Cardiovascular disease protein biomarkers are associated with kidney function: the Framingham Heart Study

Background. Biomarkers common to chronic kidney disease (CKD) and cardiovascular disease (CVD) may reflect early impairments underlying both diseases. Methods. We evaluated associations of 71 CVD-related plasma proteins measured in 2,873 Framingham Heart Study (FHS) Offspring cohort participants with cross-sectional continuous eGFR and with longitudinal change in eGFR from baseline to follow-up (ΔeGFR). We also evaluated the associations of the 71 CVD proteins with the following dichotomous secondary outcomes: prevalent CKD stage ≥3(cross-sectional), new-onset CKD stage ≥3 (longitudinal), and rapid decline in eGFR (longitudinal). Proteins significantly associated with eGFR and ΔeGFR were subsequently validated in 3,951 FHS Third Generation cohort participants and were tested using Mendelian randomization (MR) analysis to infer putatively causal relations between plasma protein biomarkers and kidney function. Results. In cross-sectional analysis, 37 protein biomarkers were significantly associated with eGFR at FDR<0.05 in the FHS Offspring cohort and 20 of these validated in the FHS Third Generation cohort at p<0.05/37. In longitudinal analysis, 27 protein biomarkers were significantly associated with ΔeGFR at FDR<0.05 and 12 of these were validated in the FHS Third Generation cohort at p<0.05/27. Additionally, 35 protein biomarkers were significantly associated with prevalent CKD, five were significantly associated with new-onset CKD, and 17 were significantly associated with rapid decline in eGFR. MR suggested putatively causal relations of melanoma cell adhesion molecule (MCAM; -0.011±0.003 mL/min/1.73m2, p=5.11E-5) and epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1; -0.006±0.002 mL/min/1.73m2, p=0.0001) concentration with eGFR. Discussion/Conclusions: Eight protein biomarkers were consistently associated with eGFR in cross-sectional and longitudinal analysis in both cohorts and may capture early kidney impairment; others were implicated in association and causal inference analyses. A subset of CVD protein biomarkers may contribute causally to the pathogenesis of kidney impairment and should be studied as targets for CKD treatment and early prevention.

Intake of Flavonoids and Odds of Frailty Onset in Adults in the Framingham Offspring Cohort

Polyphenols (antioxidants derived from plant-foods) could play a role in inhibition of oxidative stress and frailty reduction, yet data on the polyphenol subclass of dietary flavonoids is limited. This study sought to determine the association between dietary flavonoids and frailty onset in middle-aged and older adults. This prospective cohort study included non-frail individuals from the Framingham Offspring Cohort (FOC) with total flavonoid intake (mg/day; defined as sum flavonols, flavan-3-ols, flavonones, flavones, and anthocyanins via Harvard Food Frequency Questionnaire), frailty (via Fried phenotype), and covariate information measured at baseline (1998-2001). Follow-up frailty was evaluated in 2011-2014. Logistic regression estimated odds ratio (OR) and 95% confidence intervals (95% CI) adjusting for relevant confounders. Participants (n=1,701; 55.5% female) had a mean age of 58.4 years (SD ± 8.3). Mean flavonoid intake was 309 mg/d (SD ± 266). After 12.4 years (SD ± 0.8), 224 (13.2%) individuals exhibited frailty. In age and sex adjusted models, every 50 mg/day of higher total flavonoid intake was associated with 3% reduced odds of frailty [OR (95%CI): 0.97 (0.94-1.00), p-value: 0.05). Further adjustment for smoking, energy and protein intake, and disease indicators did not appreciably change the association, and associations became non-significant (p-value=0.12). Thus, there was no association between flavonoid intake and odds of frailty onset in adults in the FOC. This could be due to participants' higher intake of flavonoids compared to average intake of ~200 mg/d in Americans.

Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study

Background Nausea and vomiting of pregnancy (NVP) is common and underlying mechanisms are poorly understood. Longer-term offspring outcomes are also not well documented. This study aimed to determine if NVP, even in milder forms, is associated with adverse pregnancy and childhood growth outcomes. Methods In the GUSTO prospective mother-offspring cohort, women with singleton pregnancies (n = 1172) recruited in first trimester responded to interviewer-administered questions at 26–28 weeks’ gestation about earlier episodes of NVP since becoming pregnant. Pregnancy outcomes were obtained from medical records. Offspring height and weight measured at 15 time-points between birth to 72 months (m) were standardised for age and sex. Results 58.5% (n = 686) reported mild-moderate vomiting (mNVP), 10.5% (n = 123) severe vomiting (sNVP) and 5.7% (n = 67) severe vomiting with hospitalisation (shNVP). There was no difference in odds of gestational diabetes, hypertensive disorders of pregnancy, labour induction or caesarean section after adjustment for covariates. sNVP was associated with late preterm delivery [34+ 0–36+ 6 weeks’, adjusted OR = 3.04 (95% CI 1.39,6.68)], without increased odds of neonatal unit admission. Compared with no NVP, boys born to mothers with sNVP were longer at birth [adjusted β = 0.38 standard deviations (SDs) (95% CI 0.02,0.73)], remained taller [0.64 SDs (0.23,1.04) at 72 m] and heavier [0.57 SDs (0.05,1.08) at 60 m] without differences in BMI. Conversely, girls born to mothers with shNVP were lighter from 48 m [− 0.52 SDs (− 1.00, − 0.03)] onwards with lower BMI [− 0.61 SDs (− 1.12,-0.09)]. Conditional growth modelling revealed significant sex-divergence in weight-gain at birth-3 m, 6-9 m and 4–5 years. Conclusions Severe NVP was associated with late preterm delivery, and both mild-moderate and severe NVP associated with sex-dependent differences in early childhood growth. Boys whose mothers had NVP were taller and heavier from birth with faster growth in the first year, whereas, girls had poorer weight gain and were lighter by 48 m. As even milder severities of NVP could have long-term impact on offspring growth, further research is needed to determine mechanisms involved and implications on future health. Trial registration Clinicaltrials.gov identifier NCT01174875.

Cumulative Consumption of Sulfur Amino Acids Intake and Incidence of Diabetes

Objectives Increasing evidence in animal models and humans suggests that diets high in sulfur-containing amino acids (SAA) could be associated a greater risk for type 2 diabetes (T2D). However, data from longitudinal human studies linking dietary SAA intake with T2D is lacking. The present study aimed to examine the association between long-term dietary intake of SAA including total SAAs, methionine, and cysteine and incident T2D in participants of the Framingham Heart Study (FHS). Methods Adult participants were selected from two prospective FHS cohorts: The Offspring Cohort (followed from 1991 to 2015, n = 3799) and the Third Generation Cohort (followed from 2002 to 2011, n = 4096). Individuals identified as diabetes patients before baseline, having missing diet or covariates data, or reported extreme daily energy intake were excluded. Energy-adjusted intake of dietary SAAs was calculated from responses to a 131-item food frequency questionnaire. Cox proportional hazards models were used to evaluate associations between intakes of SAAs (in quintiles) and risk of T2D in each cohort. A combined analysis was also performed pooling subjects from both cohorts. Results Overall, we documented 471 T2D events during 9–23 years of follow-up. In both cohorts, higher SAA intake was associated with a higher risk of T2D after adjustment for demographics, traditional risk factors and related nutrients. Comparing participants in the highest quintile with those in the lowest quintile of intake, adjusted hazard ratios (95% CI) were 1.98 (1.15–3.41) for total intake (P for trend = 0.04) in the Offspring cohort, and 4.37 (1.40–13.67) (P for trend = 0.01) in the Third Generation cohort. In the combination analysis of two cohorts, adjusted hazard ratios (95% CI) were 1.98 (1.23–3.21) for total intake, 2.21 (1.38–3.53) for methionine, and 1.79 (1.12–2.87) for cysteine (P for trends &lt; 0.03). Conclusions Higher long-term SAA intake was associated with higher risk for T2D in humans, suggesting that dietary patterns emphasizing low SAA intake are protective against development of T2D. Funding Sources No funding.

Higher Dietary Inflammatory Index Scores Are Associated With Higher Concentrations of Inflammatory Markers in the Framingham Heart Study

Objectives We evaluated whether higher (i.e., pro-inflammatory) Dietary Inflammatory Index (DII) scores were associated with increased concentrations of inflammatory markers in the community-based Framingham Heart Study (FHS) Offspring Cohort. Methods We studied 1978 participants (age 61 [SD, 9] years, 53.9% women) from the Offspring cohort who completed a validated 126-item Food Frequency Questionnaire (FFQ) at exam 7 (1998–2001) and at least one of exams 5 (1991–1995) or exam 6 (1995–1998), and on whom inflammatory markers were measured at exam 7. We created a DII score based on the published scoring algorithm by Shivappa et al. 2014, (developed from previous studies linking individual dietary factors to six inflammatory markers); a cumulative DII score was calculated by averaging across a maximum of three FFQs. We used linear regression models to test associations between the cumulative DII score and natural log-transformed concentrations of adiponectin, cluster of differentiation 40 (CD40), C-reactive protein (CRP), fibrinogen, intracellular adhesion molecule (ICAM), interleukin (IL)-6, IL-18, resistin, and TNF-α. Results Higher DII scores were independently associated with higher mean concentrations of four inflammatory markers after adjustment for demographic, clinical, and lifestyle covariates (β± SE, CRP 0.14 mg/L ± 0.04; P &lt; 0.0001, IL-6 0.07 pg/mL ± 0.02; P &lt; 0.003, resistin 0.04 ng/mL ± 0.02 ng/mL; P = 0.01). Exclusion of individuals who smoke currently did not change the results. Additionally, we observed that body mass index had a partially mediating effect on all relationships except the relationships with TNF-α. Further, we observed no significant interactions between higher DII scores and sex in their associations with each inflammatory marker. Conclusions Higher DII scores were associated with higher concentrations of four out of nine inflammatory markers. Our results suggest that anti-inflammatory diets, which correlate with low DII scores may lower systemic chronic inflammation, a process that plays an important role in the development and progression of chronic disease. Funding Sources ASPEN Rhoads Research Foundation and NIH.

Association of dietary fiber and risk of hip fracture in men from the Framingham Osteoporosis Study and the Concord Health and Ageing in Men Project

Background: Data in the Offspring Framingham Osteoporosis Study (FOS) suggested that higher intake of dietary fiber was modestly protective against loss of bone mineral density at the femoral neck in men but not in women. Aim: To examine the relationship of fiber intake with risk of hip fractures in men. Methods: We included 367 men from the FOS Original cohort, 1730 men from the FOS Offspring cohort, and 782 men from the Concord Health and Ageing in Men Project (CHAMP) in the analysis. Incident fractures were defined as medically confirmed first occurrence of osteoporotic fractures at the proximal femur. Fiber intake was estimated via a validated food frequency questionnaire (FFQ) or diet history. Cox proportional hazards models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). A random-effects model was used to estimate the pooled relative risk in meta-analysis. Results: Seventy-two incident hip fractures were identified, of which 24 occurred in the FOS Original cohort [mean (SD): age 75.3 (5.1) years; follow-up time: 8.5 (6.2) years; dietary fiber: 19 (8) (g/d)], 19 in the FOS Offspring cohort [58.8 (9.8) years; 11.0 (5.9) years; 19 (8) (g/d)], and 29 in CHAMP [81.4 (4.5) years; 5.2 (1.5) years; 28 (10) (g/d)]. We did not find significant associations within each cohort between fiber intake and risk of hip fractures. The pooled HR (95% CI) was 0.80 (0.39, 1.66) comparing energy-adjusted dietary fiber at tertile 3 vs. tertile 1 (I2 = 0, p = 0.56). Conclusion: These data suggested that dietary fiber was not associated with risk of incident hip fractures in men.

Comparison of Indices of Carbohydrate Quality and Food Sources of Dietary Fiber on Longitudinal Changes in Waist Circumference in the Framingham Offspring Cohort

The long-term impact of carbohydrate quality on abdominal weight gain is not fully understood. We aimed to examine the prospective relation of a carbohydrate quality index (CQI; defined by four criteria: dietary fiber, glycemic index, whole grain-to-total grain ratio, and solid-to-total carbohydrate ratio), total, cereal grain, vegetable, and fruit fiber, carbohydrate-to-total fiber ratio, and carbohydrate-to-cereal fiber ratio with changes in waist circumference (WC). Subjects were middle-aged to older, mostly white, participants in the Framingham Offspring cohort (n = 3101 subjects), with mean baseline age 54.9 ± 0.2 years (mean ± SE) and body mass index (BMI) 27.2 ± 0.1 kg/m2. Food frequency questionnaire (FFQ), health, and lifestyle data were collected approximately every four years over a median total follow-up of 18 years. Repeated measure mixed models were used to estimate adjusted mean change in WC per four-year interval across quartiles of carbohydrate variables. In the most adjusted model, a higher CQI was marginally associated with a smaller increase in WC (2.0 ± 0.1 vs. 2.4 ± 0.1 cm in highest vs. lowest quartile, p-trend = 0.04). Higher ratios of carbohydrate-to-fiber and carbohydrate-to-cereal fiber were associated with greater increases in WC per four-year interval (2.6 ± 0.1 vs. 2.0 ± 0.1 cm, p-trend < 0.001, and 2.5 ± 0.1 vs. 2.1 ± 0.1 cm in highest versus lowest categories, p-trend = 0.007, respectively); whereas higher intake of total fiber (1.8 ± 0.1 vs. 2.7 ± 0.1 cm, p-trend < 0.001), cereal fiber (2.0 ± 0.1 vs. 2.5 ± 0.1 cm, p-trend = 0.001), and fruit fiber (2.0 ± 0.1 vs. 2.7 ± 0.1 cm, p-trend < 0.001) were associated with smaller increases in WC compared to lower intakes. There was a significant interaction between total fiber and total carbohydrate (as % of total energy intake). After stratification, the association between fiber intake and change in WC was not maintained in the context of a high carbohydrate diet. Better carbohydrate quality, primarily higher fiber intake and lower carbohydrate-to-fiber ratios, may help attenuate increases in abdominal adiposity over time.

Self-Reported DHA Supplementation during Pregnancy and Its Association with Obesity or Gestational Diabetes in Relation to DHA Concentration in Cord and Maternal Plasma: Results from NELA, a Prospective Mother-Offspring Cohort

Maternal supplementation of docosahexaenoic acid (DHA) during pregnancy has been recommended due to its role in infant development, but its effect on materno-fetal DHA status is not well established. We evaluated the associations between DHA supplementation in pregnant women with obesity or gestational diabetes mellitus (GDM) and maternal and neonatal DHA status. Serum fatty acids (FA) were analyzed in 641 pregnant women (24 weeks of gestation) and in 345 venous and 166 arterial cord blood samples of participants of the NELA cohort. Obese women (n = 47) presented lower DHA in serum than those lean (n = 397) or overweight (n = 116) before pregnancy. Linoleic acid in arterial cord was elevated in obese women, which indicates lower fetal retention. Maternal DHA supplementation (200 mg/d) during pregnancy was associated with enhanced maternal and fetal DHA levels regardless of pre-pregnancy body mass index (BMI), although higher arterial DHA in overweight women indicated an attenuated response. Maternal DHA supplementation was not associated with cord venous DHA in neonates of mothers with GDM. The cord arteriovenous difference was similar for DHA between GDM and controls. In conclusion, maternal DHA supplementation during pregnancy enhanced fetal DHA status regardless of the pre-pregnancy BMI while GDM may reduce the effect of DHA supplementation in newborns.

Association Between Frailty and Atrial Fibrillation in Older Adults: The Framingham Heart Study Offspring Cohort

Background Frailty is associated bidirectionally with cardiovascular disease. However, the relations between frailty and atrial fibrillation (AF) have not been fully elucidated. Methods and Results Using the FHS (Framingham Heart Study) Offspring cohort, we sought to examine both the association between frailty (2005–2008) and incident AF through 2016 and the association between prevalent AF and frailty status (2011–2014). Frailty was defined using the Fried phenotype. Models adjusted for age, sex, and smoking. Cox proportional hazards models, adjusted for competing risk of death, assessed the association between prevalent frailty and incident AF. Logistic regression models assessed the association between prevalent AF and new‐onset frailty. For the incident AF analysis, we included 2053 participants (56% women; mean age, 69.7±6.9 years). By Fried criteria, 1018 (50%) were robust, 903 (44%) were prefrail, and 132 (6%) were frail. In total, 306 incident cases of AF occurred during an average 9.2 (SD, 3.1) follow‐up years. After adjustment, there was no statistically significant association between prevalent frailty status and incident AF (prefrail versus robust: hazard ratio [HR], 1.22 [95% CI, 0.95–1.55]; frail versus robust: HR, 0.92 [95% CI, 0.57–1.47]). At follow‐up, there were 111 new cases of frailty. After adjustment, there was no statistically significant association between prevalent AF and new‐onset frailty (odds ratio, 0.48 [95% CI, 0.17–1.36]). Conclusions Although a bidirectional association between frailty and cardiovascular disease has been suggested, we did not find evidence of an association between frailty and AF. Our findings may be limited by sample size and should be further explored in other populations.