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

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.

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Ancestry specific associations of a genetic risk score, dietary patterns and metabolic syndrome: a longitudinal ARIC study

BMC Medical Genomics ◽

10.1186/s12920-021-00961-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Dale S. Hardy ◽

Susan B. Racette ◽

Jane T. Garvin ◽

Hirut T. Gebrekristos ◽

Tesfaye B. Mersha

Keyword(s):

Metabolic Syndrome ◽

African Americans ◽

Risk Score ◽

Dietary Patterns ◽

Dietary Pattern ◽

Genetic Risk ◽

Genetic Risk Score ◽

Genome Wide Association Studies ◽

High Fat ◽

Western Dietary Pattern

Abstract Background Associations have been observed among genetic variants, dietary patterns, and metabolic syndrome (MetS). A gap in knowledge is whether a genetic risk score (GRS) and dietary patterns interact to increase MetS risk among African Americans. We investigated whether MetS risk was influenced by interaction between a GRS and dietary patterns among Whites and African Americans. A secondary aim examined if molecular genetic clusterings differed by racial ancestry. Methods We used longitudinal data over 4-visits (1987–1998) that included 10,681 participants aged 45–64y at baseline from the Atherosclerosis Risk in Communities study (8451 Whites and 2230 African Americans). We constructed a simple-count GRS as the linear weighted sum of high-risk alleles (0, 1, 2) from cardiovascular disease polymorphisms from the genome-wide association studies catalog associated with MetS risk. Three dietary patterns were determined by factor analysis of food frequency questionnaire data: Western, healthy, and high-fat dairy. MetS was defined according to the 2016 National Cholesterol Education Program Adult Treatment Panel III criteria but used 2017 American Heart Association/American College of Cardiology criteria for elevated blood pressure. Analyses included generalized linear model risk ratios (RR), 95% confidence intervals (CI), and Bonferroni correction for multiple testing. Results The Western dietary pattern was associated with higher risk for MetS across increasing GRS tertiles among Whites (p < 0.017). The high-fat dairy pattern was protective against MetS, but its impact was most effective in the lowest GRS tertile in Whites (RR = 0.62; CI: 0.52–0.74) and African Americans (RR = 0.67; CI: 0.49–0.91). Among each racial group within GRS tertiles, the Western dietary pattern was associated with development and cycling of MetS status between visits, and the high-fat dairy pattern with being free from MetS (p < 0.017). The healthy dietary pattern was associated with higher risk of MetS among African Americans which may be explained by higher sucrose intake (p < 0.0001). Fewer genes, but more metabolic pathways for obesity, body fat distribution, and lipid and carbohydrate metabolism were identified in African Americans than Whites. Some polymorphisms were linked to the Western and high-fat dairy patterns. Conclusion The influence of dietary patterns on MetS risk appears to differ by genetic predisposition and racial ancestry.

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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.

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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

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

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(20)32821-7 ◽

2020 ◽

Vol 75 (11) ◽

pp. 2194

Author(s):

Nicholas Marston ◽

Giorgio Melloni ◽

Yared Gurmu ◽

Christina Lee ◽

Frederick Kamanu ◽

...

Keyword(s):

Venous Thromboembolism ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Cardiometabolic Disease

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Ancestry Specific Associations of a Genetic Risk Score, Dietary Patterns and Metabolic Syndrome: A Longitudinal ARIC Study

10.21203/rs.3.rs-362376/v1 ◽

2021 ◽

Author(s):

Dale Sharon Hardy ◽

Susan B. Racette ◽

Jane T. Garvin ◽

Hirut T. Gebrekristos ◽

Tesfaye B. Mersha

Keyword(s):

Metabolic Syndrome ◽

African Americans ◽

Risk Score ◽

Dietary Patterns ◽

Dietary Pattern ◽

Genetic Risk ◽

Genetic Risk Score ◽

Genome Wide Association Studies ◽

High Fat ◽

Western Dietary Pattern

Abstract Background: Associations have been observed among genetic variants, dietary patterns, and metabolic syndrome (MetS). A gap in knowledge is whether a genetic risk score (GRS) and dietary patterns interact to increase MetS risk among African Americans. We investigated whether MetS risk was influenced by interaction between a GRS and dietary patterns among Whites and African Americans. A secondary aim examined if molecular genetic clusterings differed by racial ancestry.Methods: We used longitudinal data over 4-visits (1987-1998) that included 10,681 participants aged 45-64y at baseline from the Atherosclerosis Risk in Communities study (8,451 Whites and 2,230 African Americans). We constructed a simple-count GRS as the linear weighted sum of high-risk alleles (0, 1, 2) from cardiovascular disease polymorphisms from the genome-wide association studies catalog associated with MetS risk. Three dietary patterns were determined by factor analysis of food frequency questionnaire data: Western, healthy, and high-fat dairy. MetS was defined according to the 2016 National Cholesterol Education Program Adult Treatment Panel III criteria but used 2017 American Heart Association/American College of Cardiology criteria for elevated blood pressure. Analyses included generalized linear model risk ratios (RR), 95% confidence intervals (CI), and Bonferroni correction for multiple testing.Results: The Western dietary pattern was associated with higher risk for MetS across increasing GRS tertiles among Whites (p<.017). The high-fat dairy pattern was protective against MetS, but its impact was most effective in the lowest GRS tertile in Whites (RR=0.62; CI:0.52-0.74) and African Americans (RR=0.67; CI:0.49-0.91). Among each racial group within GRS tertiles, the Western dietary pattern was associated with development and cycling of MetS status between visits, and the high-fat dairy pattern with being free from MetS (p<.017). The healthy dietary pattern was associated with higher risk of MetS among African Americans which may be explained by higher sucrose intake (p<.0001). Fewer genes, but more metabolic pathways for obesity, body fat distribution, and lipid and carbohydrate metabolism were identified in African Americans than Whites. Some polymorphisms were linked to the Western and high-fat dairy patterns.Conclusion: A dietary pattern characterized by high-fat dairy foods may be protective against MetS among individuals with a genetic predisposition.

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