PERFORMANCE OF A NOVEL GENETIC RISK SCORE TO IDENTIFY RISK OF VENOUS THROMBOEMBOLISM IN PATIENTS WITH CARDIOMETABOLIC DISEASE

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.

Download Full-text

Abstract P254: Genetic Risk Score for Height and the Incidence of Venous Thromboembolism: A Prospective Study

Circulation ◽

10.1161/circ.133.suppl_1.p254 ◽

2016 ◽

Vol 133 (suppl_1) ◽

Author(s):

Nicholas S Roetker ◽

James S Pankow ◽

Pamela L Lutsey ◽

Weihong Tang ◽

Michael A Rosenberg ◽

...

Keyword(s):

Venous Thromboembolism ◽

Causal Relationship ◽

Risk Score ◽

Genetic Risk ◽

Mendelian Randomization ◽

Genetic Risk Score ◽

Statistical Significance ◽

Body Height ◽

Health Study ◽

Cardiovascular Health Study

Introduction: Several observational studies have shown that taller body height is associated with greater risk of venous thromboembolism (VTE), but it is not known whether the association is causal. We used instrumental variable analysis (Mendelian randomization) to explore the causal relationship between height and VTE using a genetic risk score (GRS) for height as the instrument. Hypothesis: There is a causal relationship between taller standing height and greater risk of VTE, as demonstrated by a Mendelian randomization approach. Methods: We created a weighted GRS for height in white men and women in the Longitudinal Investigation of Thromboembolism Etiology [consisting of two longitudinal cohort studies: Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS)] using 668 single nucleotide polymorphisms from a recently published meta-analysis. Incident hospitalized VTE events were identified and verified by physician review of medical records. We estimated the association and causal risk differences (RD) and 95% confidence intervals (CI) for VTE incidence per standard deviation (SD) increment in height (9.4 cm). The association models were adjusted for age, sex, waist circumference, and study site. Results: There were 9,137 ARIC and 3,163 CHS participants at risk for VTE at baseline and with genetic data, and they experienced 367 (ARIC) and 105 (CHS) incident VTE events over a median 22.7 and 11.8 years of follow-up, respectively. Baseline age ranges were 45-64 and 65-98 years and mean heights were 169 and 165 cm in ARIC and CHS, respectively. The GRS was a strong instrument for height (R 2 =0.08 in ARIC and R 2 =0.07 in CHS) and had little to no correlation with other measured VTE risk factors (all R 2 ≤0.01). In ARIC, taller height was associated with greater risk of VTE [association VTE RD: 1.0% per SD in height (95% CI: 0.3 to 1.6%)]. The causal RD had the same magnitude as the association RD, but did not quite reach statistical significance [causal VTE RD per SD in height: 1.1% (95% CI: -0.3 to 2.5%)]. Predicted risks of VTE at the 10th and 90th percentiles of height (157 and 181 cm) were 2.6% and 5.4%, respectively, representing more than a doubling of risk. There was no association between height and VTE risk in CHS [association VTE RD per SD in height: 0.1% (95% CI: -1.0 to 1.2%); causal VTE RD per SD in height: -0.3% (95% CI: -2.5 to 1.9%)]. Conclusion: Taller height was associated with greater VTE risk with some supporting causal evidence in middle-aged adults from ARIC, but there was no relation between height and VTE in older adults from CHS. Future studies should further explore the causal relation between height and VTE among different age groups.

Download Full-text

Interactions of established risk factors and a GWAS-based genetic risk score on the risk of venous thromboembolism

Thrombosis and Haemostasis ◽

10.1160/th16-02-0172 ◽

2016 ◽

Vol 116 (10) ◽

pp. 705-713 ◽

Cited By ~ 6

Author(s):

Marta Crous-Bou ◽

Immaculata De Vivo ◽

Carlos A. Camargo ◽

Raphaëlle Varraso ◽

Francine Grodstein ◽

...

Keyword(s):

Risk Factors ◽

Venous Thromboembolism ◽

Risk Score ◽

Environmental Risk ◽

Genetic Risk ◽

Genetic Risk Score ◽

Environmental Risk Factors ◽

Health Study ◽

Targeted Prevention ◽

Genome Wide

SummaryMultiple genetic and environmental risk factors contribute to venous thromboembolism (VTE) risk. Understanding how genes and environmental risk factors interact may provide key insight into the pathophysiology of VTE and may identify opportunities for targeted prevention and treatment. It was our aim to examine the main effects and the potential effect-modification between single nucleotide polymorphisms (SNPs) at established loci and lifestyle risk factors for VTE. We performed a nested case-control study using data on 1,040 incident VTE cases and 16,936 controls from the Nurses’ Health Study, Nurses’ Health Study II, and Health Professionals Follow-up Study cohorts, who gave blood, were selected as participants in a previous genome-wide association study (GWAS), and completed a biennial questionnaire at time of blood draw. We selected SNPs that were associated with VTE risk in previous GWAS studies. A genetic risk score (GRS) was constructed to evaluate the combined effect of the 16 SNPs that have reached genome-wide significance in previous GWAS of VTE. Interactions between SNPs and VTE risk factors (BMI and smoking) were also assessed. We found a significant association between our GRS and VTE risk. The risk of VTE among individuals in the highest GRS tertile was 2.02 times that of individuals in the lowest GRS tertile (p-trend = 9.69x10-19). The OR was 1.52 (p=1.03x10-8) for participants in the highest GRS tertile compared to those in the medium GRS tertile. However, while BMI and smoking were associated with VTE, and their effects were additive to each other we did not observe any significant multiplicative gene-environment interactions.Supplementary Material to this article is available online at www.thrombosis-online.com.

Download Full-text

Replication of a genetic risk score for venous thromboembolism in whites but not in African Americans

Journal of Thrombosis and Haemostasis ◽

10.1111/jth.13193 ◽

2015 ◽

Vol 14 (1) ◽

pp. 83-88 ◽

Cited By ~ 11

Author(s):

A. R. Folsom ◽

W. Tang ◽

L.-C. Weng ◽

N. S. Roetker ◽

M. Cushman ◽

...

Keyword(s):

Venous Thromboembolism ◽

African Americans ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score

Download Full-text

A genetic risk score comprising known venous thromboembolism loci is associated with chronic venous disease in a multi-ethnic cohort

Thrombosis Research ◽

10.1016/j.thromres.2015.09.016 ◽

2015 ◽

Vol 136 (5) ◽

pp. 966-973 ◽

Cited By ~ 7

Author(s):

Christina L. Wassel ◽

Laura J. Rasmussen-Torvik ◽

Peter W. Callas ◽

Julie O. Denenberg ◽

J. Peter Durda ◽

...

Keyword(s):

Venous Thromboembolism ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Chronic Venous Disease ◽

Venous Disease

Download Full-text

Abstract 13702: A Novel Genetic Risk Score Predicts Ischemic Stroke in Patients With Cardiometabolic Disease

Circulation ◽

10.1161/circ.142.suppl_3.13702 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Parth N Patel ◽

Nicholas A Marston ◽

Frederick K Kamanu ◽

Lu Chen Weng ◽

Marc P Bonaca ◽

...

Keyword(s):

Risk Factors ◽

Clinical Trials ◽

Ischemic Stroke ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

European Ancestry ◽

Cardiometabolic Disease ◽

Genome Wide Association Studies ◽

Increased Risk

Introduction: Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for first ischemic stroke after accounting for traditional risk factors in four clinical trials across the spectrum of cardiometabolic disease. Methods: Subjects who had consented for genetic testing, were of European ancestry, and had no prior history of stroke from the SOLID-TIMI 52, SAVOR-TIMI 53, PEGASUS-TIMI 54, and FOURIER trials were included in this analysis. A recently validated GRS composed of 36 SNPs associated with ischemic stroke was calculated in each patient. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for age, sex, ancestry, hypertension, hyperlipidemia, smoking, diabetes mellitus, atrial fibrillation, coronary artery disease, and congestive heart failure. Results: In 23,089 subjects across the four trials, a total of 313 ischemic strokes occurred over a median follow-up of 3 years. Those with higher genetic risk were at significantly increased risk for ischemic stroke with an adjusted HR per 1-SD GRS of 1.12 (1.004-1.25; p=0.043). Individuals in the top 10% of genetic risk had a 42% greater hazard for ischemic stroke than those in the lower 90% of genetic risk (adjusted HR 1.42 [1.03-1.97]; p=0.034). The magnitude of risk conferred by high genetic risk was similar or greater than the risk provided by well-established clinical risk factors (Figure). Conclusions: Across four large clinical trials of subjects with cardiometabolic disease, a 36-SNP GRS was a strong, independent predictor of first ischemic stroke. The risk of stroke was particularly high in patients in the top 10% of genetic risk.

Download Full-text