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1.
Am J Clin Nutr ; 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34258619

RESUMO

BACKGROUND: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. OBJECTIVES: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. METHODS: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. RESULTS: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. CONCLUSIONS: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34244157

RESUMO

BACKGROUND: Prolactin is synthesized in the ovaries and may play a role in ovarian cancer etiology. One prior prospective study observed a suggestive positive association between prolactin levels and risk of ovarian cancer. METHODS: We conducted a pooled case-control study of 703 cases and 864 matched controls nested within five prospective cohorts. We used unconditional logistic regression to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between prolactin and ovarian cancer risk. We examined heterogeneity by menopausal status at blood collection, body mass index (BMI), age, and histotype. RESULTS: Among women with known menopausal status, we observed a positive trend in the association between prolactin and ovarian cancer risk (P trend = 0.045; OR, quartile 4 vs. 1 = 1.34; 95% CI = 0.97-1.85), but no significant association was observed for premenopausal or postmenopausal women individually (corresponding OR = 1.38; 95% CI = 0.74-2.58; P trend = 0.32 and OR = 1.41; 95% CI = 0.93-2.13; P trend = 0.08, respectively; P heterogeneity = 0.91). In stratified analyses, we observed a positive association between prolactin and risk for women with BMI ≥ 25 kg/m2, but not BMI < 25 kg/m2 (corresponding OR = 2.68; 95% CI = 1.56-4.59; P trend < 0.01 and OR = 0.90; 95% CI = 0.58-1.40; P trend = 0.98, respectively; P heterogeneity < 0.01). Associations did not vary by age, postmenopausal hormone therapy use, histotype, or time between blood draw and diagnosis. CONCLUSIONS: We found a trend between higher prolactin levels and increased ovarian cancer risk, especially among women with a BMI ≥ 25 kg/m2. IMPACT: This work supports a previous study linking higher prolactin with ovarian carcinogenesis in a high adiposity setting. Future work is needed to understand the mechanism underlying this association.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34264743

RESUMO

Backgrounds - Branched-chain amino acids (BCAAs; isoleucine, leucine and valine) correlate with insulin resistance and poor glucose control, which may in part explain associations between type 2 diabetes (T2D) and cardiovascular disease (CVD). However, the relationships of BCAAs with other cardiometabolic pathways, including inflammation and dyslipidemia, are unclear. We hypothesized that plasma BCAAs would correlate with multiple pathways of cardiometabolic dysfunction. Methods - We conducted a cross-sectional analysis among 19,472 participants (mean age=54.9 years, SD=7.2 years) in the Women's Health Study without a history of T2D, CVD, or cancer. We quantified the concentrations of individual biomarkers of inflammation and lipids, across quartiles of BCAAs, adjusting for age, smoking, BMI, physical activity, and other established CVD risk factors at blood draw. Results - Women in the highest vs. lowest quartiles of plasma BCAAs had higher inflammatory markers including high-sensitivity C-reactive protein (multivariable-adjusted means: 1.96 vs. 1.43 mg/L), fibrinogen (367 vs. 362 mg/dL), soluble intercellular cell adhesion molecule-1 (361 vs. 353 ng/mL), and glycoprotein acetylation (407 vs. 371 µmol/L) (p-trend=0.0002 for fibrinogen; p<0.0001 for others). Similarly for lipids, women with higher BCAAs had lower HDL-c (49.0 vs. 55.0 mg/dL), and higher triglycerides (143 vs. 114 mg/dL), LDL-c (133 vs. 124 mg/dL), and lipoprotein insulin resistance score (52.6 vs. 37.3) (all: p<0.0001). Similar associations with these biomarkers were observed in isoleucine, leucine and valine, respectively. Conclusions - Higher circulating BCAA concentrations are associated with adverse profiles of biomarkers of inflammation and dyslipidemia independent of established CVD risk factors, and thus may reflect poorer cardiometabolic health through multiple pathways.

4.
Clin Nutr ; 40(5): 2475-2482, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33932789

RESUMO

BACKGROUND AND AIMS: Data on the relation of egg consumption with risk of type 2 diabetes (T2D) and coronary heart disease (CHD) are limited and inconsistent. Few studies have controlled for overall dietary patterns in egg-T2D or egg-CHD analyses, and it is unclear whether any observed elevated risks of T2D and CHD with frequent egg consumption is real or due to confounding by dietary habits. We tested the hypothesis that frequent egg consumption is associated with a higher risk of T2D and CHD risk after adjustment for overall dietary patterns among adults. DESIGN: We used prospective cohort design to complete time-to-event analyses. METHODS: We pooled de novo, harmonized, individual-level analyses from nine US cohorts (n = 103,811). Cox regression was used to estimate hazard ratios separately in each cohort adjusting for age, ethnicity, body mass index (BMI), exercise, smoking, alcohol intake, and dietary patterns. We pooled cohort-specific results using an inverse-variance weighted method to estimate summary relative risks. RESULTS: Median age ranged from 25 to 72 years. Median egg consumption was 1 egg per week in most of the cohorts. While egg consumption up to one per week was not associated with T2D risk, consumption of ≥2 eggs per week was associated with elevated risk [27% elevated risk of T2D comparing 7+ eggs/week with none (95% CI: 16%-37%)]. There was little evidence for heterogeneity across cohorts and we observed similar conclusions when stratified by BMI. Overall, egg consumption was not associated with the risk of CHD. However, in a sensitivity analysis, there was a 30% higher risk of CHD (95% CI: 3%-56%) restricted to older adults consuming 5-6 eggs/week. CONCLUSIONS: Our data showed an elevated risk of T2D with egg consumption of ≥2 eggs per week but not with <2 eggs/week. While there was no overall association of egg consumption with CHD risk, the elevated CHD observed with consumption of 5-6 eggs/week in older cohorts merits further investigation.

5.
Cancer Res ; 81(8): 2246-2255, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33820799

RESUMO

The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31-39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer. Over a median 10 years of follow-up, 60,968 women were diagnosed with a first primary incident cancer. Inverse linear associations were observed for seven of 19 cancers studied. Each additional year in the age at menarche was associated with reduced risks of endometrial cancer (HR = 0.91; 95% CI, 0.89-0.94), liver cancer (HR = 0.92; 95% CI, 0.85-0.99), melanoma (HR = 0.95; 95% CI, 0.93-0.98), bladder cancer (HR = 0.96; 95% CI, 0.93-0.99), and cancers of the colon (HR = 0.97; 95% CI, 0.96-0.99), lung (HR = 0.98; 95% CI, 0.96-0.99), and breast (HR = 0.98; 95% CI, 0.93-0.99). All but one of these associations remained statistically significant following adjustment for baseline body mass index. Similarities in the observed associations between menarche and seven cancers suggest shared underlying causes rooted early in life. We propose as a testable hypothesis that early exposure to sex hormones increases mid-life cancer risks by altering functional capacities of stem cells with roles in systemic energy balance and tissue homeostasis. SIGNIFICANCE: Age at menarche is associated with risk for seven cancers in middle-aged women, and understanding the shared underlying causal pathways across these cancers may suggest new avenues for cancer prevention.

6.
BMC Pregnancy Childbirth ; 21(1): 313, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879069

RESUMO

BACKGROUND: The association of antenatal depression with adverse pregnancy, birth, and postnatal outcomes has been an item of scientific interest over the last decades. However, the evidence that exists is controversial or limited. We previously found that one in five women in Kuwait experience antenatal depressive symptoms. Therefore, the aim of this study was to examine whether antenatal depressive symptoms are associated with preterm birth (PTB), small for gestational age (SGA), or large for gestational age (LGA) babies in this population. METHODS: This was a secondary analysis based on data collected in the Transgenerational Assessment of Children's Environmental Risk (TRACER) Study that was conducted in Kuwait. Logistic regression analysis was used to examine whether antenatal depressive symptoms assessed using the Edinburgh Depression Scale (EDS) were associated with preterm birth, small for gestational age, and large for gestational age babies. RESULTS: A total of 1694 women had complete information about the outcomes of interest. Women with depressive symptoms in pregnancy had increased, albeit non-significant, odds of having PTB (OR = 1.41; 95%CI: 0.81, 2.45), SGA babies (OR = 1.26; 0.80, 1.98), or LGA babies (OR = 1.27; 0.90, 1.79). Antenatal depressive symptoms had similar increased odds for the three outcomes even after adjusting for several covariates though none of these reached statistical significance. CONCLUSIONS: In the present study, the depressive symptoms in pregnancy did not predict adverse birth outcomes, such as PTB, SGA, and LGA, which adds to the currently non-conclusive literature. However, further research is needed to examine these associations, as the available evidence is quite limited.


Assuntos
Depressão/epidemiologia , Complicações na Gravidez/epidemiologia , Adulto , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Kuweit/epidemiologia , Gravidez , Nascimento Prematuro/epidemiologia , Estudos Prospectivos , Adulto Jovem
7.
JAMA ; 325(11): 1061-1073, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33724323

RESUMO

Importance: Atrial fibrillation (AF) is the most common heart rhythm disturbance, continues to increase in incidence, and results in significant morbidity and mortality. The marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D have been reported to have both benefits and risks with respect to incident AF, but large-scale, long-term randomized trial data are lacking. Objective: To test the effects of long-term administration of marine omega-3 fatty acids and vitamin D on incident AF. Design, Setting, and Participants: An ancillary study of a 2 × 2 factorial randomized clinical trial involving 25 119 women and men aged 50 years or older without prior cardiovascular disease, cancer, or AF. Participants were recruited directly by mail between November 2011 and March 2014 from all 50 US states and were followed up until December 31, 2017. Interventions: Participants were randomized to receive EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA) and vitamin D3 (2000 IU/d) (n = 6272 analyzed); EPA-DHA and placebo (n = 6270 analyzed); vitamin D3 and placebo (n = 6281 analyzed); or 2 placebos (n = 6296 analyzed). Main Outcomes and Measures: The primary outcome was incident AF confirmed by medical record review. Results: Among the 25 119 participants who were randomized and included in the analysis (mean age, 66.7 years; 50.8% women), 24 127 (96.1%) completed the trial. Over a median 5.3 years of treatment and follow-up, the primary end point of incident AF occurred in 900 participants (3.6% of study population). For the EPA-DHA vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.24; P = .19). For the vitamin D3 vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.25; P = .19). There was no evidence for interaction between the 2 study agents (P = .39). Conclusions and Relevance: Among adults aged 50 years or older, treatment with EPA-DHA or vitamin D3, compared with placebo, resulted in no significant difference in the risk of incident AF over a median follow-up of more than 5 years. The findings do not support the use of either agent for the primary prevention of incident AF. Trial Registration: ClinicalTrials.gov Identifiers: NCT02178410; NCT01169259.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Colecalciferol/uso terapêutico , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Vitaminas/uso terapêutico , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Falha de Tratamento , Deficiência de Vitamina D/tratamento farmacológico
8.
Cancer Res ; 81(11): 3134-3143, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33574088

RESUMO

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10-8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, P interaction = 3.08 × 10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r 2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.

9.
J Clin Endocrinol Metab ; 106(5): 1377-1388, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33513226

RESUMO

CONTEXT: Although observational studies show inverse associations between vitamin D status and body weight/adiposity, there are few large randomized controlled trials (RCTs) investigating this relationship. OBJECTIVE: To determine whether vitamin D3 supplementation lowers weight or improves body composition. DESIGN: The VITamin D and OmegA-3 TriaL (VITAL) was a double-blinded, placebo-controlled RCT including 25 871 US adults. This ancillary study was completed in a sub-cohort that underwent body composition assessments at baseline and 2-year follow-up (89% retention). SETTING: Harvard Clinical and Translational Science Center in Boston. PARTICIPANTS: 771 participants (men ≥ 50 and women ≥ 55 years). INTERVENTIONS: 2 × 2 factorial design of supplemental vitamin D3 (2000 IU/day) and/or omega-3 fatty acids (1 g/day). MAIN OUTCOME MEASURES: Endpoints were 2-year changes in weight, body mass index (BMI), waist circumference, and total and/or regional fat and lean tissue measures determined by dual-energy X-ray absorptiometry. Effect modification by clinical variables and total and free 25-hydroxyvitamin D (25[OH]D) levels was explored. RESULTS: There were no effects of supplemental vitamin D3vs placebo on weight, BMI, or measures of adiposity and lean tissue. Effects did not vary by sex, race/ethnicity, fat mass index, or baseline total or free 25(OH)D levels. Vitamin D3 supplementation did slightly improve body fat percentage in participants with normal BMI at baseline, but not in the overweight or obese (P for interaction = 0.04). CONCLUSIONS: Daily vitamin D3 supplementation vs placebo in the general older population did not improve weight or body composition. Whether supplemental vitamin D3 may benefit individuals with normal BMI warrants further study.

10.
Am J Med ; 134(6): 756-762.e5, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33444588

RESUMO

BACKGROUND: There is interest in whether supplements, including vitamin D and marine omega-3 (n-3) fatty acids, may be effective migraine prophylaxis. However, few studies have evaluated whether vitamin D or n-3 fatty acid supplementation may reduce migraine frequency or severity. METHODS: Participants in the VITamin D and OmegA-3 TriaL (VITAL) were assigned to vitamin D3 (2000 IU/d) or marine n-3 fatty acid (1 g/d) supplementation in a 2-by-2 factorial design. Lifetime history of migraine was assessed a median of 4.6 years after the start of the trial. Individuals were asked to self-report changes in migraine frequency (no change, more frequent, or less frequent) and severity (no change, more severe, less severe) in the past 5 years. We used χ2 tests to compare proportions of individuals reporting changes in migraine frequency and severity between active and placebo groups. RESULTS: Among the 25,871 participants in VITAL, 1032 participants had a history of probable migraine and provided information on changes in migraine frequency and severity. The percentage of individuals reporting decreases in migraine frequency did not differ between active (69.0%) and placebo vitamin D (68.4%) (P value = 0.54) or between active (67.8%) and placebo n-3 fatty acid (69.6%) (P value = 0.82). Similarly, the percentage of individuals reporting decreases in migraine severity did not differ between active (64.1%) and placebo vitamin D (65.0%) (P value = 0.86) or between active (64.5%) and placebo n-3 fatty acid (64.5%) (P value = 0.96). CONCLUSIONS: Neither vitamin D nor marine n-3 fatty acid supplementation, compared to placebo, affected migraine frequency or severity among middle-aged or older adults.


Assuntos
Ácidos Graxos Ômega-3/farmacologia , Transtornos de Enxaqueca/tratamento farmacológico , Vitamina D/farmacologia , Idoso , Método Duplo-Cego , Ácidos Graxos Ômega-3/uso terapêutico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/fisiopatologia , Dor/tratamento farmacológico , Dor/prevenção & controle , Inquéritos e Questionários , Vitamina D/uso terapêutico
11.
J Clin Lipidol ; 15(2): 266-274, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33500188

RESUMO

BACKGROUND: The link between nut consumption and cardiovascular (CV) mortality remains unclear. OBJECTIVE: to examine whether nut consumption is associated with CV mortality and estimate the proportion of reduced risk of CV mortality explained by intermediate factors. METHODS: We studied 39,167 women from the Women's Health Study; 28,034 provided blood samples. Nut consumption was self-reported at baseline and at follow-up using a food frequency questionnaire. Our primary outcome was cardiovascular death, which was ascertained via medical records, confirmed with the national death index and death certificates. RESULTS: During a mean follow-up of 19 years, 959 CV deaths occurred. In a multivariable Cox regression model adjusting for age, body mass index, smoking, alcohol use, physical activity, postmenopausal status, marital status, family history of premature myocardial infarction and the alternate healthy eating index score, hazard ratios for CV mortality were 0.93 (0.76-1.14) for nut consumption of 1-3 times/month, 0.84 (0.69-1.01) for nut intake of 1 time/week, and 0.73 (0.61-0.87) for nut consumption of ≥2 times/week when compared to women who did not consume nuts (p = 0.0004). LDL and total cholesterol accounted for about 19%, HbA1c 18% and all mediating factors together accounted for about 6.6% of the lower risk of CV mortality for those who consumed nuts ≥2 times/week. For the secondary outcome of CV events, although the effect was noted to be in the same direction with increasing nut consumption associated with lower risk of CV events, it was not statistically significant (p = 0.07). CONCLUSION: This study suggests that nut consumption is inversely associated with cardiovascular mortality in women. Lipids, inflammatory markers and glucose metabolism account for a modest proportion of the lowered CV mortality observed with nut consumption, assuming a causal nut-CV mortality association.

12.
Diabetologia ; 64(2): 437-447, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33098434

RESUMO

AIMS/HYPOTHESIS: Interventions that reduce inflammation may delay progression of microvascular and macrovascular complications in diabetes. We examined the effects of vitamin D3 and/or n-3 fatty acid supplementation vs placebo on 5 year changes in serum inflammatory and cardiac biomarkers in adults with type 2 diabetes. METHODS: This study reports pre-specified secondary outcomes of the Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease, in which 1312 US adults with type 2 diabetes and without known cardiovascular disease, malignancy, or end-stage kidney disease were randomised using computer-generated random numbers in blocks of eight to vitamin D3 (2000 IU/day) vs placebo and n-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]; 1 g/day) vs placebo in a 2 × 2 factorial design. Participants, examiners, and researchers assessing outcomes were blinded to intervention assignment. We measured serum IL-6, high-sensitivity C-reactive protein (hsCRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and after 2 and 5 years. RESULTS: A total of 333 participants were randomised to vitamin D3 and placebo n-3 fatty acids, 289 to n-3 fatty acids and placebo vitamin D3, 370 to vitamin D3 and n-3 fatty acids, and 320 to 2 placebos; 989 (75%) and 934 (71%) participants returned blood samples at 2 and 5 years, respectively. Participants had a mean age of 67.6 years (46% women). Overall, baseline geometric means of IL-6, hsCRP and NT-proBNP were 1.2 pg/ml, 1.9 mg/l and 262 ng/l, respectively. After 5 years, mean IL-6 and hsCRP remained within 6% of their baseline values while mean NT-proBNP increased by 55% overall. Compared with placebo, participants assigned to vitamin D3 had a 1.24-fold greater increase in NT-proBNP over 5 years (95% CI 1.09, 1.41; p = 0.003), while IL-6 and hsCRP did not have a significant difference in change. Comparing n-3 fatty acids with placebo, there was no significant difference in change in IL-6, hsCRP or NT-proBNP. No heterogeneity was observed in subgroup analyses accounting for baseline eGFR, urine albumin to creatinine ratio, initial biomarker concentration, 25-hydroxyvitamin D level or EPA+DHA index. CONCLUSIONS/INTERPRETATION: Among adults with type 2 diabetes, supplementation with vitamin D3 or n-3 fatty acids did not reduce IL-6, hsCRP or NT-proBNP over 5 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT01684722 FUNDING: The study was funded by grant R01DK088762 from the National Institute of Diabetes and Digestive and Kidney Diseases. Graphical abstract.

13.
Clin Gastroenterol Hepatol ; 19(1): 128-135.e6, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32062040

RESUMO

BACKGROUND & AIMS: The effects of vitamin D on risk of colorectal cancer precursors are not clear. We examined the influence of vitamin D supplementation on risk of colorectal adenomas and serrated polyps in a prespecified ancillary study of a large-scale prevention trial (the vitamin D and omegA-3 trial, VITAL) of individuals who were free of cancer and cardiovascular disease at enrollment. METHODS: In VITAL trial, 25,871 adults with no history of cancer or cardiovascular disease (12,786 men 50 years or older and 13,085 women 55 years or older) were randomly assigned to groups given daily dietary supplements (2000 IU vitamin D3 and 1 g marine n-3 fatty acid) or placebo. Patients were assigned to groups from November 2011 through March 2014 and the study ended on December 31, 2017. We confirmed conventional adenomas and serrated polyps by reviewing histopathology reports from participants who had reported a diagnosis of polyps and were asked by their doctors to return for a repeat colonoscopy or sigmoidoscopy in 5 years or less. We calculated the odds ratios (ORs) and 95% CIs by logistic regression, after adjusting for age, sex, n-3 treatment assignment, and history of endoscopy at time of randomization. RESULTS: During a median follow-up of 5.3 years, we documented 308 cases of conventional adenomas in 12,927 participants in the vitamin D group and 287 cases in 12,944 participants in the placebo group (OR for the association of vitamin D supplementation with adenoma, 1.08; 95% CI, 0.92-1.27). There were 172 cases of serrated polyps in the vitamin D group and 169 cases in the placebo group (OR for the association of vitamin D supplementation with serrated polyp, 1.02; 95% CI, 0.82-1.26). Supplementation was not associated with polyp size, location, multiplicity, or histologic features. We found evidence for an interaction between vitamin D supplementation and serum level of 25-hydroxyvitamin D, measured in 15,787 participants at randomization. Among individuals with serum levels of 25-hydroxyvitamin D below 30 ng/mL, the OR associated with supplementation for conventional adenoma was 0.82 (95% CI, 0.60-1.13), whereas among individuals with serum levels of 25-hydroxyvitamin D above 30 ng/mL, the OR for conventional adenoma was 1.20 (95% CI, 0.92-1.55) (P for interaction = .07). There was a significant interaction between vitamin D supplementation and serum level of 25-hydroxyvitamin D in their association with advanced adenoma (P for interaction = .04). CONCLUSIONS: Based on an ancillary study of data from the VITAL trial, daily vitamin D supplementation (2000 IU) was not associated with risk of colorectal cancer precursors in average-risk adults not selected for vitamin D insufficiency. A potential benefit for individuals with low baseline level of vitamin D requires further investigation. ClinicalTrials.gov number: NCT01169259.

14.
Eur J Epidemiol ; 36(1): 37-55, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33128203

RESUMO

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m2, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.


Assuntos
Peso Corporal/fisiologia , Neoplasias da Mama/epidemiologia , Menopausa/fisiologia , Receptores de Estrogênio/análise , Ganho de Peso , Adulto , Idoso , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Pré-Menopausa , Estudos Prospectivos , Fatores de Risco
16.
Metabolism ; 117: 154391, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33069808

RESUMO

BACKGROUND: Circulating branched chain amino acids (BCAA) are associated with cardiometabolic risk, although the mechanisms leading to their accumulation remain uncertain. Examining the relationship between fasting status, metabolic syndrome, and type 2 diabetes (T2D) with circulating BCAA levels may provide insights into their metabolic handling. METHODS: We conducted cross-sectional analyses among 25,740 Women's Health Study participants (mean age 55 years). RESULTS: In multivariable linear regression models, fasting was associated with lower plasma BCAAs vs. non-fasting in women without metabolic syndrome or T2D (% mean difference = -5.1%; 95% CI = -5.8, -4.5) and among women with metabolic syndrome only (-3.7%; -4.9, -2.6), pinteraction = 0.002. However, there was no difference in BCAAs by fasting status among women with T2D (0.4%; -3.7, 4.7). CONCLUSIONS: We observed higher BCAAs with worsening metabolic health status. Fasting is modestly associated with lower plasma BCAAs, except among women with T2D. These findings support hypotheses that impaired BCAA catabolism may be a feature of T2D pathophysiology.


Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Jejum/metabolismo , Plasma/metabolismo , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Risco
17.
Eur J Neurol ; 28(3): 809-815, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33131164

RESUMO

BACKGROUND AND PURPOSE: Among stroke patients, low serum 25-hydroxyvitamin D predicts poor outcomes. In mice, higher omega-3 (n-3) fatty acid intake diminishes brain damage after stroke. In this study, we tested whether vitamin D or n-3 fatty acids supplementation prior to stroke reduces the risk of functional limitations and physical disability after stroke. METHODS: We used data from VITAL (the VITamin D and OmegA-3 TriaL) which randomized middle-aged and older men and women without cardiovascular disease to vitamin D3 (2000 IU/day) and/or marine n-3 fatty acids (1 g/day) and followed them for incident stroke events. Individuals experiencing a non-fatal stroke were mailed questionnaires assessing functional limitations (the physical performance scale adapted from Nagi) and physical disability (the modified Katz Activities of Daily Living and Rosow-Breslau Functional Health scales). We used logistic regression to analyze associations between randomized treatment and limitations on each scale. RESULTS: A total of 290 individuals experienced their first stroke during the trial, of whom 197 stroke survivors completed the stroke outcomes questionnaire a median of 1.4 years after diagnosis. We observed no associations between randomized treatment to vitamin D and functional limitations (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.52, 1.97) or physical disability (Rosow-Breslau scale: OR 0.92, 95% CI 0.50, 1.67; Katz scale: OR 1.03, 95% CI 0.31, 3.42). Those randomized to n-3 fatty acids had a non-significantly lower risk of functional limitations (OR 0.55, 95% CI 0.28, 1.09) and physical disability (Rosow-Breslau scale: OR 0.56, 95% CI 0.31, 1.02; Katz sclae: OR 0.32, 95% CI 0.50, 1.67). CONCLUSION: Vitamin D or omega-3 fatty acid supplementation prior to stroke did not result in significantly improved post-stroke outcomes.

18.
JAMA Netw Open ; 3(11): e2025850, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33206192

RESUMO

Importance: Epidemiologic and trial data suggest that vitamin D supplementation may reduce metastatic cancer and cancer mortality, reflecting shared biological pathways. Objective: To follow up on the possible reduction in cancer death in the Vitamin D and Omega-3 Trial (VITAL) with an evaluation of whether vitamin D reduces the incidence of advanced (metastatic or fatal) cancer and an examination possible effect modification by body mass index. Design, Setting, and Participants: VITAL is a randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial of vitamin D3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d). This multicenter clinical trial was conducted in the United States; participants included men aged 50 years or older and women aged 55 years or older who were free of cancer and cardiovascular disease at baseline. Randomization took place from November 2011 through March 2014, and study medication ended on December 31, 2017. Data for this secondary analysis were analyzed from November 1, 2011, to December 31, 2017. Interventions: Vitamin D3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d) supplements. Main Outcomes and Measures: For the present analysis, the primary outcome was a composite incidence of metastatic and fatal invasive total cancer, because the main VITAL study showed a possible reduction in fatal cancer with vitamin D supplementation and effect modification by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) for total cancer incidence reduction for individuals with normal BMI, but not for individuals with overweight or obesity. Secondary analyses included examination of BMI (<25, 25 to < 30, and ≥30) as effect modifiers of the observed associations. Results: Among 25 871 randomized VITAL participants (51% female; mean [SD] age, 67.1 [7.1] years), 1617 were diagnosed with invasive cancer over a median intervention period of 5.3 years (range, 3.8-6.1 years). As previously reported, no significant differences for cancer incidence by treatment arm were observed. However, a significant reduction in advanced cancers (metastatic or fatal) was found for those randomized to vitamin D compared with placebo (226 of 12 927 assigned to vitamin D [1.7%] and 274 of 12 944 assigned to placebo [2.1%]; HR, 0.83 [95% CI, 0.69-0.99]; P = .04). When stratified by BMI, there was a significant reduction for the vitamin D arm in incident metastatic or fatal cancer among those with normal BMI (BMI<25: HR, 0.62 [95% CI, 0.45-0.86]) but not among those with overweight or obesity (BMI 25-<30: HR, 0.89 [95% CI, 0.68-1.17]; BMI≥30: HR, 1.05 [95% CI, 0.74-1.49]) (P = .03 for interaction by BMI). Conclusions and Relevance: In this randomized clinical trial, supplementation with vitamin D reduced the incidence of advanced (metastatic or fatal) cancer in the overall cohort, with the strongest risk reduction seen in individuals with normal weight. Trial Registration: ClinicalTrials.gov Identifier: NCT01169259.


Assuntos
Colecalciferol/uso terapêutico , Metástase Neoplásica , Neoplasias/mortalidade , Vitaminas/uso terapêutico , Idoso , Comorbidade , Suplementos Nutricionais , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/patologia , Obesidade/epidemiologia , Sobrepeso/epidemiologia , Modelos de Riscos Proporcionais
19.
Metabolites ; 10(11)2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33120862

RESUMO

Omega-3 (n-3) treatment may lower cardiovascular risk, yet its effects on the circulating lipidome and relation to cardiovascular risk biomarkers are unclear. We hypothesized that n-3 treatment is associated with favorable changes in downstream fatty acids (FAs), oxylipins, bioactive lipids, clinical lipid and inflammatory biomarkers. We examined these VITAL200, a nested substudy of 200 subjects balanced on demographics and treatment and randomly selected from the Vitamin D and Omega-3 Trial (VITAL). VITAL is a randomized double-blind trial of 840 mg/d eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) vs. placebo among 25,871 individuals. Small polar bioactive lipid features, oxylipins and FAs from plasma and red blood cells were measured using three independent assaying techniques at baseline and one year. The Women's Health Study (WHS) was used for replication with dietary n-3 intake. Randomized n-3 treatment led to changes in 143 FAs, oxylipins and bioactive lipids (False Discovery Rate (FDR) < 0.05 in VITAL200, validated (p-values < 0.05)) in WHS with increases in 95 including EPA, DHA, n-3 docosapentaenoic acid (DPA-n3), and decreases in 48 including DPA-n6, dihomo gamma linolenic (DGLA), adrenic and arachidonic acids. N-3 related changes in the bioactive lipidome were heterogeneously associated with changes in clinical lipid and inflammatory biomarkers. N-3 treatment significantly modulates the bioactive lipidome, which may contribute to its clinical benefits.

20.
Sci Rep ; 10(1): 16534, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024201

RESUMO

Obesity is a risk factor for > 13 cancer sites, although it is unknown whether there is a common mechanism across sites. Evidence suggests a role for impaired branched-chain amino acid (BCAAs; isoleucine, leucine, valine) metabolism in obesity, insulin resistance, and immunity; thus, we hypothesized circulating BCAAs may be associated with incident obesity-related cancers. We analyzed participants in the prospective Women's Health Study without a history of cancer at baseline blood collection (N = 26,711, mean age = 54.6 years [SD = 7.1]). BCAAs were quantified via NMR spectroscopy, log-transformed, and standardized. We used Cox proportional regression models adjusted for age, race, smoking, diet, alcohol, physical activity, menopausal hormone use, Body Mass Index (BMI), diabetes, and other risk factors. The endpoint was a composite of obesity-related cancers, defined per the International Agency for Research on Cancer 2016 report, over a median 24 years follow-up. Baseline BMI ≥ 30 kg/m2 compared with BMI 18.5-25.0 kg/m2 was associated with 23% greater risk of obesity-related cancers (n = 2751 events; multivariable HR 1.23, 95% CI 1.11-1.37). However, BCAAs were not associated with obesity-related cancers (multivariable HR per SD = 1.01 [0.97-1.05]). Results for individual BCAA metabolites suggested a modest association for leucine with obesity-related cancers (1.04 [1.00-1.08]), and no association for isoleucine or valine (0.99 [0.95-1.03] and 1.00 [0.96-1.04], respectively). Exploratory analyses of BCAAs with individual sites included positive associations between leucine and postmenopausal breast cancer, and isoleucine with pancreatic cancer. Total circulating BCAAs were unrelated to obesity-related cancer incidence although an association was observed for leucine with incident obesity-related cancer.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Neoplasias/etiologia , Obesidade/complicações , Obesidade/metabolismo , Aminoácidos de Cadeia Ramificada/sangue , Medicamentos Biossimilares , Índice de Massa Corporal , Neoplasias da Mama/etiologia , Feminino , Humanos , Resistência à Insulina , Leucina/sangue , Leucina/metabolismo , Pessoa de Meia-Idade , Neoplasias Pancreáticas/etiologia , Fatores de Risco , Fatores de Tempo
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