Patrick T Ellinor1,2, Marc S Sabatine3, Christian T Ruff3, Nicholas A Marston3, Giorgio E M Melloni3, Yared Gurmu3, Marc P Bonaca4, Frederick K Kamanu3, Carolina Roselli1,5, Christina Lee1, Ilaria Cavallari6, Robert P Giugliano3, Benjamin M Scirica3, Deepak L Bhatt7, Philippe Gabriel Steg8, Marc Cohen9, Robert F Storey10, Anthony C Keech11, Itamar Raz12, Ofri Mosenzon12, Eugene Braunwald3, Steven A Lubitz1,2. 1. Cardiovascular Disease Initiative, Broad Institute of MIT & Harvard, Cambridge, MA (C.R., C.L., S.A.L., P.T.E.). 2. Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.A.L., P.T.E.). 3. TIMI Study Group, Division of Cardiovascular Medicine, Department of Medicine (N.A.M., G.E.M.M., Y.G., F.K.K., R.P.G., B.M.S., E.B., M.S.S., C.T.R.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 4. CPC Clinical Research, Cardiovascular Division, Department of Medicine, University of Colorado School of Medicine, Aurora (M.P.B.). 5. University Medical Center Groningen, University of Groningen, NL (C.R.). 6. Department of Cardiovascular Sciences, Campus Bio-Medico University of Rome, Italy (I.C.). 7. Division of Cardiovascular Medicine, Department of Medicine (D.L.B.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 8. Université de Paris, Assistance Publique-Hôpitaux de Paris, France (P.G.S.). 9. Newark Beth Israel Medical Center, Rutgers Medical School, NJ (M.C.). 10. University of Sheffield, United Kingdom (R.F.S.). 11. Sydney Medical School, National Health & Medical Research Council Clinical Trials Centre, University of Sydney, Australia (A.C.K.). 12. Department of Endocrinology and Metabolism, Hadassah Hebrew University Hospital, Jerusalem, Israel (I.R., O.M.).
Abstract
BACKGROUND: Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality and has a known genetic contribution. We tested the performance of a genetic risk score for its ability to predict VTE in 3 cohorts of patients with cardiometabolic disease. METHODS: We included patients from the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) trials (history of a major atherosclerotic cardiovascular event, myocardial infarction, and diabetes, respectively) who consented for genetic testing and were not on baseline anticoagulation. We calculated a VTE genetic risk score based on 297 single nucleotide polymorphisms with established genome-wide significance. Patients were divided into tertiles of genetic risk. Cox proportional hazards models were used to calculate hazard ratios for VTE across genetic risk groups. The polygenic risk score was compared with available clinical risk factors (age, obesity, smoking, history of heart failure, and diabetes) and common monogenic mutations. RESULTS: A total of 29 663 patients were included in the analysis with a median follow-up of 2.4 years, of whom 174 had a VTE event. There was a significantly increased gradient of risk across VTE genetic risk tertiles (P-trend <0.0001). After adjustment for clinical risk factors, patients in the intermediate and high genetic risk groups had a 1.88-fold (95% CI, 1.23-2.89; P=0.004) and 2.70-fold (95% CI, 1.81-4.06; P<0.0001) higher risk of VTE compared with patients with low genetic risk. In a continuous model adjusted for clinical risk factors, each standard deviation increase in the genetic risk score was associated with a 47% (95% CI, 29-68) increased risk of VTE (P<0.0001). CONCLUSIONS: In a broad spectrum of patients with cardiometabolic disease, a polygenic risk score is a strong, independent predictor of VTE after accounting for available clinical risk factors, identifying 1/3 of patients who have a risk of VTE comparable to that seen with established monogenic thrombophilia.
BACKGROUND: Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality and has a known genetic contribution. We tested the performance of a genetic risk score for its ability to predict VTE in 3 cohorts of patients with cardiometabolic disease. METHODS: We included patients from the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) trials (history of a major atherosclerotic cardiovascular event, myocardial infarction, and diabetes, respectively) who consented for genetic testing and were not on baseline anticoagulation. We calculated a VTE genetic risk score based on 297 single nucleotide polymorphisms with established genome-wide significance. Patients were divided into tertiles of genetic risk. Cox proportional hazards models were used to calculate hazard ratios for VTE across genetic risk groups. The polygenic risk score was compared with available clinical risk factors (age, obesity, smoking, history of heart failure, and diabetes) and common monogenic mutations. RESULTS: A total of 29 663 patients were included in the analysis with a median follow-up of 2.4 years, of whom 174 had a VTE event. There was a significantly increased gradient of risk across VTE genetic risk tertiles (P-trend <0.0001). After adjustment for clinical risk factors, patients in the intermediate and high genetic risk groups had a 1.88-fold (95% CI, 1.23-2.89; P=0.004) and 2.70-fold (95% CI, 1.81-4.06; P<0.0001) higher risk of VTE compared with patients with low genetic risk. In a continuous model adjusted for clinical risk factors, each standard deviation increase in the genetic risk score was associated with a 47% (95% CI, 29-68) increased risk of VTE (P<0.0001). CONCLUSIONS: In a broad spectrum of patients with cardiometabolic disease, a polygenic risk score is a strong, independent predictor of VTE after accounting for available clinical risk factors, identifying 1/3 of patients who have a risk of VTE comparable to that seen with established monogenic thrombophilia.
Authors: Ilaria Cavallari; David A Morrow; Mark A Creager; Jeffrey Olin; Deepak L Bhatt; P Gabriel Steg; Robert F Storey; Marc Cohen; Benjamin S Scirica; Gregory Piazza; Erica L Goodrich; Eugene Braunwald; Marc S Sabatine; Marc P Bonaca Journal: Circulation Date: 2017-10-30 Impact factor: 29.690
Authors: Nicholas A Marston; Frederick K Kamanu; Francesco Nordio; Yared Gurmu; Carolina Roselli; Peter S Sever; Terje R Pedersen; Anthony C Keech; Huei Wang; Armando Lira Pineda; Robert P Giugliano; Steven A Lubitz; Patrick T Ellinor; Marc S Sabatine; Christian T Ruff Journal: Circulation Date: 2019-11-11 Impact factor: 29.690
Authors: Benedetto Simone; Valerio De Stefano; Emanuele Leoncini; Jeppe Zacho; Ida Martinelli; Joseph Emmerich; Elena Rossi; Aaron R Folsom; Wassim Y Almawi; Pierre Y Scarabin; Martin den Heijer; Mary Cushman; Silvana Penco; Amparo Vaya; Pantep Angchaisuksiri; Gulfer Okumus; Donato Gemmati; Simona Cima; Nejat Akar; Kivilcim I Oguzulgen; Véronique Ducros; Christoph Lichy; Consuelo Fernandez-Miranda; Andrzej Szczeklik; José A Nieto; Jose Domingo Torres; Véronique Le Cam-Duchez; Petar Ivanov; Carlos Cantu-Brito; Veronika M Shmeleva; Mojka Stegnar; Dotun Ogunyemi; Suhair S Eid; Nicola Nicolotti; Emma De Feo; Walter Ricciardi; Stefania Boccia Journal: Eur J Epidemiol Date: 2013-07-31 Impact factor: 8.082
Authors: J L Mega; N O Stitziel; S Kathiresan; M S Sabatine; J G Smith; D I Chasman; M Caulfield; J J Devlin; F Nordio; C Hyde; C P Cannon; F Sacks; N Poulter; P Sever; P M Ridker; E Braunwald; O Melander Journal: Lancet Date: 2015-03-04 Impact factor: 79.321
Authors: Scott M Damrauer; Pradeep Natarajan; Derek Klarin; Emma Busenkell; Renae Judy; Julie Lynch; Michael Levin; Jeffery Haessler; Krishna Aragam; Mark Chaffin; Mary Haas; Sara Lindström; Themistocles L Assimes; Jie Huang; Kyung Min Lee; Qing Shao; Jennifer E Huffman; Christopher Kabrhel; Yunfeng Huang; Yan V Sun; Marijana Vujkovic; Danish Saleheen; Donald R Miller; Peter Reaven; Scott DuVall; William E Boden; Saiju Pyarajan; Alex P Reiner; David-Alexandre Trégouët; Peter Henke; Charles Kooperberg; J Michael Gaziano; John Concato; Daniel J Rader; Kelly Cho; Kyong-Mi Chang; Peter W F Wilson; Nicholas L Smith; Christopher J O'Donnell; Philip S Tsao; Sekar Kathiresan; Andrea Obi Journal: Nat Genet Date: 2019-11-01 Impact factor: 38.330
Authors: Junqing Xie; Albert Prats-Uribe; Maria Gordillo-Marañón; Victoria Y Strauss; Dipender Gill; Daniel Prieto-Alhambra Journal: J Thromb Haemost Date: 2022-09-15 Impact factor: 16.036