Mitigation of Venous Thromboembolism Risk through Favorable Lifestyle: The ARIC Study

Background: Venous thromboembolism (VTE) is a common disease with a strong genetic basis. Unhealthy lifestyle factors contribute to risk, but it is unknown whether healthier lifestyle can mitigate the risk for VTE in those at high genetic risk. We studied whether greater adherence to the American Heart Association's (AHA's) cardiovascular health metric called Life's Simple 7 (LS7) is associated with a lower rate of VTE in individuals with high genetic risk score (GRS) for VTE. Methods: We followed 9,026 middle-aged white participants from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective cohort of 15,792 individuals enrolled in 1987-89. A validated GRS was used, comprising 5 well known genetic conditions associated with VTE (factor V Leiden, prothrombin 20210A, non-O blood group, factor XI rs4241824, and fibrinogen gamma FGG rs2066865). Only white participants were included, as the GRS did not predict VTE in others. AHA's LS7 categories of inadequate, average, and optimal health were determined based on smoking status, body mass index, physical activity, diet, total cholesterol, blood pressure, and fasting glucose. VTE events were adjudicated by expert medical record review. We calculated hazard ratios (HRs) and 95% confidence intervals (CI) of incident VTE by LS7 categories, stratified by GRS (low, intermediate, high), adjusting for age, sex, and education. HRs were also calculated for individual LS7 components stratified by GRS. Results: There were 466 incident VTE over 22.8 years of follow-up. Compared to those with optimal health, those with inadequate LS7 score had higher rates of VTE (5.7% vs. 3.9%). In Figure 1, compared to the high GRS / inadequate LS7 group, the HR of VTE in the low GRS group with optimal health was lowest at 0.39 (95% CI 0.25-0.61), but moreover, the HR in the high GRS group with optimal health was also attenuated to 0.65 (95% CI 0.48-0.89). The pattern of association was similar for provoked and unprovoked VTE. Of the LS7 components, obesity was most strongly related to VTE. In Figure 2, compared to obese / high GRS participants, the HR of VTE with normal weight / low GRS was 0.36 (95% CI 0.23-0.57), while the HR in high GRS / normal weight participants was reduced by 45%, at 0.55 (95% CI 0.4-0.76). Conclusion: Among all participants, even those at high genetic risk, healthier lifestyle factors, particularly obesity, were associated with decreased incidence of VTE. Further studies should determine the impact of lifestyle change among patients at high genetic risk of VTE, such as in thrombophilic families. Disclosures Heckbert: National Institutes of Health: Other: Grants.

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Lifestyle Moderates Genetic Risk of Venous Thromboembolism

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314668 ◽

2020 ◽

Vol 40 (11) ◽

pp. 2756-2763

Author(s):

Christina R. Evans ◽

Ching-Ping Hong ◽

Aaron R. Folsom ◽

Susan R. Heckbert ◽

Nicholas L. Smith ◽

...

Keyword(s):

Venous Thromboembolism ◽

Lower Incidence ◽

Genetic Risk ◽

Lifestyle Factors ◽

Normal Weight ◽

Hazard Ratio ◽

Lifestyle Changes ◽

Common Disease ◽

High Genetic Risk ◽

The Impact

Objective: Venous thromboembolism (VTE) is a common disease that has a genetic basis. Lifestyle factors contribute to risk, but it is unknown whether healthy lifestyle can mitigate the genetic risk. We studied whether greater adherence to the American Heart Association’s cardiovascular health metric, Life’s Simple 7 (LS7), is associated with lower incidence of VTE in individuals across categories of a genetic risk score (GRS) for VTE. Approach AND RESULTS: We followed 9026 White participants from the ARIC (Atherosclerosis Risk in Communities) Study, a prospective cohort enrolled in 1987 to 1989 until 2015. We tested the joint associations with VTE of a validated VTE GRS comprising 5 well-known gene variants and baseline LS7 categories. There were 466 incident VTE events over 22.8 years. Participants with an optimal LS7 score had a lower incidence of VTE (3.9%) than those with inadequate LS7 (5.7%). Compared with the high GRS and inadequate LS7 group (hazard ratio=1), those with high GRS and optimal LS7 indeed had a reduced hazard ratio of VTE: 0.65 (95% CI, 0.48–0.89). The group with low GRS and optimal LS7 had the lowest hazard ratio of VTE (0.39 [95% CI, 0.25–0.61]). Of the LS7 components, in all GRS groups, the factor most strongly protective for VTE was normal weight. Conclusions: Among people at low or high genetic risk for VTE, healthier lifestyle factors, particularly normal weight, were associated with a lower incidence of VTE. Further studies should determine the impact of lifestyle changes among patients at high genetic risk of VTE, such as in thrombophilic families.

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Genetic risk, adherence to a healthy lifestyle, and type 2 diabetes risk among 550,000 Chinese adults: results from 2 independent Asian cohorts

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqz310 ◽

2020 ◽

Vol 111 (3) ◽

pp. 698-707 ◽

Cited By ~ 2

Author(s):

Haoxin Li ◽

Chiea-Chuen Khor ◽

Junning Fan ◽

Jun Lv ◽

Canqing Yu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Genetic Risk ◽

Lower Risk ◽

Healthy Lifestyle ◽

Genetic Risk Score ◽

Lifestyle Factors ◽

Diabetes Risk ◽

Unhealthy Lifestyle ◽

High Genetic Risk

ABSTRACT Background Whether genetic susceptibility to type 2 diabetes is modified by a healthy lifestyle among Chinese remains unknown. Objectives The aim of the study was to determine whether genetic risk and adherence to a healthy lifestyle contribute independently to the risk of developing type 2 diabetes. Methods We defined a lifestyle score using BMI, alcohol intake, smoking, physical activities, and diets in 461,030 participants from the China Kadoorie Biobank and 38,434 participants from the Singapore Chinese Health Study. A genetic risk score was constructed based on type 2 diabetes loci among 100,175 and 16,172 participants in each cohort, respectively. A Cox proportional-hazards model was used to estimate the interaction between genetic and lifestyle factors on the risk of type 2 diabetes. Results In 2 independent Asian cohorts, we consistently found a healthy lifestyle (the bottom quintile of lifestyle score) was associated with a substantially lower risk of type 2 diabetes than an unhealthy lifestyle (the top quintile of lifestyle score) regardless of genetic risk. In those at a high genetic risk, the risk of type 2 diabetes was 57% lower among participants with a healthy lifestyle than among those with an unhealthy lifestyle in the pooled cohorts. Among participants at high genetic risk, the standardized 10-y incidence of type 2 diabetes was 7.11% in those with an unhealthy lifestyle vs. 2.45% in those with a healthy lifestyle. Conclusions In 2 independent cohorts involving 558,302 Chinese participants, we did not observe an interaction between genetics and lifestyle with type 2 diabetes risk, but our findings provide replicable evidence to show lifestyle factors and genetic factors were independently associated with the risk of type 2 diabetes. Within any genetic risk category, a healthy lifestyle was associated with a significantly lower risk of type 2 diabetes among the Chinese population.

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Abstract P284: Role of a Genetic Risk Score with Dietary Intake and Physical Activity in Relation to Metabolic Syndrome

Circulation ◽

10.1161/circ.133.suppl_1.p284 ◽

2016 ◽

Vol 133 (suppl_1) ◽

Author(s):

Dale S Hardy ◽

Tesfaye Mersha ◽

Hongyan Xu ◽

Susan Racette

Keyword(s):

Physical Activity ◽

Logistic Regression ◽

African Americans ◽

Food Intake ◽

Genetic Risk ◽

Genetic Risk Score ◽

Statistical Significance ◽

Multivariate Logistic Regression ◽

Animal Fat ◽

Aric Study

Background: Studies have found associations between genetic polymorphisms, food intake, physical activity, body mass index, and metabolic syndrome (METs). Objective: We hypothesized that a genetic risk score (GRS) with food intake and physical activity are influenced by mediational and interaction effects to increase METs among White and African American adults. Methods: We used the Atherosclerosis Risk In Communities (ARIC) study data at the third visit from 1996-1998. Data included 8,416 Whites and 2,061 African Americans aged 41-71y with 1,484 and 517 cases of METs, respectively. METs was defined according to the International Diabetes Federation criteria. Dietary data were obtained from the ARIC study food frequency questionnaire. The GRS was composed of eight single nucleotide polymorphisms involved in cardiovascular and lipid metabolism, known to have defects in protein binding and function. Mediational path analysis using linear-and-logistic regression was used to test simultaneous associations, and interaction using multivariate logistic regression tested relationships between the GRS, food intake, physical activity and METs. In mediational path analysis, Root Mean Square Error of Approximation, p>0.05, Comparative Factor Index, p>0.90, Tucker-Lewis Index, p>0.90, and chi-square test, p>0.05 were used to assess statistical significance. For interaction using logistic regression analysis, odds ratios (OR) and 95% confidence intervals with p<0.05 were used to judge statistical significance. Results: In multivariate logistic regression, the GRS was associated with a 22% increased risk for METs among Whites (OR=1.22; 1.03-1.44), while this association was not significant in African Americans. After adjustment for Bonferonni correction for mass significance (p<0.001), we found among Whites that energy-adjusted total fat, animal fat, caloric intake, sugar-sweetened drinks, red meat, fried foods, and processed meats were associated with higher risk for METs, while energy-adjusted total carbohydrates, crude fiber, dietary fiber, and cereal fiber had a protective association with METs. These results were similar in African Americans but did not meet Bonferonni significance. In mediational analysis, we observed insignificant mediational effects, but significant direct effects for the GRS to METs for physical activity (OR=1.164; p=0.047) and fish intake (OR=1.161; p=0.050) among Whites and for carbohydrate intake (OR=1.164; p=0.058) and drinks consumed (OR=4.445; p<0.0000) among overweight/obese Whites. In interaction models, energy-adjusted carbohydrate, protein, animal fat, fructose, and sugary drinks interacted with the GRS to affect METs among Whites, but not African Americans. Conclusion: A GRS operates through interaction with dietary factors and physical activity rather than by their mediational effects on METs among White adults.

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Genetic Risk Score, Combined Lifestyle Factors and Risk of Colorectal Cancer

Cancer Research and Treatment ◽

10.4143/crt.2018.447 ◽

2019 ◽

Vol 51 (3) ◽

pp. 1033-1040 ◽

Cited By ~ 8

Author(s):

Young Ae Cho ◽

Jeonghee Lee ◽

Jae Hwan Oh ◽

Hee Jin Chang ◽

Dae Kyung Sohn ◽

...

Keyword(s):

Colorectal Cancer ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Lifestyle Factors

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

Genetic Epidemiology ◽

10.1002/gepi.22118 ◽

2018 ◽

Vol 42 (4) ◽

pp. 354-365 ◽

Cited By ~ 9

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

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P3399Influence of TCF21 rs12190287 in the coronary artery disease risk prediction. An association study in a Portuguese population

European Heart Journal ◽

10.1093/eurheartj/ehz745.0275 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

J Sousa ◽

M Mendonca ◽

A Pereira ◽

F Mendonca ◽

J Monteiro ◽

...

Keyword(s):

Risk Score ◽

Genetic Variants ◽

Genetic Risk ◽

Disease Risk ◽

Smoking Status ◽

Genetic Risk Score ◽

Strong Association ◽

Portuguese Population ◽

The Impact ◽

Cad Risk

Abstract TCF21 is a member of the basic-helix-loop-helix (bHLH) transcriptor factor family, being critical for embryogenesis of the heart, kidney and spleen. TCF21 also regulates epicardium-derived cells differentiation into smooth muscle and fibroblast lineages. Aim Investigate the impact of TCF21 rs12190287 in the prediction and discrimination of CAD risk, individually or into a genetic risk score (GRS) formed by a set of 13 genetic variants. Methods We performed a case-control study with 3050 subjects (1619 coronary patients with 53.3±8 years; 78.9% male and 1431 controls with 52.8±8 years; 76.6% male) from GENEMACOR study. We investigated all traditional risk factors (TRF), as well as 13 genetic variants from GWAS with unknown pathophysiological pathway so far, including TCF21 (rs12190287), ZC3HC1 (rs11556924), PSRC1/SORTI (rs599839), PHACTR1 (rs1332844), MIA3 (rs17465637), SMAD3 (rs17228212), ZNF259 (rs964184), ADAMTS7 (rs3825807), CDKN2B (rs4977574), 9p21.3 (rs1333049), KIF6 (rs20455), PCSK9 (rs2114580) and GJA4 (rs618675). A multiplicative genetic risk score with these 13 genetic variants (m13GRS), was calculated. Subsequently, two logistic regressions were performed; primarily with all the TRF and all the genes individually and the second with TRF and m13GRS. Results The first multivariate analysis shows that, besides the strong association of the TRF with CAD risk (with smoking status on the top of the list, with an OR of 3.2; p<0.0001), TCF21 rs12190287 was the most significant variant from all the studied genetic set with a CAD risk of 1.5 (95% CI: 1.1–1.9; p=0.004), followed by the well-known genetic determinant CDKN2B rs4977574 (OR=1.4; 95% CI: 1.1–1.7; p<0.002) and ZC3HC1 rs11556924 (OR=1.3; 95% CI: 1.0–1.7; p=0.034). When GRS is included to the model, all the TRF remain in the equation by the same order, and the m13GRS persisted as an independent predictor for CAD risk (OR=1.7; 95% CI: 1.4–2.0; p<0.0001). Conclusion TCF21 rs12190287 is a risk factor for CAD in the Portuguese population, either individually or incorporated in a m13GRS. TCF21 risk is independent from TRF. In the future, TCF21 can provide a new clues to identify patients at high cardiovascular risk and become a potential target for gene therapy.

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

Thrombosis Research ◽

10.1016/s0049-3848(17)30080-4 ◽

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

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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.

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The impact of sex, age at onset, recurrence, mode of ascertainment and medical complications on the family genetic risk score profiles for alcohol use disorder

Psychological Medicine ◽

10.1017/s0033291721003317 ◽

2021 ◽

pp. 1-9

Author(s):

Kenneth S. Kendler ◽

Henrik Ohlsson ◽

Jan Sundquist ◽

Kristina Sundquist

Keyword(s):

Alcohol Use ◽

Genetic Risk ◽

Criminal Behavior ◽

Alcohol Use Disorder ◽

Genetic Risk Score ◽

Age At Onset ◽

Risk Scores ◽

Medical Complications ◽

The Family ◽

The Impact

Abstract Background Alcohol use disorder (AUD) is clinically heterogeneous. We examine its potential genetic heterogeneity as a function of sex, age, clinical features and mode of ascertainment. Methods In the Swedish population born 1932–1995 (n = 5 829 952), we examined the genetic risk profiles for AUD, major depression (MD), anxiety disorders, bipolar disorder, drug use disorder (DUD), attention deficit-hyperactivity disorder (ADHD) and criminal behavior (CB) in 361 124 cases of AUD subdivided by sex, age at onset (AAO), recurrence, mode of ascertainment and medical complications. Family genetic risk scores (FGRS), calculated from 1st to 5th-degree relatives controlling of cohabitation, assesses genetic risk from phenotypes in the family, not from DNA variants. Results FGRS profiles differed modestly across sex with all scores higher in females. Differences were more pronounced for AAO and recurrence with the FGRS for AUD, DUD, ADHD and CB substantially higher in cases with early AAO or high recurrence rates. Genetic profiles differed considerably by mode of ascertainment, with higher FGRS for AUD and most other disorders in patients seen in hospital v. primary care settings. Cases of AUD with medical complications had higher FGRS for AUD. AUD cases comorbid with MD and DUD had higher FGRS risk for AUD, but this genetic may be less specific given increases in FGRS for multiple other disorders. Conclusions From a genetic perspective, AUD differs substantially as a function of AAO, recurrence, mode of ascertainment and patterns of comorbidity, suggesting caution in cross-sample comparisons of AUD cohorts that differ in these features.

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The Nordic Nutrition Recommendations and prostate cancer risk in the Cancer of the Prostate in Sweden (CAPS) study

Public Health Nutrition ◽

10.1017/s1368980012000778 ◽

2012 ◽

Vol 15 (10) ◽

pp. 1897-1908 ◽

Cited By ~ 1

Author(s):

Elisabeth Möller ◽

Carlotta Galeone ◽

Hans-Olov Adami ◽

Jan Adolfsson ◽

Therese M-L Andersson ◽

...

Keyword(s):

Prostate Cancer ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Prostate Cancer Risk ◽

Positive Association ◽

Population Based ◽

Lifestyle Factors ◽

Cancer Of The Prostate ◽

Nordic Nutrition Recommendations

AbstractObjectiveThe Nordic Nutrition Recommendations (NNR) aim at preventing diet-associated diseases such as cancer in the Nordic countries. We evaluated adherence to the NNR in relation to prostate cancer (PC) in Swedish men, including potential interaction with a genetic risk score and with lifestyle factors.DesignPopulation-based case–control study (Cancer of the Prostate in Sweden (CAPS), 2001–2002). Using data from a semi-quantitative FFQ, we created an NNR adherence score and estimated relative risks of PC by unconditional logistic regression. Individual score components were modelled separately and potential modifying effects were assessed on the multiplicative scale.SettingFour regions in the central and northern parts of Sweden.SubjectsIncident PC patients (n 1386) and population controls (n 940), frequency-matched on age and region.ResultsNo overall association with PC was found, possibly due to the generally high adherence to the NNR score and its narrow distribution in the study population. Among individual NNR score components, high compared with low intakes of polyunsaturated fat were associated with an increased relative risk of localized PC. No formal interaction with genetic or lifestyle factors was observed, although in stratified analysis a positive association between the NNR and PC was suggested among men with a high genetic risk score but not among men with a medium or low genetic risk score.ConclusionsOur findings do not support an association between NNR adherence and PC. The suggestive interaction with the genetic risk score deserves further investigations in other study populations.

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