Abstract
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 (AHA) 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:
We followed 9,026 white participants from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective cohort enrolled in 1987-89 until 2015. We tested the joint associations with VTE of a validated VTE GRS comprising 5 well-known gene variants and baseline LS7 categories.
Results:
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 to the high GRS and inadequate LS7 group (HR=1), those with high GRS and optimal LS7 indeed had a reduced HR of VTE: 0.65 (95% CI 0.48-0.89). The group with low GRS and optimal LS7 had the lowest HR 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.
Keywords: Venous thromboembolism, lifestyle, genetics, health status, risk factor
Introduction
Venous thromboembolism (VTE) is the one of the most common cardiovascular diseases with high global burden.1 Estimates suggest 1 to 2 per 1,000 individuals sustain a VTE each year in the United States, and once VTE has occurred, the recurrence risk is about 30% over 8 years.1,2 Based on these statistics, the US Surgeon General issued a “Call to Action” to prevent deep vein thrombosis (DVT) and pulmonary embolism (PE).3 In addition to triggers such as malignancy, surgery, and immobility, lifestyle factors and genetic predisposition are key determinants of VTE.4
The American Heart Association is using a metric called Life’s Simple 7 (LS7) to track the cardiovascular health of the population.5 The LS7 metric includes smoking status, body mass index (BMI), physical activity, diet score, total cholesterol, blood pressure and fasting glucose, which are each classified as ideal, average, or poor. Several research studies have shown that favorable scores for the LS7 metric are linked to lower incidence of cardiovascular outcomes including VTE.6,7 The BMI and physical activity metrics are most closely related to VTE risk.7,8
Additionally, 50–60% of the variance in VTE incidence relates to genetic factors.9 Several single nucleotide polymorphisms (SNPs), particularly those located in or near genes encoding coagulation proteins, are associated with increased VTE risk.10-13 Availability of a genetic risk score (GRS) for VTE risk, which we previously validated among whites but not African-Americans,14 allows further investigation of whether healthy lifestyle might lower the genetic risk of VTE.
We hypothesized that greater adherence to LS7 is associated with lower VTE risk in the setting of high genetic risk. We then explored which components of the LS7 metric are associated with attenuated genetic risk. We anticipated that favorable health factors, specifically BMI and physical activity, assessed as LS7 may mitigate VTE occurrence in high GRS individuals.
Methods
The data underlying the findings include potentially identifying participant information, and cannot be made publicly available due to ethical/legal restrictions. However, data including statistical code from this manuscript are available to researchers who meet the criteria for access to confidential data. Data can be obtained upon request through the University of Alabama at Birmingham at regardsadmin@uab.edu
Subjects
Participants were from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective cohort of 15,792 participants.15,16 The cohort was enrolled in 1987-1989 in four communities: Forsyth County, North Carolina; Washington County, Maryland; suburban Minneapolis, Minnesota; Jackson, Mississippi. Individuals were mostly white or African-American and included men and women. Participants were followed by periodic clinic visits, annual or semiannual telephone calls, and surveillance of community hospitals and the national death index.17,18 For the present analysis, follow-up ended in 31 December 2015, as this was the last date of VTE validation. Demographic data analyzed included baseline self-reported age, sex, and education.
Participants were excluded from analysis if they reported prebaseline VTE and/or were taking anticoagulation (n=252), were African-American (as the GRS was not associated with VTE risk in African-Americans, n=4,315), were missing data for at least one of the 5 SNPs in the GRS (n=1,706), and/or were missing LS7 components (n=609, mainly due to not fasting, missing or implausible dietary data defined as extreme energy intake of <600 or >4,200 kcal/day for men or <500 or >3,600 kcal/day for women). The final analytic sample was 9,026.
Life’s Simple 7
Each of the 7 components of the metric was measured and defined at baseline as previously published and given a score of 0, 1, or 2 to represent poor, average, or ideal health status (Table 1), according to the AHA definition.7 A sum of the scores from the 7 metrics, ranging from 0-14, was calculated to develop a summary score. Those with a score of 0-7 were classified as having inadequate health, those with a score of 8-9 were considered to have average health, and those with a score of 10-14 were classified as having optimal health.19
Table 1.
Definitions of Life’s Simple 7 Categories
| Metric5 | Poor (0 Points) | Average (1 Point) | Ideal (2 Points) |
|---|---|---|---|
| Smoking status | Current | Former ≤12 months | Never or quit >12 months |
| Body mass index | ≥30 kg/m2 | 25 to <30 kg/m2 | <25 kg/m2 |
| Physical activity* | None | 1 to 3 times per week | ≥4 times per week |
| Healthy diet** | 0 to 1 components | 2 to 3 components | 4 to 5 components |
| Total cholesterol | ≥240 mg/dL | 200 to 239 mg/dL or treated to goal |
<200 mg/dL (not on treatment) |
| Blood pressure | SBP ≥ 140 mmHg or DBP ≥90 mmHg | SBP 120 to 130 mmHg or DBP 80 to 89 mmHg or treated to goal | SBP <120 mmHG and DBP <80 mmHG (not on treatment) |
| Fasting serum glucose | ≥126 mg/dL | 100 to 125 mg/dL or treated to goal | <100 mg/dl (not on treatment) |
Inadequate health: 0-7 points; Average health: 8-9 points; Optimal health: 10-14 points
Ideal: ≥150 min/wk moderate intensity or ≥75 min/wk vigorous intensity or ≥150 min/wk moderate+vigorous; Intermediate: 1 to 149 min/wk moderate intensity or 1 to 74 min/wk vigorous intensity or 1 to 149 min/wk moderate+vigorous; Poor: none
Derived from the Food Frequency Questionnaire based on 5 healthy diet components, each worth 1 point: (1) fruits and vegetables: ≥4.5 servings per day; (2) fish: ≥ two 3.5 oz of servings per week; (3) fiber-rich whole grains (>1 g of fiber per 10 g of carbohydrate): ≥ 3 1 oz equivalent servings per day; (4) sodium: <1500 mg per day; and (5) sugar-sweetened foods and beverages: ≤450 kcal (36 oz) per week
VTE ascertainment
Information from all hospitalizations was collected and potential VTE cases were identified based on ICD-9 CM codes suggesting VTE. Potential cases were reviewed by two physicians who reached consensus on classification. DVT was defined as duplex ultrasound, venogram, or rarely computed tomography showing proximal or distal DVT. PE was determined by ventilation/perfusion scans, angiography, computed tomography or autopsy.15 Provoked VTE was defined based on information in the record as VTE within 90 days of trauma, surgery, immobility, or cancer, while all other VTE was defined as unprovoked. Recurrent VTE was not considered.
GRS
As previously published, the GRS was based on five SNPs associated with VTE (F5 Leiden rs6025, F2 rs1799963, ABO rs8176719 (O vs. non-O groups), FGG rs2066865, and F11 rs2036914).14 Risk alleles for each SNP were assigned literature-established weights, based on average odds ratios of VTE for each SNP, to calculate a GRS ranging from 0 to 10, with higher values associated with greater risk.14
Statistical Analysis
Participant characteristics according to the GRS were tabulated. Analysis of risk relationships was conducted for VTE overall and for unprovoked and provoked VTE separately. Kaplan-Meier probabilities were used to show the time to VTE by LS7 categories stratified by GRS. We evaluated the association of LS7 and GRS with VTE using Cox proportional hazards models, calculating hazard ratios (HRs) and 95% confidence intervals (CIs) of VTE by LS7 categories (inadequate, average, optimal), stratified by GRS (low, intermediate, high), adjusted for age, sex, and education. The individual metrics of LS7 were then examined separately to determine which factors in LS7 might be more important in risk reduction for people with high GRS. Multiplicative interactions between GRS tertiles and LS7 categories were tested using cross-product terms in the models. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Results
Baseline characteristics of the 9,026 participants were similar by GRS category (Table 2). Over an average (SD) follow-up of 22.9 ± 6.7 years, 466 (5.2%) had an incident VTE. Accounting for varying follow-up times, the overall incidence rate of VTE was 2.3 per 1,000 person-years.
Table 2.
Characteristics of White ARIC Participants by Venous Thromboembolism Genetic Risk Score (GRS) at baseline, 1987-89
| Variable | GRS | ||
|---|---|---|---|
| Low (n=2192 ) | Intermediate (n=2843) | High (n=3991 ) | |
| Age (Years) | 54 | 54 | 54 |
| Male | 48% | 46% | 47% |
| Education ≤12 years | 51% | 52% | 52% |
| Body mass index (kg/m2) | 27.0 | 26.7 | 27.1 |
| Systolic blood pressure (mmHg) | 119 | 118 | 118 |
| Diastolic blood pressure (mmHg) | 72 | 71 | 71 |
| Antihypertensive medication use (yes) | 20% | 19% | 19% |
| Total cholesterol (mg/dL) | 213 | 214 | 215 |
| Glucose (mg/dL) | 105 | 104 | 104 |
| Smoking Status | |||
| Never or Former >1 yr | 74% | 72% | 73% |
| Former <1 yr | 3% | 3% | 3% |
| Current | 23% | 25% | 24% |
| Physical activity | |||
| Poor | 30% | 30% | 30% |
| Average | 25% | 25% | 27% |
| Ideal | 45% | 45% | 43% |
| Healthy diet score | |||
| Poor | 30% | 28% | 29% |
| Average | 65% | 67% | 65% |
| Ideal | 5% | 5% | 6% |
| Prebaseline coronary artery disease | 5% | 5% | 5% |
| Prebaseline stroke | 1% | 1% | 1% |
Figure 1 depicts the incidence rate of VTE per 1,000 person-years by LS7 category. Compared to those with optimal or average LS7, those with inadequate LS7 score had higher rates of total, provoked and unprovoked VTE. The total VTE incidence rate in those with inadequate LS7 was 2.9 per 1000 person-years compared to 1.6 per 1000 person-years for optimal LS7. Figure 2 displays the incidence rate of VTE by GRS categories; those with high GRS had a rate of 3.6 per 1000 person-years and those with low GRS had a rate of 1.6 per 1000 person-years. The rates for provoked and unprovoked VTE separately also were higher in the high compared to the low GRS category.
Figure 1.
Incidence Rate of Venous Thromboembolism (VTE) by Life’s Simple 7 (LS7) Category, ARIC Whites, 1987-89 through 2015
Figure 2.
Incidence Rate of Venous Thromboembolism (VTE) by Genetic Risk Score (GRS) Category, ARIC Whites, 1987-89 through 2015
As shown in Table 3 and Figure 3, compared to the highest risk participants with a high GRS and inadequate LS7, participants with a low GRS and inadequate LS7 had a 46% lower hazard of VTE [HR of 0.54 (0.36-0.80)] and participants with low GRS and optimal LS7 had a 61% lower hazard of VTE [HR 0.39 (0.25-0.61)]. Moreover, within the high GRS group, the HR was 35% lower for participants in the optimal LS7 group than for participants in the inadequate LS7 group [HR 0.65 (0.48-0.89)]. Results were similar for provoked and unprovoked VTE separately.
Table 3.
Hazard Ratios (HRs) of Incident Venous Thromboembolism (VTE) according to Life’s Simple 7 score and VTE Genetic Risk Score (GRS) category, ARIC whites, 1987-89 through 2015
| Life Simple 7 Categories |
n VTE / N at risk HR (95% CI)* |
|||
|---|---|---|---|---|
| All VTE | n VTE / N at risk |
Low GRS | Intermediate GRS | High GRS |
| Inadequate | 181/3124 | 31/774 0.54 (0.36,0.80) |
52/969 0.74 (0.53,1.04) |
98/1381 1 (Referent) |
| Average | 165/2843 | 25/660 0.48 (0.31,0.74) |
48/902 0.65 (0.46,0.92) |
92/1281 0.90 (0.68,1.20) |
| Optimal | 120/3059 | 24/758 0.39 (0.25,0.61) |
26/972 0.33 (0.21,0.51) |
70/1329 0.65 (0.48,0.89) |
| Provoked VTE | N=8850 | |||
| Inadequate | 66/3005 | 20/763 0.52 (0.32,0.87) |
36/953 0.79 (0.52,1.18) |
64/1347 1 (Referent) |
| Average | 209/5428 | 18/653 0.53 (0.31,0.90) |
37/891 0.77(0.52,1.16) |
49/1238 0.75 (0.52,1.09) |
| Optimal | 15/417 | 12/746 0.31 (0.16,0.57) |
19/965 0.37 (0.22,0.63) |
35/1294 0.51 (0.34,0.78) |
| Unprovoked VTE | N=8736 | |||
| Inadequate | 61/3004 | 11/754 0.54 (0.27,1.06) |
16/933 0.65 (0.36,1.18) |
34/1317 1 (Referent) |
| Average | 61/2739 | 7/642 0.37 (0.16,0.83) |
11/865 0.42 (0.21,0.82) |
43/1232 1.17 (0.75,1.84) |
| Optimal | 54/2993 | 12/746 0.52 (0.27,1.01) |
7/953 0.24 (0.10,0.54) |
35/1294 0.87 (0.54,1.41) |
Adjusted for age, sex, education
P interaction for GRS by LS7 for overall (p=0.58), provoked (p=0.82), unprovoked VTE (p=0.26)
Figure 3.
Life’s Simple 7 (LS7) Score and Hazard Ratio (95% CI) of Incident Venous Thromboembolism (VTE) stratified by Genetic Risk Score (GRS) Category, ARIC Whites, 1987-89 through 2015. Numbers above bars are number of events/ number at risk
The BMI and physical activity components of LS7 were most strongly related to VTE risk (Table 4). In the high GRS subgroup, lower BMI (HR: 0.79, 0.59-1.06 for average BMI and HR: 0.55, 0.44-0.76 for ideal BMI) and greater physical activity (HR: 0.72, 0.52-1.00 for average physical activity and HR: 0.79, 0.69-1.05 for ideal physical activity) were associated with reduced VTE risk. Average and ideal blood pressure were associated with decreased VTE risk in the low and intermediate GRS groups, and there were associations of cholesterol with VTE in some GRS groups. Supplemental Figures 1 and 2 depict the joint associations of GRS and individual BMI or physical activity metrics with incident VTE.
Table 4.
Associations between individual Life's Simple 7 components and incident venous thromboembolism (VTE) stratified by genetic risk score (GRS), ARIC whites, 1987-89 through 2015
| Component | HR (95% CI)* | ||
|---|---|---|---|
| Low GRS | Intermediate GRS | High GRS | |
| Total cholesterol | |||
| Poor | 0.42 (0.24,0.72) | 0.67 (0.44,1.01) | 1 (Referent) |
| Average | 0.47 (0.31,0.74) | 0.67 (0.47,0.97) | 0.96 (0.71,1.31) |
| Ideal | 0.72 (0.48,1.08) | 0.66 (0.45,0.96) | 1.03 (0.74,1.41) |
| Blood pressure | |||
| Poor | 0.66 (0.41,1.08) | 0.95 (0.63,1.43) | 1 (Referent) |
| Average | 0.45 (0.27,0.75) | 0.66 (0.44,0.98) | 1.05 (0.76,1.47) |
| Ideal | 0.47 (0.31,0.71) | 0.45 (0.30,0.67) | 0.79 (0.57,1.10) |
| Blood glucose | |||
| Poor | 0.73 (0.26,2.07) | 1.23 (0.55,2.74) | 1 (Referent) |
| Average | 0.77 (0.40,1.48) | 0.97 (0.52,1.80) | 1.43 (0.79,2.58) |
| Ideal | 0.60 (0.31,1.14) | 0.66 (0.35,1.23) | 1.08 (0.60,1.96) |
| Physical activity | |||
| Poor | 0.38 (0.23,0.62) | 0.64 (0.44,0.92) | 1 (Referent) |
| Average | 0.70 (0.46,1.05) | 0.65 (0.44,0.95) | 0.72 (0.52,1.00) |
| Ideal | 0.38 (0.26,0.58) | 0.46 (0.32,0.65) | 0.79 (0.60,1.05) |
| Healthy diet score | |||
| Poor | 0.56 (0.35,0.91) | 0.68 (0.45,1.03) | 1 (Referent) |
| Average | 0.64 (0.45,0.91) | 0.73 (0.53,1.00) | 1.14 (0.86,1.51) |
| Ideal | 0.14 (0.02,1.03) | 0.73 (0.34,1.59) | 0.69 (0.36,1.30) |
| Smoking | |||
| Poor | 0.69 (0.41,1.16) | 0.78 (0.50,1.23) | 1 (Referent) |
| Average | 0.91 (0.28,2.90) | 0.52 (0.16,1.66) | 0.79 (0.34,1.83) |
| Ideal | 0.51 (0.35,0.75) | 0.65 (0.46,0.92) | 1.02 (0.75,1.38) |
| Body mass index | |||
| Poor | 0.65 (0.42,1.01) | 0.81 (0.55,1.19) | 1 (Referent) |
| Average | 0.32 (0.21,0.50) | 0.42 (0.29,0.61) | 0.79 (0.59,1.06) |
| Ideal | 0.36 (0.23,0.57) | 0.42 (0.29,0.62) | 0.55 (0.40,0.76) |
Adjusted for age, sex, education
Discussion
We hypothesized that a cardiovascular-healthy lifestyle can reduce VTE occurrence in high GRS individuals and anticipated that better adherence to LS7, particularly the BMI and physical activity metrics, would be associated with lower VTE risk than other LS7 metrics.20-23 Similar to prior findings that lifestyle can reduce genetic risk for coronary heart disease24, we demonstrated that a more favorable health score attenuated the risk associated with a high VTE GRS by 35%.
Among the LS7 components, ideal BMI was associated with the lowest risk of VTE in participants with high GRS. Ideal BMI was also favorable to reduce risk in the low and intermediate GRS groups. Across all categories of GRS, higher physical activity was associated with lower VTE incidence, although the relationship was not larger (and not quite statistically significant) in those with high GRS. The remaining 5 metrics (cholesterol, blood pressure, glucose, healthy diet and smoking status) had little or no association with VTE in high GRS individuals. Lower cholesterol seemed associated with higher VTE risk in the low GRS group and ideal blood pressure seemed protective within intermediate and low GRS groups. Findings raise a possibility that thrombus formation may have a different biological basis in the setting of lower compared to higher GRS, but since these factors are not generally considered VTE risk factors it is also possible the findings occurred by chance.25-28
While epidemiological evidence suggests that lifestyle factors influence VTE risk, we are aware of only one other study that examined the influence of healthy lifestyle on those at high risk of VTE based on a GRS. Using a 16 SNP GRS, Kim and colleagues reported that greater BMI and high GRS synergistically increased VTE risk. They found no such interaction between physical activity or sedentary activity and their GRS.29 Two other studies demonstrated that obesity and single genetic defects, such as Factor V Leiden, jointly augmented VTE risk.29,30
Directed efforts at primary prevention of VTE are currently limited to very high risk populations, such as surgery patients and those who are hospitalized.31 Outside of these populations, it is difficult to identify sufficiently high-risk groups based on known risk factors to warrant pharmacologic prophylaxis. Additionally, we are not aware of studies evaluating the implementation of lifestyle interventions to lower VTE risk. Our findings suggest that for individuals with high GRS and obesity or physical inactivity, primary prevention efforts directed at lifestyle interventions to reduce weight or increase activity might reduce VTE risk. Encouragingly, individuals with a high GRS may only have to reach an average level of activity to reduce VTE. This may be a more realistic target than ideal activity for many individuals. In consideration of potential studies of lifestyle interventions to reduce VTE risk in individuals with high GRS, because VTE incidence rates are relatively low in the general population, a high risk population should be selected for study. Family members of those with VTE may be best for such study due to their inherently higher incidence of VTE.32,33 Interventions such as statins in these high risk populations could also be considered.33
Finally, people with previous VTE have high risk of recurrent VTE, and whether a lifestyle intervention could reduce recurrent VTE is unknown. Some data suggests that exercise programs in VTE patients improve physical activity and fitness, and are safe, though whether this attenuates risk of recurrent VTE is unknown.34,35
Strengths of this study include the prospective study design and large middle-aged cohort with representation of men and women examining the relation between lifestyle, genetics and VTE. VTE was carefully adjudicated. There are nevertheless potential limitations of the study. Even though VTE events were validated, ascertainment of VTE relied on hospital diagnosis codes and cases may have been missed, especially in later years when VTEs may have been treated more in the outpatient setting. Although there were a large number of incident VTEs, numbers of participants in some LS7 categories were low. For example, only 5.5% of participants had an ideal diet score thus assessment of ideal diet and VTE was limited. Low numbers within joint categories of LS7 and GRS often yielded wide confidence intervals for VTE. LS7 variables, such as diet, exercise and smoking status, relied on participant report at a single point in time at baseline and status may have changed during the lengthy follow-up. Finally, lack of inclusion of racial groups other than whites means that our findings may not be generalized to these groups. While one report found that LS7 was also associated with lower VTE risk in African-Americans7, racial differences in VTE reduction by healthy lifestyle factors, and development of GRS’s in non-whites requires more study.
The findings of this study suggest that in primary care practice, as for other diseases, among those at high genetic risk for VTE, lifestyle interventions should be considered to reduce VTE. Further research should determine the best populations and effective interventions for this purpose.
Supplementary Material
Highlights:
It is known that healthier lifestyle factors reduce venous thromboembolism (VTE), and genetic factors raise risk
In a prospective cohort we analyzed whether healthier lifestyle mitigates VTE risk in those at high genetic risk
Among people at low or high genetic risk, healthier lifestyle factors, particularly normal weight, were associated with lower VTE risk.
Further studies can assess impact of lifestyle improvement to reduce first VTE in people at high genetic risk, like those with a family history of VTE
Acknowledgements
The authors thank the staff and participants of the ARIC study for their important contributions.
Sources of Funding
The National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services supported ARIC via contracts with Federal funds from the HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I and LITE via HL0597367. This work was also supported by a Research Fellowship from the North American Society of Thrombosis and Hemostasis (NASTH).
Nonstandard Abbreviations
- LS7
Life’s Simple 7
- GRS
genetic risk score
- ARIC
Atherosclerosis Risk in Communities
- AHA
American Heart Association
Footnotes
Conflict of Interest Disclosures
Authors have no disclosures
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