58

59}, John A Spertus^{60

61}, Alexandre F R Stewart^{32

54}, Wojciech Szczeklik⁴⁹, Joachim Thiery^{37

62}, Frank L J Visseren⁶³, Johannes Waltenberger⁶⁴, A Mark Richards^{28

65}, Chim C Lang²³, Vicky A Cameron²⁸, Axel Åkerblom^{13

35}, Guillaume Pare^{66

67}, Winfried März^{4

68

69}, Nilesh J Samani^{11

12}, Aroon D Hingorani⁷, Jurriën M Ten Berg¹, Lars Wallentin^#¹³, Folkert W Asselbergs^#^{3

7

70}, Riyaz S Patel^#^{7

71}

Affiliations

¹ St. Antonius Hospital, Department of Cardiology, Nieuwegein, the Netherlands (B.K.M., T.O.B., J.M.t.B.).
² Division of Hemostasis and Thrombosis, Department of Hematology, UMC Groningen, University of Groningen, The Netherlands (B.K.M.).
³ Department of Cardiology, Division Heart and Lungs (V.T., A.F.S., J.v.S., A.O.K., F.W.A.), UMC Utrecht, Utrecht University, the Netherlands.
⁴ Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Germany (M.E.K., G.E.D., W.M.).
⁵ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health and Medical Research Council Population Health Research Unit, University of Oxford, United Kingdom (M.V.H.).
⁶ National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, United Kingdom (M.V.H.).
⁷ Institute of Cardiovascular Science and UCL BHF Research Accelerator, Faculty of Population Health Science, University College London, United Kingdom (A.F.S., L.J.H., K.D., J.D., A.D.H., F.W.A., R.S.P.).
⁸ Intermountain Heart Institute, Intermountain Medical Center, Salt Lake City, UT (R.O.McC.).
⁹ Departments of Preventive Medicine and Biochemistry and Molecular Medicine (H.A., J.H.), Keck School of Medicine of University of Southern California, Los Angeles.
¹⁰ Division of Pharmacoepidemiology and Clinical Pharmacology (E.V.B., O.H.K., A.H.M.-v.d.Z.), UMC Utrecht, Utrecht University, the Netherlands.
¹¹ Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, United Kingdom (P.S.B., C.P.N., N.J.S.).
¹² NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (P.S.B., C.P.N., N.J.S.).
¹³ Uppsala Clinical Research Center, Sweden (N.E., S.J., C.H., A.Å., L.W.).
¹⁴ Laboratory of Experimental Cardiology (C.M.G.), UMC Utrecht, Utrecht University, the Netherlands.
¹⁵ Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (Y.G., R.M.C.-D.H., J.A.J.), University of Florida, Gainesville.
¹⁶ Institute for Genetic Medicine (J.H.), Keck School of Medicine of University of Southern California, Los Angeles.
¹⁷ Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA (M.H., J.D.M.).
¹⁸ Harvard Medical School, Harvard University, Boston, MA (M.H., J.D.M.).
¹⁹ Department of Clinical Chemistry (G.Pasterkamp), UMC Utrecht, Utrecht University, the Netherlands.
²⁰ Assistance Publique-Hôpitaux de Paris (APHP), Department of Clinical Pharmacology, Platform of Clinical Research of East Paris (URCEST-CRCEST-CRB HUEP-UPMC), France (S.K.).
²¹ Departments of Cardio-Thoracic Surgery (P.K., J.O.L.), Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Techonology, Tampere University, Finland.
²² Department of Genetics, Statistical Genomics Division (P.A.L., S.C.), Washington University School of Medicine, Saint Louis, MO.
²³ Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Scotland, United Kingdom (D.L., I.R.M., C.C.L.).
²⁴ Clinical Chemistry (L.-P.L., T.L.), Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Techonology, Tampere University, Finland.
²⁵ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland (L.-P.L., T.L.).
²⁶ Cardiology (K.N.), Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Techonology, Tampere University, Finland.
²⁷ Department of Cardiology (K.N.), Heart Center, Tampere University Hospital, Finland.
²⁸ The Christchurch Heart Institute, University of Otago Christchurch, New Zealand (A.P.P., A.M.R., V.A.C.).
²⁹ Department of Cardiovascular and Metabolic Sciences, Lerner Research institute (W.H.W.T., S.L.H.), Cleveland Clinic, OH.
³⁰ Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, OH.
³¹ Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics (S.W.v.d.L.), UMC Utrecht, Utrecht University, the Netherlands.
³² Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ontario, Canada (R.O.V., A.F.R.S.).
³³ William Harvey Research Institute, Barts and the London Medical School, and the Centre for Genomic Health, Queen Mary University of London, United Kingdom (P.D.).
³⁴ Department of Health Sciences, University of Leicester, United Kingdom (F.D.).
³⁵ Department of Medical Sciences, Cardiology, Uppsala University, Sweden (S.J., E.H., C.H., A.Å., L.W.).
³⁶ Heart Center Leipzig, Germany (A.T.).
³⁷ LIFE Research Center for Civilization Diseases (A.T., R.B., M.Scholz, J.T.), University of Leipzig, Germany.
³⁸ Department of Anesthesiology, Boston University School of Medicine, MA (S.C.B.).
³⁹ Julius Center for Health Sciences and Primary Care (M.B., D.E.G.), UMC Utrecht, Utrecht University, the Netherlands.
⁴⁰ Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Germany (R.B.).
⁴¹ College of Medicine, Division of Cardiovascular Medicine (R.M.C.-D.H., J.A.J., C.J.P.), University of Florida, Gainesville.
⁴² Department of Medicine, Cardiovascular Division (S.C.), Washington University School of Medicine, Saint Louis, MO.
⁴³ Assistance Publique-Hôpitaux de Paris (APHP), Department of Cardiology, Hôpital Européen Georges Pompidou; FACT (french Alliance for cardiovascular trials); and Université Paris Descartes, France (N.D.).
⁴⁴ Heart Health Research Group, University of Auckland, New Zealand (R.N.D.).
⁴⁵ Department of Cardiology, Uppsala University, and Uppsala Clinical Research Center, Sweden (E.H.).
⁴⁶ Center for Microbiome and Human Health (S.L.H.), Cleveland Clinic, OH.
⁴⁷ Department of Clinical Chemistry and Hematology (I.E.H.), UMC Utrecht, Utrecht University, the Netherlands.
⁴⁸ Department of Vascular Medicine (G.K.H.), Academic Medical Center, University of Amsterdam, The Netherlands.
⁴⁹ Department of Internal Medicine, Jagiellonian University Medical College, Kraków, Poland (M.P.K., M.Sanak, W.S.).
⁵⁰ Clinical Physiology (M.K.), Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Techonology, Tampere University, Finland.
⁵¹ Department of Clinical Physiology, Tampere University Hospital, Finland (M.K.).
⁵² Department of Cardio-Thoracic Surgery (J.O.L.), Heart Center, Tampere University Hospital, Finland.
⁵³ Department of Respiratory Medicine (A.H.M.-v.d.Z.), Academic Medical Center, University of Amsterdam, The Netherlands.
⁵⁴ Departments of Medicine and Biochemistry, Microbiology, and Immunology, University of Ottawa, Ontario, Canada (R.McP. R.O.V., A.F.R.S.).
⁵⁵ Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.N.P.).
⁵⁶ Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.S.).
⁵⁷ Institute for Medical Informatics, Statistics, and Epidemiology (M.Scholz), University of Leipzig, Germany.
⁵⁸ Assistance Publique-Hôpitaux de Paris (APHP), Department of Clinical Pharmacology, Platform of Clinical Research of East Paris (URCEST-CRCEST-CRB HUEP-UPMC), FACT (French Alliance for Cardiovascular trials); Sorbonne Université, Paris-06, France (T.S.).
⁵⁹ Paris-Sorbonne University, UPMC-Site St Antoine, France (T.S.).
⁶⁰ University of Missouri-Kansas City (J.A.S.).
⁶¹ Saint Luke's Mid America Heart Institute, Kansas City, MO (J.A.S.).
⁶² Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital, Leipzig, Germany (J.T.).
⁶³ Department of Vascular Medicine (F.L.J.V.), UMC Utrecht, Utrecht University, the Netherlands.
⁶⁴ Department of Cardiovascular Medicine, University of Münster, Germany (J.W.).
⁶⁵ Cardiovascular Research Institute, National University of Singapore (A.M.R.).
⁶⁶ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada (G.Pare).
⁶⁷ Population Health Research Institute, Hamilton, Ontario, Canada (G.Pare).
⁶⁸ Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany (W.M.).
⁶⁹ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria (W.M.).
⁷⁰ Health Data Research UK and Institute of Health Informatics, University College London, United Kingdom (F.W.A.).
⁷¹ Bart's Heart Centre, St Bartholomew's Hospital, London, United Kingdom (R.S.P.).

^# Contributed equally.

PMID: 32654539
PMCID: PMC7493828
DOI: 10.1161/CIRCULATIONAHA.119.045526

Meta-Analysis

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data

Bakhtawar K Mahmoodi et al. Circulation. 2020.

. 2020 Aug 11;142(6):546-555.

doi: 10.1161/CIRCULATIONAHA.119.045526. Epub 2020 Jul 13.

Authors

Affiliations

¹ St. Antonius Hospital, Department of Cardiology, Nieuwegein, the Netherlands (B.K.M., T.O.B., J.M.t.B.).
² Division of Hemostasis and Thrombosis, Department of Hematology, UMC Groningen, University of Groningen, The Netherlands (B.K.M.).
³ Department of Cardiology, Division Heart and Lungs (V.T., A.F.S., J.v.S., A.O.K., F.W.A.), UMC Utrecht, Utrecht University, the Netherlands.
⁴ Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Germany (M.E.K., G.E.D., W.M.).
⁵ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health and Medical Research Council Population Health Research Unit, University of Oxford, United Kingdom (M.V.H.).
⁶ National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, United Kingdom (M.V.H.).
⁷ Institute of Cardiovascular Science and UCL BHF Research Accelerator, Faculty of Population Health Science, University College London, United Kingdom (A.F.S., L.J.H., K.D., J.D., A.D.H., F.W.A., R.S.P.).
⁸ Intermountain Heart Institute, Intermountain Medical Center, Salt Lake City, UT (R.O.McC.).
⁹ Departments of Preventive Medicine and Biochemistry and Molecular Medicine (H.A., J.H.), Keck School of Medicine of University of Southern California, Los Angeles.
¹⁰ Division of Pharmacoepidemiology and Clinical Pharmacology (E.V.B., O.H.K., A.H.M.-v.d.Z.), UMC Utrecht, Utrecht University, the Netherlands.
¹¹ Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, United Kingdom (P.S.B., C.P.N., N.J.S.).
¹² NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (P.S.B., C.P.N., N.J.S.).
¹³ Uppsala Clinical Research Center, Sweden (N.E., S.J., C.H., A.Å., L.W.).
¹⁴ Laboratory of Experimental Cardiology (C.M.G.), UMC Utrecht, Utrecht University, the Netherlands.
¹⁵ Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (Y.G., R.M.C.-D.H., J.A.J.), University of Florida, Gainesville.
¹⁶ Institute for Genetic Medicine (J.H.), Keck School of Medicine of University of Southern California, Los Angeles.
¹⁷ Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA (M.H., J.D.M.).
¹⁸ Harvard Medical School, Harvard University, Boston, MA (M.H., J.D.M.).
¹⁹ Department of Clinical Chemistry (G.Pasterkamp), UMC Utrecht, Utrecht University, the Netherlands.
²⁰ Assistance Publique-Hôpitaux de Paris (APHP), Department of Clinical Pharmacology, Platform of Clinical Research of East Paris (URCEST-CRCEST-CRB HUEP-UPMC), France (S.K.).
²¹ Departments of Cardio-Thoracic Surgery (P.K., J.O.L.), Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Techonology, Tampere University, Finland.
²² Department of Genetics, Statistical Genomics Division (P.A.L., S.C.), Washington University School of Medicine, Saint Louis, MO.
²³ Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Scotland, United Kingdom (D.L., I.R.M., C.C.L.).
²⁴ Clinical Chemistry (L.-P.L., T.L.), Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Techonology, Tampere University, Finland.
²⁵ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland (L.-P.L., T.L.).
²⁶ Cardiology (K.N.), Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Techonology, Tampere University, Finland.
²⁷ Department of Cardiology (K.N.), Heart Center, Tampere University Hospital, Finland.
²⁸ The Christchurch Heart Institute, University of Otago Christchurch, New Zealand (A.P.P., A.M.R., V.A.C.).
²⁹ Department of Cardiovascular and Metabolic Sciences, Lerner Research institute (W.H.W.T., S.L.H.), Cleveland Clinic, OH.
³⁰ Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, OH.
³¹ Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics (S.W.v.d.L.), UMC Utrecht, Utrecht University, the Netherlands.
³² Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ontario, Canada (R.O.V., A.F.R.S.).
³³ William Harvey Research Institute, Barts and the London Medical School, and the Centre for Genomic Health, Queen Mary University of London, United Kingdom (P.D.).
³⁴ Department of Health Sciences, University of Leicester, United Kingdom (F.D.).
³⁵ Department of Medical Sciences, Cardiology, Uppsala University, Sweden (S.J., E.H., C.H., A.Å., L.W.).
³⁶ Heart Center Leipzig, Germany (A.T.).
³⁷ LIFE Research Center for Civilization Diseases (A.T., R.B., M.Scholz, J.T.), University of Leipzig, Germany.
³⁸ Department of Anesthesiology, Boston University School of Medicine, MA (S.C.B.).
³⁹ Julius Center for Health Sciences and Primary Care (M.B., D.E.G.), UMC Utrecht, Utrecht University, the Netherlands.
⁴⁰ Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Germany (R.B.).
⁴¹ College of Medicine, Division of Cardiovascular Medicine (R.M.C.-D.H., J.A.J., C.J.P.), University of Florida, Gainesville.
⁴² Department of Medicine, Cardiovascular Division (S.C.), Washington University School of Medicine, Saint Louis, MO.
⁴³ Assistance Publique-Hôpitaux de Paris (APHP), Department of Cardiology, Hôpital Européen Georges Pompidou; FACT (french Alliance for cardiovascular trials); and Université Paris Descartes, France (N.D.).
⁴⁴ Heart Health Research Group, University of Auckland, New Zealand (R.N.D.).
⁴⁵ Department of Cardiology, Uppsala University, and Uppsala Clinical Research Center, Sweden (E.H.).
⁴⁶ Center for Microbiome and Human Health (S.L.H.), Cleveland Clinic, OH.
⁴⁷ Department of Clinical Chemistry and Hematology (I.E.H.), UMC Utrecht, Utrecht University, the Netherlands.
⁴⁸ Department of Vascular Medicine (G.K.H.), Academic Medical Center, University of Amsterdam, The Netherlands.
⁴⁹ Department of Internal Medicine, Jagiellonian University Medical College, Kraków, Poland (M.P.K., M.Sanak, W.S.).
⁵⁰ Clinical Physiology (M.K.), Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Techonology, Tampere University, Finland.
⁵¹ Department of Clinical Physiology, Tampere University Hospital, Finland (M.K.).
⁵² Department of Cardio-Thoracic Surgery (J.O.L.), Heart Center, Tampere University Hospital, Finland.
⁵³ Department of Respiratory Medicine (A.H.M.-v.d.Z.), Academic Medical Center, University of Amsterdam, The Netherlands.
⁵⁴ Departments of Medicine and Biochemistry, Microbiology, and Immunology, University of Ottawa, Ontario, Canada (R.McP. R.O.V., A.F.R.S.).
⁵⁵ Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.N.P.).
⁵⁶ Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.S.).
⁵⁷ Institute for Medical Informatics, Statistics, and Epidemiology (M.Scholz), University of Leipzig, Germany.
⁵⁸ Assistance Publique-Hôpitaux de Paris (APHP), Department of Clinical Pharmacology, Platform of Clinical Research of East Paris (URCEST-CRCEST-CRB HUEP-UPMC), FACT (French Alliance for Cardiovascular trials); Sorbonne Université, Paris-06, France (T.S.).
⁵⁹ Paris-Sorbonne University, UPMC-Site St Antoine, France (T.S.).
⁶⁰ University of Missouri-Kansas City (J.A.S.).
⁶¹ Saint Luke's Mid America Heart Institute, Kansas City, MO (J.A.S.).
⁶² Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital, Leipzig, Germany (J.T.).
⁶³ Department of Vascular Medicine (F.L.J.V.), UMC Utrecht, Utrecht University, the Netherlands.
⁶⁴ Department of Cardiovascular Medicine, University of Münster, Germany (J.W.).
⁶⁵ Cardiovascular Research Institute, National University of Singapore (A.M.R.).
⁶⁶ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada (G.Pare).
⁶⁷ Population Health Research Institute, Hamilton, Ontario, Canada (G.Pare).
⁶⁸ Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany (W.M.).
⁶⁹ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria (W.M.).
⁷⁰ Health Data Research UK and Institute of Health Informatics, University College London, United Kingdom (F.W.A.).
⁷¹ Bart's Heart Centre, St Bartholomew's Hospital, London, United Kingdom (R.S.P.).

^# Contributed equally.

PMID: 32654539
PMCID: PMC7493828
DOI: 10.1161/CIRCULATIONAHA.119.045526

Abstract

Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD.

Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality.

Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I²=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity.

Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

Keywords: coronary artery disease; genetic association studies; myocardial infarction; prognosis; secondary prevention; single nucleotide polymorphism; thrombosis.

PubMed Disclaimer

Figures

**Figure 1.. Pooled associations of factor V Leiden with the primary outcome in patients with overall and subtypes of baseline CHD.**
CHD= coronary heart disease, ACS= acute coronary syndrome, CAD=coronary artery disease, MI=myocardial infarction, E=number of the primary outcome (i.e., composite of myocardial infarction and CHD death), N= total number of included participants, S= number of studies contributing to the pooled estimates, HR= hazard ratio, and CI= confidence interval. Estimates are adjusted for sex and age and are based on fixed-effect meta-analysis.

**Figure 2.. Pooled associations of factor V Leiden with the primary outcome across traditional cardiovascular risk factors strata in the overall CHD population.**
BMI= body-mass index, E=number of the primary outcome (i.e., composite of myocardial infarction and CHD death), N= total number of included participants, S= number of contributing studies, HR= hazard ratio, CI= confidence interval, and P-dif= P for difference across the strata of the variable. Estimates are adjusted for sex and age, when appropriate, and are based on fixed-effect meta-analysis.

**Figure 3.. Association between study-level characteristics and the log-hazard ratios for the primary outcome in the overall CHD population.**
The middle of each bubble represents the log-hazard ratio of the primary outcome from the individual studies against the study-characteristics shown on the x-axis. The sizes of the bubbles are proportional to the inverse of the standard-errors of the log-hazard ratios.

**Figure 4.. Pooled associations of factor V Leiden with the secondary outcomes in the overall CHD population.**
MI= myocardial infarction, CV= cardiovascular, E=number of the outcome, N= total number of included participants, S= number of contributing studies, HR= hazard ratio and CI= confidence interval. Estimates are adjusted for sex and age and are based on fixed-effect meta-analysis. For the estimates of the individual studies contributing to these pooled estimates see Supplemental Figures VI–XI in the Supplement.

See this image and copyright information in PMC

Cited by

Risk Prediction of Cardiovascular Events by Exploration of Molecular Data with Explainable Artificial Intelligence.
Westerlund AM, Hawe JS, Heinig M, Schunkert H. Westerlund AM, et al. Int J Mol Sci. 2021 Sep 24;22(19):10291. doi: 10.3390/ijms221910291. Int J Mol Sci. 2021. PMID: 34638627 Free PMC article. Review.
Factor V Leiden but not the factor II 20210G>A mutation is a risk factor for premature coronary artery disease: a case-control study in Iran.
Agosti P, Mancini I, Sadeghian S, Pagliari MT, Abbasi SH, Pourhosseini H, Boroumand M, Lotfi-Tokaldany M, Pappalardo E, Maino A, Rosendaal FR, Peyvandi F. Agosti P, et al. Res Pract Thromb Haemost. 2023 Jan 11;7(1):100048. doi: 10.1016/j.rpth.2023.100048. eCollection 2023 Jan. Res Pract Thromb Haemost. 2023. PMID: 36798900 Free PMC article.
Factor V Leiden Does Not Modify the Phenotype of Acute Coronary Syndrome or the Extent of Myocardial Necrosis.
Mahmoodi BK, Eriksson N, Vos GJA, Meijer K, Siegbahn A, James S, Wallentin L, Ten Berg JM. Mahmoodi BK, et al. J Am Heart Assoc. 2021 Jun;10(11):e020025. doi: 10.1161/JAHA.120.020025. Epub 2021 May 17. J Am Heart Assoc. 2021. PMID: 33998271 Free PMC article. Clinical Trial.
Association between Factor-V Leiden and occurrence of acute myocardial infarction using a large NIS database.
Zuniga L, Davis M, Movahed MR, Hashemzadeh M, Hashemzadeh M. Zuniga L, et al. Am J Blood Res. 2023 Dec 25;13(6):207-212. doi: 10.62347/XQBZ7374. eCollection 2023. Am J Blood Res. 2023. PMID: 38223312 Free PMC article.
Factor V Leiden and the Risk of Bleeding in Patients With Acute Coronary Syndromes Treated With Antiplatelet Therapy: Pooled Analysis of 3 Randomized Clinical Trials.
Mahmoodi BK, Eriksson N, Ross S, Claassens DMF, Asselbergs FW, Meijer K, Siegbahn A, James S, Pare G, Wallentin L, Ten Berg JM. Mahmoodi BK, et al. J Am Heart Assoc. 2021 Sep 7;10(17):e021115. doi: 10.1161/JAHA.120.021115. Epub 2021 Aug 28. J Am Heart Assoc. 2021. PMID: 34459239 Free PMC article.

See all "Cited by" articles

References

1. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA and Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369:64–67. - PubMed
1. Ridker PM, Miletich JP, Hennekens CH and Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA. 1997;277:1305–1307. - PubMed
1. Simone B, De Stefano V, Leoncini E, Zacho J, Martinelli I, Emmerich J, Rossi E, Folsom AR, Almawi WY, Scarabin PY, et al. Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. Eur J Epidemiol. 2013;28:621–647. - PMC - PubMed
1. Bentley P, Peck G, Smeeth L, Whittaker J and Sharma P. Causal relationship of susceptibility genes to ischemic stroke: comparison to ischemic heart disease and biochemical determinants. PLoS ONE. 2010;5:e9136. - PMC - PubMed
1. Hamedani AG, Cole JW, Mitchell BD and Kittner SJ. Meta-analysis of factor V Leiden and ischemic stroke in young adults: the importance of case ascertainment. Stroke. 2010;41:1599–1603. - PMC - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data

Affiliations

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data

Authors

Affiliations

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical