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

Originally publishedhttps://doi.org/10.1161/CIRCGEN.120.003006Circulation: Genomic and Precision Medicine. 2021;14:e003006

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.

Introduction

Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality. In the United States, there are ≈900 000 VTEs annually, resulting in up to 100 000 deaths.1,2 While acute precipitants and clinical risk factors are often the focus of determining the cause of VTE, a small minority of patients have a mutation in a limited number of genes leading to an inherited thrombophilia.3 To that end, hypercoagulability and/or genetic testing can identify some uncommon genetic mutations such as factor V Leiden, antithrombin deficiency, protein C or S deficiency, or a prothrombin gene mutation.3 However, standard testing is usually unrevealing, with mutations present in only about 5% of the general population.1,2 Thus, for many patients with VTE, no clear precipitant or risk factor is ever identified.

In contrast to uncommon thrombophilias, recent work has used genome-wide association studies to identify 297 independent single nucleotide polymorphisms associated with VTE, from which a polygenic risk score was developed.4 Application of the genetic risk score (GRS) in the general population led to the identification of many more individuals with a genetic predisposition for VTE than previously recognized. In this study, we tested the performance of this polygenic risk score in 3 TIMI (Thrombolysis in Myocardial Infarction) trials to evaluate whether a polygenic risk score predicts VTE in patients across the spectrum of cardiometabolic disease. In addition, we contrast the magnitude of risk compared with established clinical risk factors for VTE and classic monogenic thrombophilias.

Methods

This study was approved by the local institutional review committees at each study site. Complete methods outlining the study design, study population, genotyping, imputation, GRS, clinical end points, and statistical analysis are included in Appendix in the Data Supplement. Although data and study material will not be made universally available, we encourage parties interested in collaboration to contact the corresponding author directly.

Results

A total of 29 663 patients from the 3 trials were included in these analyses including 12 981 from FOURIER, 10 607 from PEGASUS-TIMI 54, and 6075 from SAVOR-TIMI 53. The baseline characteristics by tertile of genetic risk are included in Table 1; there were no clinically significant differences across genetic risk groups. The median follow-up across the study cohort was 2.4 years. There were 174 VTE events (95 deep vein thrombosis and 79 pulmonary embolism), 1232 myocardial infarctions, and 387 ischemic strokes.

Table 1. Baseline Characteristics by Tertile of Genetic Risk

Tertile 1Tertile 2Tertile 3P-value
Participants, n988898879888
 FOURIER, %424445
 PEGASUS, %373635
 SAVOR, %212020
Demographics
 Age, y ±SD64.5±8.764.2±8.664.0±8.5<0.001
 Male sex, (%)7365 (74)7442 (75)7319 (74)0.12
 BMI ±SD29.9±5.130.0±5.229.9±5.10.33
Medical history, n (%)
 Myocardial infarction7896 (80)7954 (80)7905 (80)0.53
 Stroke872 (9)906 (9)942 (10)0.23
 Peripheral artery disease1037 (11)979 (10)1093 (11)0.03
 Hypertension7833 (79)7913 (80)7892 (80)0.33
 Heart failure1900 (19)1982 (20)2043 (21)0.04
 Diabetes4487 (45)4536 (46)4463 (45)0.56
 Current smoker2164 (22)2150 (22)2302 (23)0.16

BMI indicates body mass index.

Performance of GRS

There was a significantly increased gradient of risk across VTE genetic risk tertiles (P-trend <0.0001; Figure 1). After adjustment for clinical risk factors, patients in the intermediate genetic risk group had a 1.88-fold increased risk of VTE (95% CI, 1.23–2.89; P=0.004) and patients in the high-risk group had a 2.70-fold higher risk of VTE (95% CI, 1.81–4.06; P<0.0001; Figure 2) compared with the low genetic risk group. The risk of VTE increased linearly throughout the spectrum of genetic risk (Figure I in the Data Supplement), such that each standard deviation increase in the GRS carried a 47% increased risk of VTE (Adj. hazard ratio [HR], 1.47 [1.29–1.68]; P<0.0001). The GRS for VTE was not associated with an increase in arterial events such as myocardial infarction or ischemic stroke (Table I in the Data Supplement). There was no heterogeneity in the performance of the VTE GRS across multiple clinical subgroups (Figure 3).

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 venous thromboembolism. Adjusted for age, sex, ancestry, obesity, active smoking, history of heart failure, and diabetes. BMI indicates body mass index; and HR, hazard ratio.

Figure 3.

Figure 3. Subgroup analysis of venous thromboembolism risk per 1-SD increase in genetic risk score. There were no significant interactions across subgroups. BMI indicates body mass index; and HR, hazard ratio.

Comparison to Clinical Risk Factors

Of the available clinical risk factors, only age ≥65 (HR, 1.87 [1.35–2.59]; P=0.0002) was a significant predictor of VTE, with risk similar to that conferred by an intermediate GRS. Obesity (HR, 1.34 [0.98–1.83]; P=0.07) was a weaker predictor of VTE, and there was no appreciable risk associated with diabetes (HR, 1.18 [0.86–1.61]; P=0.30), heart failure (HR, 1.1 [0.75–1.61]; P=0.64), or active smoking (HR, 1.09 [0.73–1.63]; P=0.67; Figure 2). The c-index for VTE for all the clinical factors was 0.63 (0.59–0.67), whereas for the GRS alone, it was 0.67 (0.63–0.71). The addition of the GRS to clinical risk factors increased the c-index from 0.63 (0.59–0.67) to 0.67 (0.63–0.71; P<0.0001).

Monogenic Versus Polygenic Risk

Of the entire genetic cohort, 2474 patients (8.3%) had at least 1 of the 2 monogenic mutations (Factor V Leiden or Prothrombin) with frequency and overlap displayed in Table 2. Monogenic mutations were enriched among patients with VTE (14.9%, 26/174). Polygenic risk for VTE was balanced across patients with and without monogenic risk. In the 8.3% of patients with monogenic variants, polygenic risk did not improve risk prediction of VTE. However, the performance of the polygenic risk score strengthened when restricting the analysis to the 91.7% patients without a monogenic predisposition to VTE (HRadj per 1 SD: 1.53 [1.30–1.82]; HRadj for T3 versus T1: 2.88 [1.85–4.49]; Table II in the Data Supplement).

Table 2. Prevalence of Monogenic Mutations

Factor V Leiden
Wild typeHeterozygoteHomozygoteTotal
ProthrombinWild type27 18915833728 809
Heterozygote802421845
Homozygote9009
Total28 00016253829 663

Discussion

When a patient experiences a VTE event without an acute precipitant such as recent surgery, immobilization, or trauma, one often considers clinical risk factors5 and contemplates testing for a handful of known, monogenic thrombophilia disorders. However, use of thrombophilia testing has fallen out of favor in part due to the low number of patients identified.3 These data demonstrate that consideration of broader polygenic risk can identify a much larger proportion of patients at risk for VTE and is a stronger predictor than many chronic clinical risk factors.

These findings are consistent with, and build upon, recent work done by Klarin et al, who derived and validated this polygenic risk score for VTE in a general population. We now test the same score in a population with higher baseline risk and found the top one-third of patients had >2-fold increased risk of VTE, suggesting that polygenic risk offers important insight into VTE risk among those with cardiometabolic disease. Also unique to this analysis is the comparison of the GRS to both established clinical risk factors and monogenic thrombophilias.

Importantly, this GRS was specific to venous thrombotic events and did not predict arterial thrombotic events such as myocardial infarction or ischemic stroke. This is not unexpected as the score is distinct from a previously published 27-single nucleotide polymorphism score for coronary artery disease that we and others have studied.6,7 Although there is some overlap, there is growing appreciation that risk factors and mechanisms differ between arterial and venous thrombosis. The ability of VTE GRS to strongly predict venous thromboembolic events but not arterial, such as myocardial infarction, supports this premise.

Physicians sometimes pursue hypercoagulability testing to identify uncommon but impactful etiologies for their patients with VTE. For example, Factor V Leiden (p.R506Q) is a monogenic mutation that is present in <5%3 of the population but carries a 2.3-fold increased risk of incident VTE.4 Similarly, prothrombin mutation carries an ≈2.8-fold increased risk.8 This degree of VTE risk is similar to that observed in one-third of cardiometabolic patients with high polygenic risk. These data suggest that this VTE polygenic risk score would identify far more patients with genetic risk compared with standard hypercoagulability testing. Whether this increased identification of genetic risk would improve the clinical utility of hypercoagulability testing is an area requiring further investigation.

Limitations

The study was made up of patients from 3 clinical trial populations that spanned the spectrum of cardiometabolic disease; however, the results may not be generalizable to other disease domains. In particular, malignancies and pregnancies were excluded, which are major predisposing factors for VTE, and acute precipitants such as surgery and prolonged immobility were not captured. Thus, this analysis focuses on chronic risk factors for VTE. Moreover, not all trials collected use of hormonal therapies. Additionally, this analysis only included patients of European ancestry, as this is the population for which the GRS was developed, and it is unclear how well it translates to other ethnicities. Finally, VTE events were collected as investigator reported adverse events, rather than predefined Clinical Endpoints Comittee adjudicated events. A total of 174 VTE events led to wide CIs, which limited statistical power and precision. Nonetheless, in a model with clinical risk factors and GRS, the latter remained statistically significantly associated with VTE.

Conclusions

In a broad spectrum of patients with cardiometabolic disease, a polygenic risk score is a strong predictor of VTE, identifying one-third of patients with a risk of VTE similar to patients with monogenic inherited thrombophilia.

Nonstandard Abbreviations and Acronyms

GRS

genetic risk score

HR

hazard ratio

VTE

venous thromboembolism

TIMI

Thrombolysis in Myocardial Infarction

Acknowledgments

Dr Marston contributed to study design, literature search, statistical analysis, data interpretation, figures, and drafting of the article. Drs Melloni, Gurmu, Bonaca, Kamanu, Lee, and C. Roselli contributed to data preparation, study design, and statistical analysis. Drs Cavallari, Giugliano, Scirica, Bhatt, Steg, Cohen, Storey, Keech, Raz, Mosenzon, and Braunwald contributed to data interpretation and critical review of the article. Drs Lubitz, Ellinor, Sabatine, and Ruff contributed to study design, statistical analysis, data interpretation, figures, and critical review of the article. Drs Ruff and Sabatine are the guarantors of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Sources of Funding:

FOURIER was supported by a research grant from Amgen and PEGASUS-TIMI 54 and SAVOR-TIMI 53 by a research grant from AstraZeneca, all to Brigham and Women’s Hospital.

Disclosures Dr Marston is supported by National Institutes of Health (NIH) grant funding. Drs. Melloni and Kamanu are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s from: Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences. Dr Gurmu is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s from: Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences. Dr Bonaca discloses grant support from Amgen, AstraZeneca, Bayer, Sanofi and consulting fees from Amgen, AstraZeneca, Bayer, Sanofi. C. Roselli is supported by a grant from Bayer AG to the Broad Institute focused on the development of therapeutics for cardiovascular disease. Dr Cavallari reports speaking fees from BMS-Pfizer, AstraZeneca, and Boehringer Ingelheim. Dr Giugliano reports grants from Merck, during the conduct of the study; personal fees from Akcea, grants and personal fees from Amarin, personal fees from American College of Cardiology, grants and personal fees from Amgen, personal fees from Angel Med, personal fees from Beckman-Coulter, personal fees from Boeringer-Ingelheim, personal fees from Bristol Myers Squibb, personal fees from CVS Caremark, grants and personal fees from Daiichi Sankyo, personal fees from GlaxoSmithKline, personal fees from Janssen, personal fees from Lexicon, grants and personal fees from Merck, personal fees from Portola, personal fees from Pfizer, personal fees from St Jude, personal fees from Stealth Peptide, outside the submitted work; and Institutional research grant to the TIMI Study Group at Brigham and Women’s Hospital for research he is not directly involved in from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences. Dr Scirica has received research grants from AstraZeneca, Eisai, Novartis, and Merck and consulting fees from AstraZeneca, Biogen Idec, Boehringer Ingelheim, Covance, Dr Reddy’s Laboratories, Eisai, Elsevier Practice Update Cardiology, GlaxoSmithKline, Lexicon, Merck, Novo Nordisk, Sanofi, and St Jude’s Medical; and has equity in Health [at] Scale. Dr Bhatt discloses the following relationships—Advisory Board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, www.ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and US national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. Dr Steg receives research grants from Amarin, Bayer, Sanofi, and Servier. Speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol Myers-Squibb, Idorsia, Novartis, Novo-Nordisk, Pfizer, Regeneron, Sanofi, and Servier. Dr Cohen discloses honoraria for Speakers Bureau and advisory Boards (moderate) from AstraZeneca. Dr Storey reports research grants, consultancy fees and honoraria from AstraZeneca; consulting fees and honoraria from Bayer and Bristol Myers Squibb/Pfizer; research grants and consultancy fees from GlyCardial Diagnostics and Thromboserin; consultancy fees from Amgen, Haemonetics, and Portola; honoraria from Medscape. Dr Keech reports grants and personal fees from Abbott, personal fees from Amgen, personal fees from AstraZeneca, grants and personal fees from Mylan, personal fees from Pfizer, grants from Sanofi, grants from Novartis, personal fees from Bayer, outside the submitted work. Dr Raz has received personal fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Con-center BioPharma and Silkim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Orgenesis, Pfizer, Sanofi, SmartZyme Innovation, Panaxia, FutuRx, Insuline Medical, Medial EarlySign, CameraEyes, Exscopia, Dermal Biomics, Johnson & Johnson, Novartis, Teva, GlucoMe, and DarioHealth. Dr Mosenzon reports serving on Advisory Boards for Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Novartis, AstraZeneca, BOL Pharma; Research grant support through Hadassah Hebrew University Hospital: Novo Nordisk, AstraZeneca and Bristol Myers Squibb; Speaker’s Bureau: AstraZeneca and Bristol Myers Squibb, Novo Nordisk, Eli Lilly, Sanofi, Novartis, Merck Sharp & Dohme, Boehringer Ingelheim. Dr Braunwald reports research grants through the Brigham and Women’s Hospital from Astra Zeneca, Merck, and Novartis. Consultancies with Amgen, Cardurion, MyoKardia, NovoNordisk, and Verve. Uncompensated consultancies and lectures with The Medicines Company. Dr Lubitz is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. Dr Lubitz receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, and Boehringer Ingelheim, and has consulted for Bristol Myers Squibb/Pfizer and Bayer AG. Dr Ellinor reports grants and personal fees from Bayer AG, personal fees from Novartis, personal fees from Quest Diagnostics, outside the submitted work. Dr Sabatine reports research grant support from Significant Abbott Laboratories, Amgen, AstraZeneca, Bayer, Critical Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Quark pharmaceuticals, Roche Diagnostics, and Takeda and has received consulting fees; Modest from Alnylam, AstraZeneca, Bristol Myers Squibb, CVS Caremark, Dyrnamix, Esperion, IFM Pharmaceuticals, Intarcia, Ionis, Janssen Research and Development, Medicines Company, MedImmune, Merck, MyoKardia, and Novartis. In addition, they report significant consulting fees from Amgen. Dr Ruff reports grants from Boehringer Ingelheim, grants from Daiichi Sankyo, grants from MedImmune, grants from National Institute of Health, personal fees from Bayer, personal fees from Bristol Myers Squibb, personal fees from Boehringer Ingelheim, personal fees from Daiichi Sankyo, personal fees from Janssen, personal fees from MedImmune, personal fees from Pfizer, personal fees from Portola, personal fees from Anthos, outside the submitted work; Dr Ruff is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from: Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences. The other authors report no conflicts.

Footnotes

*Drs Ellinor, Sabatine, Ruff contributed equally to this article.

The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCGEN.120.003006.

For Sources of Funding and Disclosures, see page 86.

Correspondence to: Nicholas A. Marston, MD, MPH, Brigham and Women’s Hospital, 60 Fenwood Rd, Boston, MA 02115. Email

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