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

2016 ◽  
Vol 116 (10) ◽  
pp. 705-713 ◽  
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.

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

Circulation ◽  
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.

scholarly journals Gene-Environment Interactions in Multiple Sclerosis

2021 ◽  
Vol 8 (4) ◽  
pp. e1007
Author(s):  
Benjamin Meir Jacobs ◽  
Alastair J. Noyce ◽  
Jonathan Bestwick ◽  
Daniel Belete ◽  
Gavin Giovannoni ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Childhood Obesity ◽  
Environmental Risk ◽  
Genetic Risk ◽  
Environmental Risk Factors ◽  
Age At Menarche ◽  
Targeted Prevention ◽  
Uk Biobank ◽  
Polygenic Risk

ObjectiveWe sought to determine whether genetic risk modifies the effect of environmental risk factors for multiple sclerosis (MS). To test this hypothesis, we tested for statistical interaction between polygenic risk scores (PRS) capturing genetic susceptibility to MS and environmental risk factors for MS in UK Biobank.MethodsPeople with MS were identified within UK Biobank using ICD-10–coded MS or self-report. Associations between environmental risk factors and MS risk were quantified with a case-control design using multivariable logistic regression. PRS were derived using the clumping-and-thresholding approach with external weights from the largest genome-wide association study of MS. Separate scores were created including major histocompatibility complex (MHC) (PRSMHC) and excluding (PRSnon-MHC) the MHC locus. The best-performing PRS were identified in 30% of the cohort and validated in the remaining 70%. Interaction between environmental and genetic risk factors was quantified using the attributable proportion due to interaction (AP) and multiplicative interaction.ResultsData were available for 2,250 people with MS and 486,000 controls. Childhood obesity, earlier age at menarche, and smoking were associated with MS. The optimal PRS were strongly associated with MS in the validation cohort (PRSMHC: Nagelkerke's pseudo-R2 0.033, p = 3.92 × 10−111; PRSnon-MHC: Nagelkerke's pseudo-R2 0.013, p = 3.73 × 10−43). There was strong evidence of interaction between polygenic risk for MS and childhood obesity (PRSMHC: AP = 0.17, 95% CI 0.06–0.25, p = 0.004; PRSnon-MHC: AP = 0.17, 95% CI 0.06–0.27, p = 0.006).ConclusionsThis study provides novel evidence for an interaction between childhood obesity and a high burden of autosomal genetic risk. These findings may have significant implications for our understanding of MS biology and inform targeted prevention strategies.

scholarly journals Interaction of a genetic risk score with physical activity, physical inactivity, and body mass index in relation to venous thromboembolism risk

2018 ◽  
Vol 42 (4) ◽  
pp. 354-365 ◽  
Author(s):  
Jihye Kim ◽  
Peter Kraft ◽  
Kaitlin A. Hagan ◽  
Laura B. Harrington ◽  
Sara Lindstroem ◽  
...  
Keyword(s):  
Physical Activity ◽  
Body Mass Index ◽  
Venous Thromboembolism ◽  
Body Mass ◽  
Risk Score ◽  
Genetic Risk ◽  
Physical Inactivity ◽  
Genetic Risk Score

P4455The controversial role of genetics behind premature CAD: a plausible excuse for the young?

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Sousa ◽  
M Mendonca ◽  
A Pereira ◽  
F Mendonca ◽  
M Neto ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Young Patients ◽  
Premature Cad ◽  
Artery Disease ◽  
Group B

Abstract Introduction The complex interaction between genes and environmental factors contribute to individual-level risk of coronary artery disease (CAD), often resulting in premature CAD. The role for genetic risk scores in premature CAD is still controversial. Objective To evaluate the importance of conventional risk factors and of a genetic risk score in younger and older patients with coronary artery disease Methods From a group of 1619 pts with angiographic documented CAD from the GENEMACOR study, we selected 1276 pts admitted for ACS and analysed them in 2 groups (group A: ≤50 years, n=491 pts, 87.2% male, mean age 44±4.9 and group B: >50 years, n=785 pts, 75.2% male, mean age 57±4.2). Univariate analysis was used to characterize the traits of each group and we used ROC curves and respective AUCs to evaluate the power of genetics in the prediction of CAD, through a Genetic Risk Score (GRS). Results 99.3% of the young patients had at least one modifiable risk factor, 18.4% had 2 modifiable risk factors and 75.2% had 3 or more modifiable risk factors. The pattern of risk factors contributing to CAD were different among groups: family history (A: 27.5%, B: 21.4%, p=0.015) and smoking habits (A: 64.8%, B: 42.9%, p<0.001) were more frequent among patients under 50, and traditional age-linked factors like hypertension (A: 58%, B: 75.7%, p<0.001), diabetes (A: 21.6%, B: 38.6%, p<0.001) were more common in the older group. Acute ST-elevation myocardial infarction was more frequent among the young (A: 55.4%, B: 47.4%, p=0.006), as non-ST clinical presentation was higher among elder patients. Regarding angiographic presentation, single vessel CAD was higher in group A (A: 50.3%, B: 40.9%, p<0.001), while multivessel diasease was higher in group B (A: 33.3%, B: 53.9%, p<0.001). At a mean follow-up of 5 years, older patients had a worst prognosis, registering a higher rate of cardiovascular death (A: 4.1%, B: 8.6%, p=0.002) and higher MACE (A: 26.8%, B: 31%, p=0.128),. Adding the genetic risk score (GRS), we achieved only a slight improvement in the AUC for predicting CAD (0.796->0.805, p=0.0178 and 0.748->0.761, p=0.0007 in patients under and over 50, respectively). Conclusion Coronary artery disease is not all the same, as premature CAD shares a unique and specific pattern of risk factors, clinical presentation, angiographic severity and prognosis. Genetics should not be used as an excuse to justify premature CAD, as there is frequently more than one potentially reversible risk factor present even in young patients and the additive predictive value of GRS is modest.

scholarly journals 959Coronary artery disease risk according to genetic risk score deciles, Age and cardiovascular risk factors

2017 ◽  
Vol 38 (suppl_1) ◽  
Author(s):  
A. Pereira ◽  
M. Neto ◽  
R. Rodrigues ◽  
J. Monteiro ◽  
A.C. Sousa ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Risk Score ◽  
Genetic Risk ◽  
Disease Risk ◽  
Genetic Risk Score ◽  
Artery Disease

OC-1b: A new genetic risk score for predicting venous thromboembolism events in cancer patients receiving chemotherapy

2017 ◽  
Vol 151 ◽  
pp. S103
Author(s):  
A. Muñoz ◽  
I. Ortega ◽  
C. Font ◽  
V. Pachón ◽  
V. Castellón ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Cancer Patients ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Thromboembolism Events

scholarly journals Epigenetic Mechanisms of the Aging Human Retina

2015 ◽  
Vol 9s2 ◽  
pp. JEN.S25513 ◽  
Author(s):  
Katie L. Pennington ◽  
Margaret M. Deangelis
Keyword(s):  
Gene Expression ◽  
Risk Factors ◽  
Environmental Risk ◽  
Environmental Risk Factors ◽  
Age Related Macular Degeneration ◽  
Retinal Diseases ◽  
Epigenetic Mechanisms ◽  
Tissue Samples ◽  
Age Related ◽  
Genome Wide

Degenerative retinal diseases, such as glaucoma, age-related macular degeneration, and diabetic retinopathy, have complex etiologies with environmental, genetic, and epigenetic contributions to disease pathology. Much effort has gone into elucidating both the genetic and the environmental risk factors for these retinal diseases. However, little is known about how these genetic and environmental risk factors bring about molecular changes that lead to pathology. Epigenetic mechanisms have received extensive attention of late for their promise of bridging the gap between environmental exposures and disease development via their influence on gene expression. Recent studies have identified epigenetic changes that associate with the incidence and/or progression of each of these retinal diseases. Therefore, these epigenetic modifications may be involved in the underlying pathological mechanisms leading to blindness. Further genome-wide epigenetic studies that incorporate well-characterized tissue samples, consider challenges similar to those relevant to gene expression studies, and combine the genome-wide epigenetic data with genome-wide genetic and expression data to identify additional potentially causative agents of disease are needed. Such studies will allow researchers to create much-needed therapeutics to prevent and/or intervene in disease progression. Improved therapeutics will greatly enhance the quality of life and reduce the burden of disease management for millions of patients living with these potentially blinding conditions.

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