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Apolipoprotein E and Its Association With Cognitive Change and Modification of Treatment Effects of Vitamin D3 and Omega-3s on Cognitive Change: Results From the In-Clinic Subset of a Randomized Clinical Trial.
Vyas, CM, Kang, JH, Mischoulon, D, Cook, NR, Reynolds Iii, CF, Chang, G, Mora, S, De Vivo, I, Manson, JE, Okereke, OI
The journals of gerontology. Series A, Biological sciences and medical sciences. 2024;(3)
Abstract
BACKGROUND Apolipoprotein E (APOE)-ε4 allele is associated with cognitive decline; however, its potential to modify effects of vitamin D3 and omega-3s supplementation on later-life cognition is unclear. Our objectives were to estimate among the in-clinic subset of a randomized trial: (1) associations between APOE-ε4 and global and domain-specific cognitive change, with exploration of potential sex and race differences; and (2) modification by APOE-ε4 of effects of vitamin D3 and omega-3s supplementation on cognitive change. METHODS From an ancillary study of depression prevention within a completed 2 × 2 factorial trial testing vitamin D3 (2 000 IU per day), omega-3s (1 g per day), and/or placebos, we included 743 older adults with baseline in-person neuropsychiatric assessments and APOE genotyping data. The primary outcome was change in global cognition (averaging z-scores of 9 tests) over 2 years. Secondarily, episodic memory and executive function/attention z-scores were examined. General linear models of response profiles with multiplicative interaction terms were constructed; stratified results were reported. RESULTS Mean age (standard deviation) was 67.1 (5.3) years; 50.6% were females; 24.9% were APOE-ε4 carriers. Compared to noncarriers, APOE-ε4 carriers had worse 2-year change in global cognition and episodic memory; differences were more apparent among females than males. There was no variation by race in APOE-ε4 associations with cognition. APOE-ε4 did not significantly modify effects of vitamin D3 or omega-3s, compared to placebo, on change in global cognition, episodic memory, or executive function/attention. CONCLUSIONS APOE-ε4 was associated with worse cognition but did not modify overall effects of vitamin D3 or omega-3 supplementation on cognition over 2 years.
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The Inflammation Biomarker GlycA Reflects Plasma N-Glycan Branching.
Noel, M, Chasman, DI, Mora, S, Otvos, JD, Palmer, CD, Parsons, PJ, Smoller, JW, Cummings, RD, Mealer, RG
Clinical chemistry. 2023;(1):80-87
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BACKGROUND GlycA is a nuclear magnetic resonance (NMR) signal in plasma that correlates with inflammation and cardiovascular outcomes in large data sets. The signal is thought to originate from N-acetylglucosamine (GlcNAc) residues of branched plasma N-glycans, though direct experimental evidence is limited. Trace element concentrations affect plasma glycosylation patterns and may thereby also influence GlycA. METHODS NMR GlycA signal was measured in plasma samples from 87 individuals and correlated with MALDI-MS N-glycomics and trace element analysis. We further evaluated the genetic association with GlycA at rs13107325, a single nucleotide polymorphism resulting in a missense variant within SLC39A8, a manganese transporter that influences N-glycan branching, both in our samples and existing genome-wide association studies data from 22 835 participants in the Women's Health Study (WHS). RESULTS GlycA signal was correlated with both N-glycan branching (r2 ranging from 0.125-0.265; all P < 0.001) and copper concentration (r2 = 0.348, P < 0.0001). In addition, GlycA levels were associated with rs13107325 genotype in the WHS (β [standard error of the mean] = -4.66 [1.2674], P = 0.0002). CONCLUSIONS These results provide the first direct experimental evidence linking the GlycA NMR signal to N-glycan branching commonly associated with acute phase reactive proteins involved in inflammation.
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Statin-Associated Muscle Symptoms Among New Statin Users Randomly Assigned to Vitamin D or Placebo.
Hlatky, MA, Gonzalez, PE, Manson, JE, Buring, JE, Lee, IM, Cook, NR, Mora, S, Bubes, V, Stone, NJ
JAMA cardiology. 2023;(1):74-80
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IMPORTANCE Statin-associated muscle symptoms (SAMS) are common and may lead to discontinuation of indicated statin therapy. Observational studies suggest that vitamin D therapy is associated with reduced statin intolerance, but no randomized studies have been reported. OBJECTIVE To test whether vitamin D supplementation was associated with prevention of SAMS and a reduction of statin discontinuation. DESIGN, SETTING, AND PARTICIPANTS Men 50 years or older and women 55 years or older, free of cancer and cardiovascular disease, were enrolled in a randomized, placebo-controlled, double-blind clinical trial of vitamin D supplementation. Participants who initiated statin therapy after randomization were surveyed in early 2016. The data were analyzed in early 2022. INTERVENTIONS Daily cholecalciferol (2000 international units) or placebo with assessment of statin prescriptions during follow-up. MAIN OUTCOMES AND MEASURES Muscle pain or discomfort lasting several days (primary outcome) and discontinuation of a statin due to SAMS (secondary outcome). RESULTS Statins were initiated by 1033 vitamin D-assigned participants and 1050 placebo-assigned participants; mean (SD) age was 66.8 (6.2) years and 49% were women. Over 4.8 years of follow-up, SAMS were reported by 317 participants (31%) assigned vitamin D and 325 assigned placebo (31%). The adjusted odds ratio (OR) was 0.97 (95% CI, 0.80-1.18; P = .78). Statins were discontinued by 137 participants (13%) assigned to vitamin D and 133 assigned to placebo (13%) with an adjusted OR of 1.04 (95% CI, 0.80-1.35; P = .78). These results were consistent across pretreatment 25-hydroxy vitamin D levels (interaction P value = .83). Among participants with levels less than 20 ng/mL, SAMS were reported by 28 of 85 vitamin D-assigned participants (33%) and 33 of 95 placebo-assigned participants (35%). For those with levels less than 30 ng/ml, SAMS were reported by 88 of 330 vitamin-D assigned participants (27%) and 96 of 323 of placebo-assigned participants (30%). CONCLUSIONS AND RELEVANCE Vitamin D supplementation did not prevent SAMS or reduce statin discontinuation. These results were consistent across pretreatment 25-hydroxy vitamin D levels. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01169259.
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Association of Body Weight With Response to Vitamin D Supplementation and Metabolism.
Tobias, DK, Luttmann-Gibson, H, Mora, S, Danik, J, Bubes, V, Copeland, T, LeBoff, MS, Cook, NR, Lee, IM, Buring, JE, et al
JAMA network open. 2023;(1):e2250681
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IMPORTANCE In the Vitamin D and Omega-3 Trial (VITAL), the effects of randomized vitamin D supplementation (cholecalciferol), 2000 IU/d, reduced the risk of several health outcomes among participants with normal, but not elevated, body weights. It was unclear whether weight had any association with the outcomes of the supplementation. OBJECTIVE To investigate whether baseline body mass index (BMI) modifies vitamin D metabolism and response to supplementation. DESIGN, SETTING, AND PARTICIPANTS VITAL is a completed randomized, double-blind, placebo-controlled trial for the primary prevention of cancer and cardiovascular disease. In the present cohort study, an analysis was conducted in a subset of VITAL participants who provided a blood sample at baseline and a subset with a repeated sample at 2 years' follow-up. VITAL was conducted from July 1, 2010, to November 10, 2018; data analysis for the present study was conducted from August 1, 2021, to November 9, 2021. INTERVENTIONS Treatment outcomes of vitamin D, 2000 IU/d, supplementation vs placebo associated with clinical and novel vitamin D-related biomarkers by BMI category adjusted for other factors associated with vitamin D status. MAIN OUTCOMES AND MEASURES Multivariable-adjusted means (SE) or 95% CIs of vitamin D-related serum biomarkers at baseline and follow-up: total 25-hydroxyvitamin D (25-OHD), 25-OHD3, free vitamin D (FVD), bioavailable vitamin D (BioD), vitamin D-binding protein (VDBP), albumin, parathyroid hormone (PTH), and calcium, and log-transformed as needed. RESULTS A total of 16 515 participants (mean [SD] age, 67.7 [7.0] years; 8371 women [50.7%]; 12420 non-Hispanic White [76.9%]) were analyzed at baseline, including 2742 with a follow-up blood sample. Before randomization, serum total 25-OHD levels were incrementally lower at higher BMI categories (adjusted mean [SE]: underweight, 32.3 [0.7] ng/mL; normal weight, 32.3 [0.1] ng/mL; overweight, 30.5 [0.1] ng/mL; obesity class I, 29.0 [0.2] ng/mL; and obesity class II, 28.0 [0.2] ng/mL; P < .001 for linear trend). Similarly, baseline 25-OHD3, FVD, BioD, VDBP, albumin, and calcium levels were lower with higher BMI, while PTH level was higher (all P < .001 for linear trend). Compared with placebo, randomization to vitamin D supplementation was associated with an increase in total 25-OHD, 25-OHD3, FVD, and BioD levels compared with placebo at 2 years' follow-up, but increases were significantly lower at higher BMI categories (all treatment effect interactions P < .001). Supplementation did not substantially change VDBP, albumin, PTH, or calcium levels. CONCLUSIONS AND RELEVANCE In this randomized cohort study, vitamin D supplementation increased serum vitamin D-related biomarkers, with a blunted response observed for participants with overweight or obesity at baseline. These longitudinal findings suggest that BMI may be associated with modified response to vitamin D supplementation and may in part explain the observed diminished outcomes of supplementation for various health outcomes among individuals with higher BMI.
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Serum Vitamin D: Correlates of Baseline Concentration and Response to Supplementation in VITAL-DKD.
Best, CM, Zelnick, LR, Thummel, KE, Hsu, S, Limonte, C, Thadhani, R, Sesso, HD, Manson, JE, Buring, JE, Mora, S, et al
The Journal of clinical endocrinology and metabolism. 2022;(2):525-537
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CONTEXT The effect of daily vitamin D supplementation on the serum concentration of vitamin D (the parent compound) may offer insight into vitamin D disposition. OBJECTIVE To assess the total serum vitamin D response to vitamin D3 supplementation and whether it varies according to participant characteristics. To compare results with corresponding results for total serum 25-hydroxyvitamin D [25(OH)D], which is used clinically and measured in supplementation trials. DESIGN Exploratory study within a randomized trial. INTERVENTION 2000 International Units of vitamin D3 per day (or matching placebo). SETTING Community-based. PARTICIPANTS 161 adults (mean ± SD age 70 ± 6 years; 66% males) with type 2 diabetes. MAIN OUTCOME MEASURES Changes in total serum vitamin D and total serum 25(OH)D concentrations from baseline to year 2. RESULTS At baseline, there was a positive, nonlinear relation between total serum vitamin D and total serum 25(OH)D concentrations. Adjusted effects of supplementation were a 29.2 (95% CI: 24.3, 34.1) nmol/L increase in serum vitamin D and a 33.4 (95% CI: 27.7, 39.2) nmol/L increase in serum 25(OH)D. Among those with baseline 25(OH)D < 50 compared with ≥ 50 nmol/L, the serum vitamin D response to supplementation was attenuated (15.7 vs 31.2 nmol/L; interaction P-value = 0.02), whereas the serum 25(OH)D response was augmented (47.9 vs 30.7 nmol/L; interaction P-value = 0.05). CONCLUSIONS Vitamin D3 supplementation increases total serum vitamin D and 25(OH)D concentrations with variation according to baseline 25(OH)D, which suggests that 25-hydroxylation of vitamin D3 is more efficient when serum 25(OH)D concentration is low.
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Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia-a randomized controlled feeding trial.
Ebbeling, CB, Knapp, A, Johnson, A, Wong, JMW, Greco, KF, Ma, C, Mora, S, Ludwig, DS
The American journal of clinical nutrition. 2022;115(1):154-162
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Diets high in carbohydrates and particularly processed carbohydrates can increase the risk for developing a dysfunction in the body’s ability to take up sugar from the blood, known as insulin resistance. However how this relates to insulin resistance can contribute to the development of many diseases such as type 2 diabetes, heart disease and stroke, which highlights the importance in preventing this dysfunction. This randomised control trial of 148 individuals aimed to determine the role of low, medium, and high carbohydrate diets with varying saturated fat content on measures for insulin resistance. The results showed that regardless of the fat content, it was the level of carbohydrate that determined the effect on measures of insulin resistance. High saturated fat and low-carbohydrate diets improved insulin resistance and low saturated fat high carbohydrate diets worsened insulin resistance. Improvements were also observed in blood lipids with a high fat low carbohydrate diet. It was concluded that a diet low in carbohydrates, but high in saturated fat improved insulin resistance and blood lipid levels. This study could be used by healthcare professionals to understand that a diet, which replaces fat with carbohydrates may be worsening insulin resistance and that low carbohydrate diets may be of benefit.
Abstract
BACKGROUND Carbohydrate restriction shows promise for diabetes, but concerns regarding high saturated fat content of low-carbohydrate diets limit widespread adoption. OBJECTIVES This preplanned ancillary study aimed to determine how diets varying widely in carbohydrate and saturated fat affect cardiovascular disease (CVD) risk factors during weight-loss maintenance. METHODS After 10-14% weight loss on a run-in diet, 164 participants (70% female; BMI = 32.4 ± 4.8 kg/m2) were randomly assigned to 3 weight-loss maintenance diets for 20 wk. The prepared diets contained 20% protein and differed 3-fold in carbohydrate (Carb) and saturated fat as a proportion of energy (Low-Carb: 20% carbohydrate, 21% saturated fat; Moderate-Carb: 40%, 14%; High-Carb: 60%, 7%). Fasting plasma samples were collected prerandomization and at 20 wk. Lipoprotein insulin resistance (LPIR) score was calculated from triglyceride-rich, high-density, and low-density lipoprotein particle (TRL-P, HDL-P, LDL-P) sizes and subfraction concentrations (large/very large TRL-P, large HDL-P, small LDL-P). Other outcomes included lipoprotein(a), triglycerides, HDL cholesterol, LDL cholesterol, adiponectin, and inflammatory markers. Repeated measures ANOVA was used for intention-to-treat analysis. RESULTS Retention was 90%. Mean change in LPIR (scale 0-100) differed by diet in a dose-dependent fashion: Low-Carb (-5.3; 95% CI: -9.2, -1.5), Moderate-Carb (-0.02; 95% CI: -4.1, 4.1), High-Carb (3.6; 95% CI: -0.6, 7.7), P = 0.009. Low-Carb also favorably affected lipoprotein(a) [-14.7% (95% CI: -19.5, -9.5), -2.1 (95% CI: -8.2, 4.3), and 0.2 (95% CI: -6.0, 6.8), respectively; P = 0.0005], triglycerides, HDL cholesterol, large/very large TRL-P, large HDL-P, and adiponectin. LDL cholesterol, LDL-P, and inflammatory markers did not differ by diet. CONCLUSIONS A low-carbohydrate diet, high in saturated fat, improved insulin-resistant dyslipoproteinemia and lipoprotein(a), without adverse effect on LDL cholesterol. Carbohydrate restriction might lower CVD risk independently of body weight, a possibility that warrants study in major multicentered trials powered on hard outcomes. The registry is available through ClinicialTrials.gov: https://clinicaltrials.gov/ct2/show/NCT02068885.
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Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial.
Sesso, HD, Manson, JE, Aragaki, AK, Rist, PM, Johnson, LG, Friedenberg, G, Copeland, T, Clar, A, Mora, S, Moorthy, MV, et al
The American journal of clinical nutrition. 2022;115(6):1490-1500
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Cocoa is made from the bean of the cacao tree and has a long history of potential health benefits based upon its flavanol and procyanidin content. Cocoa extract also contains methylxanthines [alkaloids] such as theobromine and caffeine, which may enhance the vascular and central nervous system effects of cocoa flavanols. The aim of this study was to evaluate the flavanol-rich cocoa extract containing all potential bioactive components of the cocoa bean on clinical cardiovascular outcomes. This study is a randomised, double-blind, placebo-controlled, 2 × 2 factorial trial testing a cocoa extract supplement and a multivitamin supplement (COSMOS). This study focuses on the cocoa extract component of the trial. A total of 21,442 participants underwent randomisation to one of the four groups. Results show that after a median of 3.6 years of treatment there was no statistically significant effect on the primary outcome of total cardiovascular events. However, cocoa flavanol supplementation significantly reduced cardiovascular disease death by 27%, whereas other individual cardiovascular outcomes had no significant reductions in risk. Authors conclude that longer-term follow-up of the trial cohort and ongoing ancillary mechanistic studies in COSMOS may further elucidate the relation between cocoa extract supplementation and clinical cardiovascular events.
Abstract
BACKGROUND Cocoa extract is a source of flavanols that favorably influence vascular risk factors in small and short-term trials, yet effects on clinical cardiovascular events are untested. OBJECTIVES We examined whether cocoa extract supplementation decreases total cardiovascular disease (CVD) among older adults. METHODS We conducted a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of cocoa extract supplementation and multivitamins for prevention of CVD and cancer among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y), free of major CVD and recently diagnosed cancer. The intervention phase was June 2015 through December 2020. This article reports on the cocoa extract intervention. Participants were randomly assigned to a cocoa extract supplement [500 mg flavanols/d, including 80 mg (-)-epicatechin] or placebo. The primary outcome was a composite of confirmed incident total cardiovascular events, including myocardial infarction (MI), stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina. RESULTS During a median follow-up of 3.6 y, 410 participants taking cocoa extract and 456 taking placebo had confirmed total cardiovascular events (HR: 0.90; 95% CI: 0.78, 1.02; P = 0.11). For secondary endpoints, HRs were 0.73 (95% CI: 0.54, 0.98) for CVD death, 0.87 (95% CI: 0.66, 1.16) for MI, 0.91 (95% CI: 0.70, 1.17) for stroke, 0.95 (95% CI: 0.77, 1.17) for coronary revascularization, neutral for other individual cardiovascular endpoints, and 0.89 (95% CI: 0.77, 1.03) for all-cause mortality. Per-protocol analyses censoring follow-up at nonadherence supported a lower risk of total cardiovascular events (HR: 0.85; 95% CI: 0.72, 0.99). There were no safety concerns. CONCLUSIONS Cocoa extract supplementation did not significantly reduce total cardiovascular events among older adults but reduced CVD death by 27%. Potential reductions in total cardiovascular events were supported in per-protocol analyses. Additional research is warranted to clarify whether cocoa extract may reduce clinical cardiovascular events. This trial is registered at www.clinicaltrials.gov as NCT02422745.
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Multivitamins in the prevention of cancer and cardiovascular disease: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial.
Sesso, HD, Rist, PM, Aragaki, AK, Rautiainen, S, Johnson, LG, Friedenberg, G, Copeland, T, Clar, A, Mora, S, Moorthy, MV, et al
The American journal of clinical nutrition. 2022;115(6):1501-1510
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Multivitamin-multimineral (MVM) formulations are the most common dietary supplement. Numerous adults continue to take MVMs for general health and well-being or to reduce the risk of chronic diseases despite inconsistency among observational studies examining long-term MVM use and risk of cancer and cardiovascular disease (CVD). The aim of this study was to test the effects of a common MVM in the prevention of cancer and CVD among women and men. This study is a randomised, double-blind, placebo-controlled, 2 × 2 factorial trial testing a cocoa extract supplement and a multivitamin supplement. A total of 21,442 participants underwent randomisation to one of the four groups. Results show that a daily MVM did not reduce the primary outcome of total invasive cancer. Furthermore, MVM supplementation did not have a significant effect on the secondary outcomes of total cardiovascular events, CVD death, or all-cause mortality. Authors conclude that their findings do not support the regular use of MVMs for cancer or CVD prevention among generally healthy older men and women. Future studies are needed to clarify the role of long-term MVM use on nutritional status and the balance of risks and benefits on cancer, CVD, and other aging-related outcomes.
Abstract
BACKGROUND Although older adults commonly take multivitamin-multimineral (MVM) supplements to promote health, evidence on the use of daily MVMs on invasive cancer is limited. OBJECTIVES The study objective was to determine if a daily MVM decreases total invasive cancer among older adults. METHODS We performed a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of a daily MVM and cocoa extract for prevention of cancer and cardiovascular disease (CVD) among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y) free of major CVD and recently diagnosed cancer. The intervention phase was from June 2015 through December 2020. This article reports on the MVM intervention. Participants were randomly assigned to daily MVM or placebo. The primary outcome was total invasive cancer, excluding nonmelanoma skin cancer. Secondary outcomes included major site-specific cancers, total CVD, all-cause mortality, and total cancer risk among those with a baseline history of cancer. RESULTS During a median follow-up of 3.6 y, invasive cancer occurred in 518 participants in the MVM group and 535 participants in the placebo group (HR: 0.97; 95% CI: 0.86, 1.09; P = 0.57). We observed no significant effect of a daily MVM on breast cancer (HR: 1.06; 95% CI: 0.79, 1.42) or colorectal cancer (HR: 1.30; 95% CI: 0.80, 2.12). We observed a protective effect of a daily MVM on lung cancer (HR: 0.62; 95% CI: 0.42, 0.92). The composite CVD outcome occurred in 429 participants in the MVM group and 437 participants in the placebo group (HR: 0.98; 95% CI: 0.86, 1.12). MVM use did not significantly affect all-cause mortality (HR: 0.93; 95% CI: 0.81, 1.08). There were no safety concerns. CONCLUSIONS A daily MVM supplement, compared with placebo, did not significantly reduce the incidence of total cancer among older men and women. Future studies are needed to determine the effects of MVMs on other aging-related outcomes among older adults. This trial is registered at www.clinicaltrials.gov as NCT02422745.
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Effects of Vitamin D3 and Marine Omega-3 Fatty Acids Supplementation on Biomarkers of Systemic Inflammation: 4-Year Findings from the VITAL Randomized Trial.
Dong, Y, Zhu, H, Chen, L, Huang, Y, Christen, W, Cook, NR, Copeland, T, Mora, S, Buring, JE, Lee, IM, et al
Nutrients. 2022;(24)
Abstract
Background: The VITAL study was a nationwide, randomized, double-blind, placebo-controlled, 2 × 2 factorial trial of vitamin D3 (2000 IU/day) and marine n-3 FAs (1 g/day) supplements. We recently reported that vitamin D supplementation with or without omega 3 fatty acids reduced autoimmune disease by 22% in the VITAL study. Objective: To investigate the effects of vitamin D3 and/or n-3 FAs on changes in systemic inflammatory biomarkers including pro- and anti-inflammatory cytokines over a 4-year period in the VITAL sub-cohort with in-person evaluations at the Center for Clinical Investigations (CCI) in Boston. Design: Serum levels of four inflammatory biomarkers (high-sensitivity C-reactive protein [hs-CRP], interleukin-6, interleukin-10, and tumor necrosis factor-α) were measured in a total of 2713 samples from those 1054 VITAL/CCI participants (aged 64.9 ± 6.5 years, 49% female, 84% white, and 9% black) at baseline, year 2, and year 4 follow-up visits. Results: In multiple-adjusted models, vitamin D3 supplementation decreased serum hs-CRP levels by 19% at 2-year follow-up (nominal p = 0.007; p-value after multiple comparison adjustment = 0.028), but not at 4-year follow-up (nominal and adjusted p-values > 0.05). The effects of vitamin D3 on other inflammatory markers were not statistically significant either at year 2 or year 4 (all adjusted p-values > 0.05). Marine n-3 FAs were not significantly associated with changes of all the above inflammatory markers either at years 2 and 4, after multiple comparison adjustment (all p-values > 0.05). Conclusions: Vitamin D3 supplementation with or without n-3 FAs decreased hs-CRP by 19% at year 2, but not other inflammatory biomarkers at year 2 or year 4, while n-3 FAs with or without vitamin D3 did not significantly affect these biomarkers at either time point. Our findings support a potential role of vitamin D supplementation in modulating the chronic inflammatory process, systemic inflammation, and possibly autoimmune disease progression.
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Association of Modifiable Lifestyle Factors with Plasma Branched-Chain Amino Acid Metabolites in Women.
Hamaya, R, Mora, S, Lawler, PR, Cook, NR, Buring, JE, Lee, IM, Manson, JE, Tobias, DK
The Journal of nutrition. 2022;(6):1515-1524
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BACKGROUND Circulating branched-chain amino acids (BCAAs-isoleucine, leucine, and valine) are strongly associated with higher risk of incident type 2 diabetes (T2D); however, determinants of elevated fasting BCAA concentrations are largely unknown. OBJECTIVES We aimed to characterize the modifiable lifestyle factors related to plasma BCAAs. METHODS We performed a cross-sectional analysis among n = 18,897 women (mean ± SD age: 54.9 ± 7.2 y) in the Women's Health Study, free of T2D and cardiovascular disease at baseline blood draw. Lifestyle factors, weight, and height were self-reported via questionnaire, including smoking status, alcohol, leisure-time physical activity (LTPA), diet quality scores [2010 Alternative Healthy Eating Index (without alcohol) (aHEI); alternate Mediterranean Diet (aMED)], and dietary sources of BCAAs. Plasma BCAAs were quantified via NMR spectroscopy. We calculated multivariable-adjusted percentage mean differences (95% CIs) and P values for linear trend of BCAAs stratified by categoric lifestyle factors. We estimated R2 from univariate cubic spline regression models to estimate the variability in BCAAs explained. RESULTS Compared with women with BMI (in kg/m2) <25.0, BCAAs were 8.6% (95% CI: 8.0%, 9.3%), 15.3% (95% CI: 14.4%, 16.3%), and 21.0% (95% CI: 18.2%, 23.9%) higher for the BMI strata 25.0-29.9, 30.0-39.9, and ≥40.0, respectively (P-trend < 0.0001). Women with higher LTPA and higher alcohol intake compared with lower had modestly (∼1%) lower plasma BCAAs (P-trend = 0.014 and 0.0003, respectively). Differences in smoking status, aHEI, and aMED score were not related to plasma BCAAs. Women with higher dietary BCAAs had dose-response higher plasma BCAA concentrations, 3.4% (95% CI: 2.5%, 4.4%) higher when comparing the highest with the lowest quintile (P-trend < 0.0001). BMI explained 11.6% of the variability of BCAAs, whereas other factors explained between 0.1% and 1%. CONCLUSIONS Our findings among a large cohort of US women indicate that BMI, but less so diet, physical activity, and other lifestyle factors, is related to plasma BCAAs.This trial was registered at clinicaltrials.gov as NCT00000479.