Framingham Offspring Study Research Articles

Regression-based negative control of homophily in dyadic peer effect analysis.

A prominent threat to causal inference about peer effects in social science studies is the presence of homophily bias , that is, social influence between friends and families is entangled with common characteristics or underlying similarities that form close connections. Analysis of social study data has suggested that certain health conditions such as obesity and psychological states including happiness and loneliness can spread between friends and relatives. However, such analyses of peer effects or contagion effects have come under criticism because homophily bias may compromise the causal statement. We develop a regression-based approach which leverages a negative control exposure for identification and estimation of contagion effects on additive or multiplicative scales, in the presence of homophily bias. We apply our methods to evaluate the peer effect of obesity in Framingham OffspringStudy.

Abstract P156: Association Of Blood Pressure Responses To Submaximal Exercise With Incident Atrial Fibrillation: The Framingham Offspring Study

Introduction: Atrial fibrillation (AF) is the most common arrhythmia and a leading cause of stroke. Blood pressure (BP) responses to submaximal exercise are associated with incident cardiovascular disease and mortality. The association of BP responses to submaximal exercise with incident AF in the community is unknown. Hypothesis: We hypothesized that higher BP during and slower BP recovery after submaximal exercise are associated with a higher risk of incident AF. Methods: We evaluated Framingham Offspring Study participants who attended examination cycle 7, were free of AF, and underwent submaximal treadmill exercise testing. Systolic BP (SBP) and diastolic BP (DBP) were obtained pre-exercise (standing), during exercise (second stage, 2.5 mph at 12% grade), and 3-minutes post-exercise (supine). ΔBP during exercise was defined as exercise BP minus pre-exercise BP. ΔBP during recovery was defined as peak exercise BP minus 3-minutes post-exercise BP. We related exercise BP variables to risk of AF using Cox proportional hazards regression, adjusting for age, sex, height, weight, resting heart rate, resting SBP, resting DBP, use of antihypertensive medication, current smoking status, and diabetes. Results: We studied 2,002 participants (mean age 58 years; 53% women). During a median follow-up of 15 years, 236 participants (39% women) developed AF. We observed a positive association of exercise DBP and ΔDBP during exercise with risk of AF (Hazards Ratio [HR] per standard deviation [SD] increase 1.28, 95% CI 1.12-1.47 and HR 1.22, 95% CI 1.07-1.39, respectively). There was also a positive association between 3 minutes post-exercise SBP and AF risk (HR per SD-increase 1.31, 95% CI 1.07-1.60) and an inverse relation between ΔSBP during recovery and AF risk (HR per SD-increase 0.79, 95% CI 0.66-0.94, Table ) Conclusions: BP responses to submaximal exercise during midlife may serve as a marker for AF risk in later life.

Biomarkers representing key aging-related biological pathways are associated with subclinical atherosclerosis and all-cause mortality: The Framingham Study.

Increased oxidative stress, leukocyte telomere length (LTL) shortening, endothelial dysfunction, and lower insulin-like growth factor (IGF)-1 concentrations reflect key molecular mechanisms of aging. We hypothesized that biomarkers representing these pathways are associated with measures of subclinical atherosclerosis and all-cause mortality. We evaluated up to 2,314 Framingham Offspring Study participants (mean age 61 years, 55% women) with available biomarkers of aging: LTL, circulating concentrations of IGF-1, asymmetrical dimethylarginine (ADMA), and urinary F2-Isoprostanes indexed to urinary creatinine. We evaluated the association of each biomarker with coronary artery calcium [ln (CAC+1)] and carotid intima-media thickness (IMT). In multivariable-adjusted linear regression models, higher ADMA levels were associated with higher CAC values (βADMA per 1-SD increase 0.25; 95% confidence interval [CI] [0.11, 0.39]). Additionally, shorter LTL and lower IGF-1 values were associated with higher IMT values (βLTL -0.08, 95%CI -0.14, -0.02, and βIGF-1 -0.04, 95%CI -0.08, -0.01, respectively). During a median follow-up of 15.5 years, 593 subjects died. In multivariable-adjusted Cox regression models, LTL and IGF-1 values were inversely associated with all-cause mortality (hazard ratios [HR] per SD increase in biomarker, 0.85, 95% CI 0.74-0.99, and 0.90, 95% CI 0.82-0.98 for LTL and IGF-1, respectively). F2-Isoprostanes and ADMA values were positively associated with all-cause mortality (HR per SD increase in biomarker, 1.15, 95% CI, 1.10-1.22, and 1.10, 95% CI, 1.02-1.20, respectively). In our prospective community-based study, aging-related biomarkers were associated with measures of subclinical atherosclerosis cross-sectionally and with all-cause mortality prospectively, supporting the concept that these biomarkers may reflect the aging process in community-dwelling adults.

Performance of Stepwise Screening Methods in Identifying Individuals at High Risk of Type 2 Diabetes in an Iranian Population.

Recent evidence recommended stepwise screening methods for identifying individuals at high risk of type 2 diabetes to be recruited in the lifestyle intervention programs for the prevention of the disease. This study aims to assess the performance of different stepwise screening methods that combine non-invasive measurements with lab-based measurements for identifying those with 5-years incident type 2 diabetes. 3037 participants aged ≥30 years without diabetes at baseline in the Tehran Lipid and Glucose Study (TLGS) were followed. Thirty-two stepwise screening methods were developed by combining a non-invasive measurement (an anthropometric measurement (waist-to-height ratio, WtHR) or a score based on a non-invasive risk score [Australian Type 2 Diabetes Risk Assessment Tool, AUSDRISK]) with a lab-based measurement (different cut-offs of fasting plasma glucose [FPG] or predicted risk based on three lab-based prediction models [Saint Antonio, SA; Framingham Offspring Study, FOS; and the Atherosclerosis Risk in Communities, ARIC]). The validation, calibration, and usefulness of lab-based prediction models were assessed before developing the stepwise screening methods. Cut-offs were derived either based on previous studies or decision-curve analyses. 203 participants developed diabetes in 5 years. Lab-based risk prediction models had good discrimination power (area under the curves [AUCs]: 0.80-0.83), achieved acceptable calibration and net benefits after recalibration for population's characteristics and were useful in a wide range of risk thresholds (5%-21%). Different stepwise methods had sensitivity ranged 20%-68%, specificity 70%-98%, and positive predictive value (PPV) 14%-46%; they identified 3%-33% of the screened population eligible for preventive interventions. Stepwise methods have acceptable performance in identifying those at high risk of incident type 2 diabetes.

DNA methylation and gene expression integration in cardiovascular disease

BackgroundThe integration of different layers of omics information is an opportunity to tackle the complexity of cardiovascular diseases (CVD) and to identify new predictive biomarkers and potential therapeutic targets. Our aim was to integrate DNA methylation and gene expression data in an effort to identify biomarkers related to cardiovascular disease risk in a community-based population. We accessed data from the Framingham Offspring Study, a cohort study with data on DNA methylation (Infinium HumanMethylation450 BeadChip; Illumina) and gene expression (Human Exon 1.0 ST Array; Affymetrix). Using the MOFA2 R package, we integrated these data to identify biomarkers related to the risk of presenting a cardiovascular event.ResultsFour independent latent factors (9, 19, 21—only in women—and 27), driven by DNA methylation, were associated with cardiovascular disease independently of classical risk factors and cell-type counts. In a sensitivity analysis, we also identified factor 21 as associated with CVD in women. Factors 9, 21 and 27 were also associated with coronary heart disease risk. Moreover, in a replication effort in an independent study three of the genes included in factor 27 were also present in a factor identified to be associated with myocardial infarction (CDC42BPB, MAN2A2 and RPTOR). Factor 9 was related to age and cell-type proportions; factor 19 was related to age and B cells count; factor 21 pointed to human immunodeficiency virus infection-related pathways and inflammation; and factor 27 was related to lifestyle factors such as alcohol consumption, smoking and body mass index. Inclusion of factor 21 (only in women) improved the discriminative and reclassification capacity of the Framingham classical risk function and factor 27 improved its discrimination.ConclusionsUnsupervised multi-omics data integration methods have the potential to provide insights into the pathogenesis of cardiovascular diseases. We identified four independent factors (one only in women) pointing to inflammation, endothelium homeostasis, visceral fat, cardiac remodeling and lifestyles as key players in the determination of cardiovascular risk. Moreover, two of these factors improved the predictive capacity of a classical risk function.

Invited Commentary: Body Mass Index and Risk of Dementia-Potential Explanations for Life-Course Differences in Risk Estimates and Future Research Directions.

The relationship between body mass index (BMI) and health outcomes of older adults, including dementia, remains controversial. Many studies find inverse associations between BMI and dementia among older adults, while in other studies high BMI in midlife is associated with increased dementia risk. In this issue, Li et al. (Am J Epidemiol. 2021;190(12):2503-2510) examine BMI from mid- to late life and risk of dementia using the extensive follow-up of the Framingham Offspring Study. They found changing trends in the association between BMI and dementia from a positive association for midlife (ages 40-49) to an inverse trend in late life. Their work demonstrates the importance of studying dementia risk factors across the life course. Midlife obesity might be an important modifiable risk factor for dementia. However, because incipient dementia can lead to weight loss, reverse causation remains a key source of bias that could explain an inverse trend between BMI and dementia in older ages. The extent of other biases, including unmeasured confounding, inaccuracy of BMI as a measure for adiposity, or selective survival, are also unclear. Triangulating evidence on body composition and dementia risk could lead to better targets for dementia intervention, but future work will need to evaluate specific pathways.

Higher Hand Grip Strength Is Associated With Greater Radius Bone Size and Strength in Older Men and Women: The Framingham Osteoporosis Study.

ABSTRACTMechanical loading by muscles elicits anabolic responses from bone, thus age‐related declines in muscle strength may contribute to bone fragility in older adults. We used high‐resolution peripheral quantitative computed tomography (HR‐pQCT) to determine the association between grip strength and distal radius bone density, size, morphology, and microarchitecture, as well as bone strength estimated by micro–finite element analysis (μFEA), among older men and women. Participants included 508 men and 651 women participating in the Framingham Offspring Study with grip strength measured in 2011–2014 and HR‐pQCT scanning in 2012–2015. Separately for men and women, analysis of covariance was used to compare HR‐pQCT measures among grip strength quartiles and to test for linear trends, adjusting for age, height, weight, smoking, and physical activity. Mean age was 70 years (range, 50–95 years), and men had higher mean grip strength than the women (37 kg vs. 21 kg). Bone strength estimated by μFEA‐calculated failure load was higher with greater grip strength in both men (p < 0.01) and women (p = 0.04). Higher grip strength was associated with larger cross‐sectional area in both men and women (p < 0.01), with differences in area of 6% and 11% between the lowest to highest grip strength quartiles in men and women, respectively. Cortical thickness was positively associated with grip strength among men only (p = 0.03). Grip strength was not associated with volumetric BMD (vBMD) in men. Conversely, there was a trend for lower total vBMD with higher grip strength among women (p = 0.02), though pairwise comparisons did not reveal any statistically significant differences in total vBMD among grip strength quartiles. Bone microarchitecture (cortical porosity, trabecular thickness, trabecular number) was not associated with grip strength in either men or women. Our findings suggest that the positive association between hand grip strength and distal radius bone strength may be driven primarily by bone size. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Modest Gains Confer Large Impact: Achievement of Optimal Cardiovascular Health in the US Population

Modest Gains Confer Large Impact: Achievement of Optimal Cardiovascular Health in the US Population

Association of Blood Pressure and Heart Rate Responses to Submaximal Exercise With Incident Heart Failure: The Framingham Heart Study.

BackgroundExercise stress tests are conventionally performed to assess risk of coronary artery disease. Using the FHS (Framingham Heart Study) Offspring cohort, we related blood pressure (BP) and heart rate responses during and after submaximal exercise to the incidence of heart failure (HF).Methods and ResultsWe evaluated Framingham Offspring Study participants (n=2066; mean age, 58 years; 53% women) who completed 2 stages of an exercise test (Bruce protocol) at their seventh examination (1998–2002). We measured pulse pressure, systolic BP, diastolic BP, and heart rate responses during stage 2 exercise (2.5 mph at 12% grade). We calculated the changes in systolic BP, diastolic BP, and heart rate from stage 2 to recovery 3 minutes after exercise. We used Cox proportional hazards regression to relate each standardized exercise variable (during stage 2, and at 3 minutes of recovery) individually to HF incidence, adjusting for standard risk factors. On follow‐up (median, 16.8 years), 85 participants developed new‐onset HF. Higher exercise diastolic BP was associated with higher HF with reduced ejection fraction (ejection fraction <50%) risk (hazard ratio [HR] per SD increment, 1.26; 95% CI, 1.01–1.59). Lower stage 2 pulse pressure and rapid postexercise recovery of heart rate and systolic BP were associated with higher HF with reduced ejection fraction risk (HR per SD increment, 0.73 [95% CI, 0.57–0.94]; 0.52 [95% CI, 0.35–0.76]; and 0.63 [95% CI, 0.47–0.84], respectively). BP and heart rate responses to submaximal exercise were not associated with risk of HF with preserved ejection fraction (ejection fraction ≥50%).ConclusionsAccentuated diastolic BP during exercise with slower systolic BP and heart rate recovery after exercise are markers of HF with reduced ejection fraction risk.

Ultra-Processed Foods and Incident Cardiovascular Disease in the Framingham Offspring Study

BackgroundUltra-processed foods provide 58% of total energy in the U.S. diet, yet their association with cardiovascular disease (CVD) remains understudied. ObjectivesThe authors investigated the associations between ultra-processed foods and CVD incidence and mortality in the prospective Framingham Offspring Cohort. MethodsThe analytical sample included 3,003 adults free from CVD with valid dietary data at baseline. Data on diet, measured by food frequency questionnaire, anthropometric measures, and sociodemographic and lifestyle factors were collected quadrennially from 1991 to 2008. Data regarding CVD incidence and mortality were available until 2014 and 2017, respectively. Ultra-processed foods were defined according to the NOVA framework. The authors used Cox proportional hazards models to determine the multivariable association between ultra-processed food intake (energy-adjusted servings per day) and incident hard CVD, hard coronary heart disease (CHD), overall CVD, and CVD mortality. Multivariable models were adjusted for age, sex, education, alcohol consumption, smoking, and physical activity. ResultsDuring follow-up (1991 to 2014/2017), the authors identified 251, 163, and 648 cases of incident hard CVD, hard CHD, and overall CVD, respectively. On average, participants consumed 7.5 servings per day of ultra-processed foods at baseline. Each additional daily serving of ultra-processed foods was associated with a 7% (95% confidence interval [CI]: 1.03 to 1.12), 9% (95% CI: 1.04 to 1.15), 5% (95% CI: 1.02 to 1.08), and 9% (95% CI: 1.02 to 1.16) increase in the risk of hard CVD, hard CHD, overall CVD, and CVD mortality, respectively. ConclusionsThe current findings support that higher consumption of ultra-processed foods is associated with increased risk of CVD incidence and mortality. Although additional research in ethnically diverse populations is warranted, these findings suggest cardiovascular benefits of limiting ultra-processed foods.

Sex Differences in Cognitive Decline Among US Adults

Sex differences in dementia risk are unclear, but some studies have found greater risk for women. To determine associations between sex and cognitive decline in order to better understand sex differences in dementia risk. This cohort study used pooled analysis of individual participant data from 5 cohort studies for years 1971 to 2017: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Linear mixed-effects models were used to estimate changes in each continuous cognitive outcome over time by sex. Data analysis was completed from March 2019 to October 2020. Sex. The primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Among 34 349 participants, 26 088 who self-reported Black or White race, were free of stroke and dementia, and had covariate data at or before the first cognitive assessment were included for analysis. Median (interquartile range) follow-up was 7.9 (5.3-20.5) years. There were 11 775 (44.7%) men (median [interquartile range] age, 58 [51-66] years at first cognitive assessment; 2229 [18.9%] Black) and 14 313 women (median [interquartile range] age, 58 [51-67] years at first cognitive assessment; 3636 [25.4%] Black). Women had significantly higher baseline performance than men in global cognition (2.20 points higher; 95% CI, 2.04 to 2.35 points; P < .001), executive function (2.13 points higher; 95% CI, 1.98 to 2.29 points; P < .001), and memory (1.89 points higher; 95% CI, 1.72 to 2.06 points; P < .001). Compared with men, women had significantly faster declines in global cognition (-0.07 points/y faster; 95% CI, -0.08 to -0.05 points/y; P < .001) and executive function (-0.06 points/y faster; 95% CI, -0.07 to -0.05 points/y; P < .001). Men and women had similar declines in memory (-0.004 points/y faster; 95% CI, -0.023 to 0.014; P = .61). The results of this cohort study suggest that women may have greater cognitive reserve but faster cognitive decline than men, which could contribute to sex differences in late-life dementia.

Trends in food consumption by degree of processing and diet quality over 17 years: results from the Framingham Offspring Study.

Ultraprocessed foods provide the majority of energy content in the American diet, yet little is known regarding consumption trends over time. We determined trends in diet processing level and diet quality from 1991 to 2008 within the prospective Framingham Offspring Cohort. Dietary intakes were collected by FFQ quadrennially 1991-2008 (total of four examinations). The analytical sample included 2893 adults with valid dietary data for ≥3 examinations (baseline mean age = 54 years). Based on the NOVA framework, we classified foods as: unprocessed/minimally processed foods; processed culinary ingredients (salt/sugar/fats/oils); and processed foods and ultraprocessed foods. We evaluated diet quality using the Dietary Guidelines for Americans Adherence Index (DGAI) 2010. Trends in consumption of foods within each processing level (servings/d) and diet quality over the four examinations were evaluated using mixed effects models with subject-specific random intercepts. Analyses were stratified by sex, BMI (<25 kg/m2, 25-29·9 kg/m2, ≥30 kg/m2) and smoking status. Over 17 years of follow-up, ultraprocessed food consumption decreased from 7·5 to 6·0 servings/d and minimally processed food consumption decreased from 11·9 to 11·3 servings/d (Ptrend < 0·001). Changes in intakes of processed foods, culinary ingredients and culinary preparations were minimal. Trends were similar by sex, BMI and smoking status. DGAI-2010 score increased from 60·1 to 61·5, P < 0·001. The current study uniquely describes trends in diet processing level in an ageing US population, highlighting the longstanding presence of ultraprocessed foods in the American diet. Given the poor nutritional quality of ultraprocessed foods, public health efforts should be designed to limit their consumption.

Yogurt Consumption Is Associated with Lower Levels of Chronic Inflammation in the Framingham Offspring Study.

Some studies suggest that dairy foods may be linked with less chronic inflammation. However, few studies have investigated the separate effects of different types of dairy on inflammation. Therefore, the current study aims to examine the separate prospective impacts of milk, yogurt and cheese on biomarkers of chronic inflammation in 1753 community-dwelling participants of the Framingham Offspring Study (FOS). Mean intakes of dairy foods were derived from two sets of three-day diet records. Six inflammatory biomarkers were assessed approximately seven years later at exam 7. Results showed that those who consumed yogurt (vs. those who did not) had statistically significantly lower levels of interleukin-6 (IL-6) (mean log-transformed levels of 1.31 and 1.26 in consumers/non-consumers, respectively, p = 0.02) and fibrin (mean log-transformed levels of 5.91 and 5.89 in consumers/non-consumers, respectively, p = 0.03). The inverse association between IL-6 and yogurt consumption was similar in participants who were of normal weight and those who were overweight. For fibrin, the effects were stronger in overweight individuals. No statistically significant associations were observed between any of these inflammation biomarkers and milk or cheese intakes. Overall, our study compared the separate impacts of three types of dairy foods on chronic inflammation and found that only yogurt intake was linked with lower levels of chronic inflammation.

Total carotenoid intake is associated with reduced loss of grip strength and gait speed over time in adults: The Framingham Offspring Study

Lower antioxidant serum concentrations have been linked to declines in lean mass and physical function in older adults. Yet population data on the effect of dietary antioxidants on loss of muscle strength and physical function are lacking. We sought to determine the association of antioxidant intake [vitamin C, vitamin E, and total and individual carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein+zeaxanthin)] with annualized change in grip strength and gait speed in adults from the Framingham Offspring study. This prospective cohort study included participants with a valid FFQ at the index examination and up to 2 prior examinations and at ≥2 measures of primary outcomes: grip strength (n=2452) and/or gait speed (n=2422) measured over 3 subsequent examinations. Annualized change in grip strength (kg/y) and change in gait speed (m/s/y) over the follow-up period were used. Linear regression was used to calculate β coefficients and P values, adjusting for covariates. Mean ± SD age of participants was 61 ± 9 y (range: 33-88 y). Median intakes (IQR, mg/d) of vitamin C, vitamin E, and total carotenoid across available examinations were 209.2 (133.1-394.2), 27.1 (7.4-199.0), and 15.3 (10.4-21.3), respectively. The mean follow-up time was ∼12 ± 2 y (range: 4.5-15.4 y). In the sex-combined sample, higher intakes of total carotenoids, lycopene, and lutein+zeaxanthin were associated with increased annualized change in grip strength [β (SE) per 10-mg higher intake/d, range: 0.0316 (0.0146) to 0.1223 (0.0603) kg/y)]. All antioxidants except for vitamin C were associated with faster gait speed [β (SE) per 10-mg higher intake/d, range: 0.00008 (0.00004) to 0.0187 (0.0081) m/s/y]. Higher antioxidant intake was associated with increase in grip strength and faster gait speed in this cohort of adults. This finding highlights the need for a randomized controlled trial of dietary antioxidants and their effect on muscle strength and physical function.

Higher Intakes of Potassium and Magnesium, but Not Lower Sodium, Reduce Cardiovascular Risk in the Framingham Offspring Study.

We explored the dose-response relations of sodium, potassium, magnesium and calcium with cardiovascular disease (CVD) risk in the Framingham Offspring Study, as well as the combined effects of these minerals. Analyses included 2362 30–64 year-old men and women free of CVD at baseline. Cox proportional-hazards models were used estimate adjusted hazard ratios (HR) and 95% confidence intervals (CIs) for mineral intakes and incident CVD. Cox models with restricted cubic spline functions were used to examine dose-response relations, adjusting for confounding by age, sex, body mass index, dietary fiber intake, and time-varying occurrence of hypertension. Lower sodium intake (<2500 vs. ≥3500 mg/d) was not associated with a lower risk of CVD. In contrast, potassium intake ≥3000 (vs. <2500) mg/d was associated with a 25% lower risk (95% CI: 0.59, 0.95), while magnesium intake ≥320 (vs. <240) mg/d led to a 34% lower risk (95% CI: 0.51, 0.87) of CVD. Calcium intake ≥700 (vs. <500) mg/d was associated with a non-statistically significant 19% lower risk. Restricted cubic spline curves showed inverse dose-response relations of potassium and magnesium with CVD risk, but no such associations were observed for sodium or calcium. These results highlight the importance of potassium and magnesium to cardiovascular health.

Association Between Elevated Depressive Symptoms and Cognitive Function Moderated by APOE4 Status: Framingham Offspring Study.

Depression and Apolipoprotein E4 (APOE4) are associated with decreased cognitive function and differences in brain structure. This study investigated whether APOE4 status moderates the association between elevated depressive symptoms, cognitive function, and brain structure. Stroke- and dementia-free participants (n = 1,968) underwent neuropsychological evaluation, brain MRI, and depression screening. Linear and logistic regression was used to examine all associations. Secondary analyses were performed using interaction terms to assess effect modification by APOE4 status. Elevated depressive symptoms were associated with lower cognitive performance in several domains. In stratified analyses, elevated depressive symptoms were associated with poorer visual short- and long-term memory performance for APOE4 + participants. Elevated depressive symptoms were not associated with any brain structure in this study sample. Elevated depressive symptoms impact cognitive function in non-demented individuals. Having the APOE4 allele may exacerbate the deleterious effects of elevated depressive symptoms on visual memory performance. Screening for elevated depressive symptoms in both research studies and clinical practice may be warranted to avoid false positive identification of neurodegeneration, particularly among those who are APOE4 + .

Proteomic Signatures of Lifestyle Risk Factors for Cardiovascular Disease: A Cross-Sectional Analysis of the Plasma Proteome in the Framingham Heart Study.

BackgroundProteomic biomarkers related to cardiovascular disease risk factors may offer insights into the pathogenesis of cardiovascular disease. We investigated whether modifiable lifestyle risk factors for cardiovascular disease are associated with distinctive proteomic signatures.Methods and ResultsWe analyzed 1305 circulating plasma proteomic biomarkers (assayed using the SomaLogic platform) in 897 FHS (Framingham Heart Study) Generation 3 participants (mean age 46±8 years; 56% women; discovery sample) and 1121 FOS (Framingham Offspring Study) participants (mean age 52 years; 54% women; validation sample). Participants were free of hypertension, diabetes mellitus, and clinical cardiovascular disease. We used linear mixed effects models (adjusting for age, sex, body mass index, and family structure) to relate levels of each inverse‐log transformed protein to 3 lifestyle factors (ie, smoking, alcohol consumption, and physical activity). A Bonferroni‐adjusted P value indicated statistical significance (based on number of proteins and traits tested, P<4.2×10−6 in the discovery sample; P<6.85×10−4 in the validation sample). We observed statistically significant associations of 60 proteins with smoking (37/40 top proteins validated in FOS), 30 proteins with alcohol consumption (23/30 proteins validated), and 5 proteins with physical activity (2/3 proteins associated with the physical activity index validated). We assessed the associations of protein concentrations with previously identified genetic variants (protein quantitative trait loci) linked to lifestyle‐related disease traits in the genome‐wide‐association study catalogue. The protein quantitative trait loci were associated with coronary artery disease, inflammation, and age‐related mortality.ConclusionsOur cross‐sectional study from a community‐based sample elucidated distinctive sets of proteins associated with 3 key lifestyle factors.

The Relationship Between Asthma and Cardiovascular Disease: An Examination of the Framingham Offspring Study

Although asthma has been suggested as a risk factor for cardiovascular disease (CVD), robust longitudinal evidence of this relationship is limited. Using Framingham Offspring Cohort data, the goal of this study was to longitudinally examine the association between asthma and lifetime risk of CVD while controlling for cardiovascular risk factors included in the Framingham Risk Score. Data were analyzed from a prospective population-based cohort of 3,612 individuals, ages 17 to 77 years, who participated in Framingham Offspring Study examinations from 1979 to 2014. Asthma was defined based on physician diagnosis during study interviews. Incident CVD included myocardial infarction, angina, coronary insufficiency, stroke, transient ischemic attack, and heart failure. Time-dependent Cox regression models were used to evaluate the relationship between asthma and CVD incidence. Overall, 533 (15%) participants had a diagnosis of asthma and 897 (25%) developed CVD during the course of the study. Unadjusted analyses revealed that asthma was associated with increased CVD incidence (hazard ratio, 1.40; 95%CI, 1.17-1.68). Cox regression also showed an adjusted association between asthma and CVD incidence (hazard ratio, 1.28; 95%CI, 1.07-1.54) after controlling for established cardiovascular risk factors. This prospective analysis with > 35 years of follow-up shows that asthma is a risk factor for CVD after adjusting for potential confounders. When assessing risk of cardiovascular disease, asthma should be evaluated and managed as a risk factor contributing to morbidity and mortality.

Atherogenic lipoproteins and atherosclerotic cardiovascular disease in the Framingham offspring study

Background and Aims: Elevated low-density lipoprotein cholesterol (LDL-C), small-dense LDL-C (sdLDL-C), LDL-triglyceride (LDL-TG), triglycerides, remnant-lipoprotein cholesterol (RLP-C), triglyceride-rich lipoprotein-C (TRL-C), very low-density lipoprotein cholesterol (VLDL-C), and lipoprotein(a) [Lp(a)] levels have been associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. We assessed the hypothesis that these atherogenic lipoprotein parameters add significant information for ASCVD risk prediction in the Framingham Offspring Study.

Metabolomics Insights into Osteoporosis Through Association With Bone Mineral Density.

Osteoporosis, a disease characterized by low bone mineral density (BMD), increases the risk for fractures. Conventional risk factors alone do not completely explain measured BMD or osteoporotic fracture risk. Metabolomics may provide additional information. We aim to identify BMD-associated metabolomic markers that are predictive of fracture risk. We assessed 209 plasma metabolites by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in 1552 Framingham Offspring Study participants, and measured femoral neck (FN) and lumbar spine (LS) BMD 2 to 10 years later using dual-energy X-ray absorptiometry. We assessed osteoporotic fractures up to 27-year follow-up after metabolomic profiling. We identified 27 metabolites associated with FN-BMD or LS-BMD by LASSO regression with internal validation. Incorporating selected metabolites significantly improved the prediction and the classification of osteoporotic fracture risk beyond conventional risk factors (area under the curve [AUC] = 0.74 for the model with identified metabolites and risk factors versus AUC = 0.70 with risk factors alone, p = .001; net reclassification index = 0.07, p = .03). We replicated significant improvement in fracture prediction by incorporating selected metabolites in 634 participants from the Hong Kong Osteoporosis Study (HKOS). The glycine, serine, and threonine metabolism pathway (including four identified metabolites: creatine, dimethylglycine, glycine, and serine) was significantly enriched (false discovery rate [FDR] p value = .028). Furthermore, three causally related metabolites (glycine, phosphatidylcholine [PC], and triacylglycerol [TAG]) were negatively associated with FN-BMD, whereas PC and TAG were negatively associated with LS-BMD through Mendelian randomization analysis. In summary, metabolites associated with BMD are helpful in osteoporotic fracture risk prediction. Potential causal mechanisms explaining the three metabolites on BMD are worthy of further experimental validation. Our findings may provide novel insights into the pathogenesis of osteoporosis. © 2021 American Society for Bone and Mineral Research (ASBMR).