Prediction of venous thromboembolism incidence in the general adult population using two published genetic risk scores

PLOS ONE RESEARCH ARTICLE Prediction of venous thromboembolism incidence in the general adult population using two published genetic risk scores Aaron R. Folsom ID1*, Weihong Tang1, Ching-Ping Hong1, Wayne D. Rosamond2, John A. Lane3, Mary Cushman4, Nathan Pankratz3 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States of America, 2 Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America, 3 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States of America, 4 Department of Medicine and Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, United States of America * Abstract OPEN ACCESS Citation: Folsom AR, Tang W, Hong C-P, Rosamond WD, Lane JA, Cushman M, et al. (2023) Prediction of venous thromboembolism incidence in the general adult population using two published genetic risk scores. PLoS ONE 18(1): e0280657. https://doi.org/10.1371/journal.pone.0280657 Editor: Mohammad-Mahdi Rashidi, Tehran University of Medical Sciences, ISLAMIC REPUBLIC OF IRAN Introduction Most strategies for prevention of venous thromboembolism focus on preventing recurrent events. Yet, primary prevention might be possible through approaches targeting the whole population or high-risk patients. To inform possible prevention strategies, population-based information on the ability of genetic risk scores to identify risk of incident venous thromboembolism is needed. Received: July 26, 2022 Materials and methods Accepted: January 5, 2023 We used proportional hazards regression to relate two published genetic risk scores (273variants versus 5-variants) with venous thromboembolism incidence in the Atherosclerosis Risk in Communities Study (ARIC) cohort (n = 11,292), aged 45–64 at baseline, drawn from 4 US communities. Published: January 30, 2023 Copyright: © 2023 Folsom et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: The data has been deposited at: Folsom, Aaron, 2023, "Replication data for PLOS ONE paper by Folsom AR et al. entitled Prediction of Venous Thromboembolism Incidence in the General Adult Population using Two Published Genetic Risk Scores", https://doi. org/10.7910/DVN/OWFJZF, Harvard Dataverse, V1. Funding: The National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services has funded the Results Over a median of 28 years, ARIC identified 788 incident venous thromboembolism events. Incidence rates rose more than two-fold across quartiles of the 273-variant genetic risk score: 1.7, 2.7, 3.4 and 4.0 per 1,000 person-years. For White participants, age, sex, and ancestry-adjusted hazard ratios (95% confidence intervals) across quartiles were strong [1 (reference), 1.30 (0.99,1.70), 1.85 (1.43,2.40), and 2.58 (2.04,3.28)] but weaker for Black participants [1, 1.05 (0.63,1.75), 1.37 (0.84,2.22), and 1.32 (0.80,2.20)]. The 5-variant genetic risk score showed a less steep gradient, with hazard ratios in Whites of 1, 1.17 (0.89,1.54), 1.48 (1.14,1.92), and 2.18 (1.71,2.79). Models including the 273-variant genetic risk score plus lifestyle and clinical factors had a c-statistic of 0.67. PLOS ONE | https://doi.org/10.1371/journal.pone.0280657 January 30, 2023 1 / 14 PLOS ONE Atherosclerosis Risk in Communities study with Federal Contract nos. HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, HHSN268201700005I, and the study of venous thromboembolism with grant R01HL059367 (ARF). NP and JAL were partially funded by R01HL154385. Genomics funding for the Atherosclerosis Risk in Communities Study also came from R01HL087641 and R01HL086694, National Human Genome Research Institute contract U01HG004402, and National Institutes of Health contract HHSN268200625226C. The funders had no role in the study design data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Genetic risk score for venous thromboembolism Conclusions In the general population, middle-aged adults in the highest quartile of either genetic risk score studied have approximately two-fold higher risk of an incident venous thromboembolism compared with the lowest quartile. The genetic risk scores show a weaker association with venous thromboembolism for Black people. Introduction Venous thromboembolism (VTE), consisting of venous thrombosis and pulmonary embolism, is an important cause of morbidity and mortality, with a lifetime risk of approximately one in 12 US adults after age 45 years [1]. One-half to two-thirds of VTEs have provoking factors (i.e., cancer, surgery, trauma, and immobility), whereas the remaining events are considered unprovoked. Advocacy organizations [2] and the US Surgeon General [3] have issued calls to action to prevent VTE, and there are established clinical guidelines and methods for acute treatment, secondary prevention, and prevention of provoked VTE in high-risk patients [2, 4–8]. Current strategies for preventing VTE fail to address primary prevention of unprovoked VTE in the general population [9]. One approach to primary prevention of unprovoked VTE would be a population-wide strategy using education, environmental changes, and policy to reduce modifiable VTE risk factors. Another would be to screen individuals for VTE risk factors and target safe interventions toward high-risk individuals. Yet, identifying individuals at high risk for VTE is challenging, as there are few published, feasible risk scores to identify those in the general population at substantial risk of incident VTE. Risk scores for screening the general population might assess lifestyle or clinical risk factors; however, except for age and obesity, many traditional arterial cardiovascular risk factors (e.g., hypertension, diabetes, hyperlipidemia, and smoking) are, at most, weak VTE risk factors [9]. We have shown, for example, that the American College of Cardiology-American Heart Association pooled risk equation for cardiovascular disease does not predict VTE in the Atherosclerosis Risk in Communities (ARIC) study [9]. On the other hand, a poor American Heart Association’s Life’s Simple 7 (LS7) score is associated with greater incident VTE [10–12], largely by the inclusion of obesity in LS7. Genetic risk scores (GRSs) can also predict VTE in the general population. In a Dutch casecontrol study, de Haan et al. derived a 5-variant GRS of hemostatic factor variants (composed of F5 Leiden rs6025, F2 rs1799963, A (...truncated)