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. 2021 Feb;14(1):e003006.
doi: 10.1161/CIRCGEN.120.003006. Epub 2021 Jan 12.

Genetic Risk Score to Identify Risk of Venous Thromboembolism in Patients With Cardiometabolic Disease

Nicholas A Marston  1 , Giorgio E M Melloni  1 , Yared Gurmu  1 , Marc P Bonaca  2 , Frederick K Kamanu  1 , Carolina Roselli  3   4 , Christina Lee  3 , Ilaria Cavallari  5 , Robert P Giugliano  1 , Benjamin M Scirica  1 , Deepak L Bhatt  6 , Philippe Gabriel Steg  7 , Marc Cohen  8 , Robert F Storey  9 , Anthony C Keech  10 , Itamar Raz  11 , Ofri Mosenzon  11 , Eugene Braunwald  1 , Steven A Lubitz  3   12 , Patrick T Ellinor #  3   12 , Marc S Sabatine #  1 , Christian T Ruff #  1
Affiliations

Genetic Risk Score to Identify Risk of Venous Thromboembolism in Patients With Cardiometabolic Disease

Nicholas A Marston et al. Circ Genom Precis Med. 2021 Feb.

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.

Keywords: genetics; genomics; myocardial infarction; pulmonary embolism; venous thromboembolism.

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Figures

Figure 1:
Figure 1:
Three-year incidence of venous thromboembolism by tertile of genetic risk.
Figure 2:
Figure 2:
Forest Plot comparing High and Intermediate Genetic Risk to Clinical Risk Factors for VTE. Adjusted for age, sex, ancestry, obesity, active smoking, history of heart failure, and diabetes.
Figure 3.
Figure 3.
Subgroup Analysis of VTE Risk per 1-SD increase in Genetic Risk Score. There were no significant interactions across subgroups
See this image and copyright information in PMC

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