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1.
Circ Res ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31739742

RESUMO

Rationale: Genome-wide association studies (GWAS) have identified genetic loci associated with insulin resistance (IR) but pinpointing the causal genes of a risk locus has been challenging. Objective: To identify candidate causal genes for IR, we screened regional and biologically plausible genes (16 in total) near the top ten IR-loci in risk-relevant cell types, namely preadipocytes and adipocytes. Methods and Results: We generated 16 human Simpson-Golabi-Behmel syndrome preadipocyte knockout lines (SGBS-KO) by lentivirus-mediated CRISPR/Cas9 system. We evaluated each gene knockout by screening IR-relevant phenotypes in the three insulin-sensitizing mechanisms, including adipogenesis, lipid metabolism and insulin signaling. We performed genetic analyses to evaluate whether candidate genes prioritized by our in vitro studies were eQTL genes in human subcutaneous adipose tissue, and were associated with risk of IR, type 2 diabetes (T2D) and cardiovascular diseases (CVD). We further validated the functions of three new adipose IR genes by phenotypic rescue in the SGBS-KO cell lines. Results: Twelve genes, PPARG, IRS-1, FST, PEPD, PDGFC, MAP3K1, GRB14, ARL15, ANKRD55, RSPO3, COBLL1 and LYPLAL1, showed diverse phenotypes in the three insulin-sensitizing mechanisms, and the first seven of these genes could affect all the three mechanisms. Five of six eQTL genes are among the top candidate causal genes and the abnormal expression levels of these genes (IRS-1, GRB14, FST, PEPD and PDGFC) in human SAT could be associated with increased risk of IR, T2D and CVD. Phenotypic rescue of FST, PEPD and PDGFC in the SGBS-KO lines confirmed their function in adipose IR. Conclusions: Twelve genes showed diverse phenotypes indicating differential roles in insulin sensitization, suggesting mechanisms bridging the association of their genomic loci with IR. We prioritized PPARG, IRS-1, GRB14, MAP3K1, FST, PEPD and PDGFC as top candidate genes. Our work points to novel roles for FST, PEPD and PDGFC in adipose tissue, with consequences for cardiometabolic diseases.

2.
Diabetes Care ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719054

RESUMO

OBJECTIVE: To assess weight and HbA1c changes in the Healthier You: National Health Service Diabetes Prevention Program (NHS DPP), the largest DPP globally to achieve universal population coverage. RESEARCH DESIGN AND METHODS: A service evaluation assessed intervention effectiveness for adults with nondiabetic hyperglycemia (HbA1c 42-47 mmol/mol [6.0-6.4%] or fasting plasma glucose 5.5-6.9 mmol/L) between program launch in June 2016 and December 2018, using prospectively collected, national service-level data in England. RESULTS: By December 2018, 324,699 people had been referred, 152,294 had attended the initial assessment, and 96,442 had attended at least 1 of 13 group-based intervention sessions. Allowing sufficient time to elapse, 53% attended an initial assessment, 36% attended at least one group-based session, and 19% completed the intervention (attended >60% of sessions). Of the 32,665 who attended at least one intervention session and had sufficient time to finish, 17,252 (53%) completed: Intention-to-treat analyses demonstrated a mean weight loss of 2.3 kg (95% CI 2.2, 2.3 kg) and an HbA1c reduction of 1.26 mmol/mol (1.20, 1.31 mmol/mol) (0.12% [0.11, 0.12%]); completer analysis demonstrated a mean weight loss of 3.3 kg (3.2, 3.4 kg) and an HbA1c reduction of 2.04 mmol/mol (1.96, 2.12 mmol/mol) (0.19% [0.18, 0.19%]). Younger age, female sex, Asian and black ethnicity, lower socioeconomic status, and normal baseline BMI were associated with less weight loss. Older age, female sex, black ethnicity, lower socioeconomic status, and baseline overweight and obesity were associated with a smaller HbA1c reduction. CONCLUSIONS: Reductions in weight and HbA1c compare favorably with those reported in recent meta-analyses of pragmatic studies and suggest likely future reductions in participant type 2 diabetes incidence.

3.
PLoS One ; 14(10): e0224225, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31652285

RESUMO

INTRODUCTION: Compensatory behaviours may be one of the reasons for the limited success of sedentary time interventions in older adults, but this possibility remains unexplored. Activity compensation is the idea that if we change activity levels at one time we compensate for them at a later time to maintain a set point. We aimed to assess, among adults aged ≥60 years, whether sedentary time and time spent in prolonged sedentary bouts (≥30 mins) on one day were associated with sedentary time and time spent in prolonged sedentary bouts (≥30 mins) on the following day. We also sought to determine whether these associations varied by sociodemographic and comorbid factors. METHODS: Sedentary time was assessed for seven days using hip-worn accelerometers (ActiGraph GT1M) for 3459 adults who participated in the EPIC-Norfolk Study between 2004 and 2011. We assessed day-to-day associations in total and prolonged bouts of sedentary time using multi-level regressions. We included interaction terms to determine whether associations varied by age, sex, smoking, body mass index, social class, retirement, education and comorbid factors (stroke, diabetes, myocardial infarction and cancer). RESULTS: Participants (mean age = 70.3, SD = 6.8 years) accumulated 540 sedentary mins/day (SD = 80.1). On any given day, every 60 minutes spent in sedentary time was associated with 9.9 extra sedentary minutes on the following day (95% CI 9.0, 10.2). This association was greater in non-retired compared to retired participants (non-retired 2.57 extra minutes, p = 0.024) and in current compared to former and never-smokers (5.26 extra mins for current vs former; 5.52 extra mins for current vs never, p = 0.023 and 0.017, respectively). On any given day, every 60 minutes spent in prolonged bouts was associated with 7.8 extra minutes in these bouts the following day (95% CI 7.6, 8.4). This association was greater in older individuals (0.18 extra minutes/year of age, 95% CI 0.061, 0.29), and for retired versus non-retired (retired 2.74 extra minutes, 95% CI 0.21, 5.74). CONCLUSION: Older adults did not display day-to-day compensation. Instead, individuals demonstrate a large stable component of day-to-day time spent sedentary and in prolonged bouts with a small but important capacity for positive variation. Therefore older adults appear to be largely habitual in their sedentary behaviour. Strategies to augment these patterns may be possible, given they may differ by age, smoking, and working status.

4.
Int J Epidemiol ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31651957

RESUMO

BACKGROUND: The advent of very large cohort studies (n > 500 000) has given rise to prospective analyses of health outcomes being undertaken after short (<4 years) follow-up periods. However, these studies are potentially at risk of reverse causality bias. We investigated differences in the associations between self-reported physical activity and all-cause and cardiovascular disease (CVD) mortality, and incident CVD, using different follow-up time cut-offs and methods to account for reverse causality bias. METHODS: Data were from n = 452 933 UK Biobank participants, aged 38-73 years at baseline. Median available follow-up time was 7 years (for all-cause and CVD mortality) and 6.1 years (for incident CVD). We additionally analysed associations at 1-, 2- and 4-year cut-offs after baseline. We fit up to four models: (1) adjusting for prevalent CVD and cancer, (2) excluding prevalent disease, (3) and (4) Model 2 excluding incident cases in the first 12 and 24 months, respectively. RESULTS: The strength of associations decreased as follow-up time cut-off increased. For all-cause mortality, Model 1 hazard ratios were 0.73 (0.69-0.78) after 1 year and 0.86 (0.84-0.87) after 7 years. Associations were weaker with increasing control for possible reverse causality. After 7-years follow-up, the hazard ratios were 0.86 (0.84-0.87) and 0.88 (0.86-0.90) for Models 1 and 4, respectively. Associations with CVD outcomes followed similar trends. CONCLUSIONS: As analyses with longer follow-up times and increased control for reverse causality showed weaker associations, there are implications for the decision about when to analyse a cohort study with ongoing data collection, the interpretation of study results and their contribution to meta-analyses.

5.
Eur J Epidemiol ; 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31564045

RESUMO

Pancreatic cancer (PC) is a highly fatal cancer with currently limited opportunities for early detection and effective treatment. Modifiable factors may offer pathways for primary prevention. In this study, the association between the Healthy Lifestyle Index (HLI) and PC risk was examined. Within the European Prospective Investigation into Cancer and Nutrition cohort, 1113 incident PC (57% women) were diagnosed from 400,577 participants followed-up for 15 years (median). HLI scores combined smoking, alcohol intake, dietary exposure, physical activity and, in turn, overall and central adiposity using BMI (HLIBMI) and waist-to-hip ratio (WHR, HLIWHR), respectively. High values of HLI indicate adherence to healthy behaviors. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and 95% confidence intervals (CI). Sensitivity analyses were performed by excluding, in turn, each factor from the HLI score. Population attributable fractions (PAF) were estimated assuming participants' shift to healthier lifestyles. The HRs for a one-standard deviation increment of HLIBMI and HLIWHR were 0.84 (95% CI: 0.79, 0.89; ptrend = 4.3e-09) and 0.77 (0.72, 0.82; ptrend = 1.7e-15), respectively. Exclusions of smoking from HLIWHR resulted in HRs of 0.88 (0.82, 0.94; ptrend = 4.9e-04). The overall PAF estimate was 19% (95% CI: 11%, 26%), and 14% (6%, 21%) when smoking was removed from the score. Adherence to a healthy lifestyle was inversely associated with PC risk, beyond the beneficial role of smoking avoidance. Public health measures targeting compliance with healthy lifestyles may have an impact on PC incidence.

6.
J Nutr Sci ; 8: e29, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31501691

RESUMO

Online self-reported 24-h dietary recall systems promise increased feasibility of dietary assessment. Comparison against interviewer-led recalls established their convergent validity; however, reliability and criterion-validity information is lacking. The validity of energy intakes (EI) reported using Intake24, an online 24-h recall system, was assessed against concurrent measurement of total energy expenditure (TEE) using doubly labelled water in ninety-eight UK adults (40-65 years). Accuracy and precision of EI were assessed using correlation and Bland-Altman analysis. Test-retest reliability of energy and nutrient intakes was assessed using data from three further UK studies where participants (11-88 years) completed Intake24 at least four times; reliability was assessed using intra-class correlations (ICC). Compared with TEE, participants under-reported EI by 25 % (95 % limits of agreement -73 % to +68 %) in the first recall, 22 % (-61 % to +41 %) for average of first two, and 25 % (-60 % to +28 %) for first three recalls. Correlations between EI and TEE were 0·31 (first), 0·47 (first two) and 0·39 (first three recalls), respectively. ICC for a single recall was 0·35 for EI and ranged from 0·31 for Fe to 0·43 for non-milk extrinsic sugars (NMES). Considering pairs of recalls (first two v. third and fourth recalls), ICC was 0·52 for EI and ranged from 0·37 for fat to 0·63 for NMES. EI reported with Intake24 was moderately correlated with objectively measured TEE and underestimated on average to the same extent as seen with interviewer-led 24-h recalls and estimated weight food diaries. Online 24-h recall systems may offer low-cost, low-burden alternatives for collecting dietary information.

7.
Circ Res ; 125(8): 773-782, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31476962

RESUMO

Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1-SD increment in ln-transformed MCP-1, 1.07; 95% CI, 1.01-1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR, 1.11 [1.02-1.21]) but not hemorrhagic stroke (HR, 1.02 [0.82-1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared with the first quartile (HRs, second quartile: 1.19 [1.00-1.42]; third quartile: 1.35 [1.14-1.59]; fourth quartile: 1.38 [1.07-1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein). Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1 signaling might represent a therapeutic target to lower stroke risk.Visual Overview: An online visual overview is available for this article.

8.
J Nutr ; 149(11): 1985-1993, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31396627

RESUMO

INTRODUCTION: Beverage consumption is a modifiable risk factor for type 2 diabetes (T2D), but there is insufficient evidence to inform the suitability of substituting 1 type of beverage for another. OBJECTIVE: The aim of this study was to estimate the risk of T2D when consumption of sugar-sweetened beverages (SSBs) was replaced with consumption of fruit juice, milk, coffee, or tea. METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study of 8 European countries (n = 27,662, with 12,333 cases of incident T2D, 1992-2007), beverage consumption was estimated at baseline by dietary questionnaires. Using Prentice-weighted Cox regression adjusting for other beverages and potential confounders, we estimated associations of substituting 1 type of beverage for another on incident T2D. RESULTS: Mean ± SD of estimated consumption of SSB was 55 ± 105 g/d. Means ± SDs for the other beverages were as follows: fruit juice, 59 ± 101 g/d; milk, 209 ± 203 g/d; coffee, 381 ± 372 g/d; and tea, 152 ± 282 g/d. Substituting coffee for SSBs by 250 g/d was associated with a 21% lower incidence of T2D (95% CI: 12%, 29%). The rate difference was -12.0 (95% CI: -20.0, -5.0) per 10,000 person-years among adults consuming SSBs ≥250 g/d (absolute rate = 48.3/10,000). Substituting tea for SSBs was estimated to lower T2D incidence by 22% (95% CI: 15%, 28%) or -11.0 (95% CI: -20.0, -2.6) per 10,000 person-years, whereas substituting fruit juice or milk was estimated not to alter T2D risk significantly. CONCLUSIONS: These findings indicate a potential benefit of substituting coffee or tea for SSBs for the primary prevention of T2D and may help formulate public health recommendations on beverage consumption in different populations.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31325308

RESUMO

OBJECTIVES: PMR and GCA are associated with increased risk of vascular disease. However, it remains unclear whether this relationship is causal or reflects a common underlying propensity. The aim of this study was to identify whether known cardiovascular risk factors increase the risk of PMR and GCA. METHODS: Clinical records were examined using key word searches to identify cases of PMR and GCA, applying current classification criteria in a population-based cohort. Associations between cardiovascular risk factors and incident PMR and GCA were analysed using Cox proportional hazards. RESULTS: In 315 022 person years of follow-up, there were 395 incident diagnoses of PMR and 118 incident diagnoses of GCA that met the clinical definition. Raised diastolic blood pressure (>90 mmHg) at baseline/recruitment was associated with subsequent incident PMR [hazard ratio=1.35 (95% CI 1.01, 1.80) P=0.045], and ever-smoking was associated with incident GCA [hazard ratio=2.01 (95% CI 1.26, 3.20) P=0.003]. Estimates were similar when the analysis was restricted to individuals whose diagnoses satisfied the current classification criteria sets. CONCLUSION: PMR and GCA shares common risk factors with vascular disease onset, suggesting a common underlying propensity. This may indicate a potential for disease prevention strategies through modifying cardiovascular risk.

10.
JAMA Ophthalmol ; 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31246245

RESUMO

Importance: Keratoconus is an important cause of visual loss in young adults, but little is known about its genetic causes. Understanding the genetic determinants of corneal biomechanical factors may in turn teach us about keratoconus etiology. Objectives: To identify genetic associations with corneal biomechanical properties and to examine whether these genetic variants are associated with keratoconus. Design, Setting, and Participants: A stage 1 discovery and replication genome-wide association study (GWAS) of corneal biomechanical properties was performed in 2 cross-sectional populations (6645 participants from the European Prospective Investigation into Cancer and Nutrition [EPIC]-Norfolk Eye Study and 2384 participants from the TwinsUK study). In stage 2, the association of genetic determinants identified in stage 1 with keratoconus was examined in a case-control study. A total of 752 patients with keratoconus were compared with 974 TwinsUK participants (undergoing direct sequencing) or 13 828 EPIC-Norfolk participants (undergoing genotyping and imputation) who were not part of the stage 1 analysis. Data were collected from March 1, 1993, through March 13, 2017, and analyzed from November 1, 2015, through February 1, 2018. Exposures: In stage 1, allele dosage at genome-wide single-nucleotide polymorphisms (SNPs); in stage 2, allele dosage at SNPs with genome-wide significance (P < 5 × 10-8) in stage 1 and not previously reported as associated with corneal disease. Main Outcomes and Measures: In stage 1, corneal hysteresis (CH) and corneal resistance factor (CRF), measured with the Ocular Response Analyzer (ORA); in stage 2, association with keratoconus compared with controls. Results: Among 6645 participants in the discovery cohort (3635 women (54.7%); mean age, 69 years [range, 48-92 years]), 7 genome-wide significant loci associated with CH or CRF were identified that were independently replicated. Two further suggestive loci were identified after meta-analysis. To date, 5 of the identified loci, at ANAPC1, ADAMTS8, ADAMTS17, ABCA6, and COL6A1, have not previously been reported as associated with corneal disease. The ABCA6 locus (rs77542162) was associated with keratoconus using the TwinsUK (odds ratio [OR], 0.50; 95% CI, 0.27-0.92; P = .03) and EPIC-Norfolk controls (OR, 0.39; 95% CI, 0.22-0.70; P = .002). The other loci were associated with keratoconus using TwinsUK (OR per effect allele for ADAMTS8, 0.51 [95% CI, 0.37-0.71; P = 7.9 × 10-5]; for COL6A1, 1.65 [95% CI, 1.05-2.59; P = .03]) or EPIC-Norfolk (OR per effect allele for ANAPC1, 0.78 [95% CI, 0.68-0.89; P = 3.7 × 10-4]; for ADAMTS17, 0.82 [95% CI, 0.68-0.99; P = .04]) controls. Conclusions and Relevance: Five loci that are associated with corneal biomechanical properties and that have suggestive associations with keratoconus were reported. These findings suggest the role of type VI collagen, extracellular matrix, and connective-tissue development for corneal biomechanics and keratoconus and the role of CH and CRF as biomarkers for keratoconus.

11.
BMJ ; 365: l2323, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31243014

RESUMO

OBJECTIVE: To assess the prospective associations of baseline and long term trajectories of physical activity on mortality from all causes, cardiovascular disease, and cancer. DESIGN: Population based cohort study. SETTING: Adults from the general population in the UK. PARTICIPANTS: 14 599 men and women (aged 40 to 79) from the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort, assessed at baseline (1993 to 1997) up to 2004 for lifestyle and other risk factors; then followed to 2016 for mortality (median of 12.5 years of follow-up, after the last exposure assessment). MAIN EXPOSURE: Physical activity energy expenditure (PAEE) derived from questionnaires, calibrated against combined movement and heart rate monitoring. MAIN OUTCOME MEASURES: Mortality from all causes, cardiovascular disease, and cancer. Multivariable proportional hazards regression models were adjusted for age, sex, sociodemographics, and changes in medical history, overall diet quality, body mass index, blood pressure, triglycerides, and cholesterol levels. RESULTS: During 171 277 person years of follow-up, 3148 deaths occurred. Long term increases in PAEE were inversely associated with mortality, independent of baseline PAEE. For each 1 kJ/kg/day per year increase in PAEE (equivalent to a trajectory of being inactive at baseline and gradually, over five years, meeting the World Health Organization minimum physical activity guidelines of 150 minutes/week of moderate-intensity physical activity), hazard ratios were: 0.76 (95% confidence interval 0.71 to 0.82) for all cause mortality, 0.71 (0.62 to 0.82) for cardiovascular disease mortality, and 0.89 (0.79 to 0.99) for cancer mortality, adjusted for baseline PAEE, and established risk factors. Similar results were observed when analyses were stratified by medical history of cardiovascular disease and cancer. Joint analyses with baseline and trajectories of physical activity show that, compared with consistently inactive individuals, those with increasing physical activity trajectories over time experienced lower risks of mortality from all causes, with hazard ratios of 0.76 (0.65 to 0.88), 0.62 (0.53 to 0.72), and 0.58 (0.43 to 0.78) at low, medium, and high baseline physical activity, respectively. At the population level, meeting and maintaining at least the minimum physical activity recommendations would potentially prevent 46% of deaths associated with physical inactivity. CONCLUSIONS: Middle aged and older adults, including those with cardiovascular disease and cancer, can gain substantial longevity benefits by becoming more physically active, irrespective of past physical activity levels and established risk factors. Considerable population health impacts can be attained with consistent engagement in physical activity during mid to late life.


Assuntos
Exercício , Mortalidade , Adulto , Idoso , Doenças Cardiovasculares/mortalidade , Causas de Morte , Metabolismo Energético , Feminino , Estilo de Vida Saudável , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Vigilância da População , Estudos Prospectivos , Fatores de Risco , Reino Unido/epidemiologia
12.
Sci Rep ; 9(1): 9386, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253830

RESUMO

Support from human genetics increases the probability of success in drug development. However, few examples exist of successful genomically-driven drug repositioning. Given that a Mendelian form of severe enterocolitis is due to up-regulation of the interleukin-18 (IL18) signaling pathway, and pharmacologic inhibition of IL18 has been shown to reverse this enterocolitis, we undertook a Mendelian randomization study to test the causal effect of elevated IL18 levels on inflammatory bowel disease susceptibility (IBD) in 12,882 cases and 21,770 controls. Mendelian randomization is an established method to assess the role of biomarkers in disease etiology in a manner that minimizes confounding and prevents reverse causation. Using three SNPs that explained almost 7% of the variance in IL18 level, we found that each genetically predicted standard deviation increase in IL18 was associated with an increase in IBD susceptibility (odds ratio = 1.22, 95% CI = 1.11-1.34, P-value = 6 × 10-5). This association was further validated in 25,042 IBD cases and 34,915 controls (odds ratio = 1.13, 95% CI = 1.05-1.20). Recently, an anti-IL18 monoclonal antibody, which decreased free IL18 levels, was found to be safe, yet ineffective in a phase II trial for type 2 diabetes. Taken together, these genomic findings implicated IBD as an alternative indication for anti-IL18 therapy, which should be tested in randomized controlled trials.

13.
Int J Behav Nutr Phys Act ; 16(1): 41, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064403

RESUMO

BACKGROUND: The evidence for the prospective relationships between specific physical activities (PA), sedentary behaviours (SB) and sleep on subsequent total PA levels is scarce. The purpose of this study was to examine prospective associations of self-reported PA, SB and sleep, and changes in these with subsequent accelerometer-measured PA. METHODS: A sub-sample of 91,648 UK Biobank participants reported moderate-to-vigorous PA (MVPA), lifestyle activities, TV viewing, computer use and sleep through screen-based questionnaires at baseline (2006-2010), and provided valid accelerometry data (dominant wrist-worn for 7 days between 2013 and 2015). A further sub-sample of 7709 participants repeated the screen-based questionnaires between 2012 and 2013. RESULTS: In both women (n = 51,545) and men (n = 40,103), positive associations were observed between all self-reported measures of PA at baseline (MVPA, lifestyle/job-related activities, active transporting modes) and accelerometer-measured PA levels at follow-up (median 5.7 years); an exception was 'walking/standing at work' in women. Sedentary time at work, TV viewing and computer use were inversely associated with PA at follow-up. Sleeping either more or less than 7 h/day at baseline was associated with lower PA at follow-up (except for ≤6 h/day in men). In the repeat self-report sub-sample (median 4.3 years), relatively higher physical activity at follow-up was observed in those who maintained or achieved favourable levels of MVPA, walking for pleasure, strenuous sports, other exercises, heavy DIY (in women), heavy physical work, and walking/standing at work (in women), sedentary time at work, getting about methods (in women), commuting methods (in women), TV viewing, computer use or sleep. CONCLUSIONS: Initial levels of PA, SB and sleep, and changes in these variables were generally associated with subsequent accelerometer-measured PA in the expected directions, suggesting these specific behaviours all contribute to the total volume of physical activity over time and could thus be targets for intervention.


Assuntos
Exercício/fisiologia , Atividades Humanas/estatística & dados numéricos , Comportamento Sedentário , Sono/fisiologia , Acelerometria , Adulto , Feminino , Monitores de Aptidão Física , Humanos , Masculino , Estudos Prospectivos , Autorrelato , Inquéritos e Questionários
14.
Breast Cancer Res ; 21(1): 68, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118087

RESUMO

BACKGROUND: Mammographic breast density, adjusted for age and body mass index, and a polygenic risk score (PRS), comprised of common genetic variation, are both strong risk factors for breast cancer and increase discrimination of risk models. Understanding their joint contribution will be important to more accurately predict risk. METHODS: Using 3628 breast cancer cases and 5126 controls of European ancestry from eight case-control studies, we evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS and quantitative mammographic density measures with breast cancer. Mammographic percent density and absolute dense area were evaluated using thresholding software and examined as residuals after adjusting for age, 1/BMI, and study. PRS and adjusted density phenotypes were modeled both continuously (per 1 standard deviation, SD) and categorically. We fit logistic regression models and tested the null hypothesis of multiplicative joint associations for PRS and adjusted density measures using likelihood ratio and global and tail-based goodness of fit tests within the subset of six cohort or population-based studies. RESULTS: Adjusted percent density (odds ratio (OR) = 1.45 per SD, 95% CI 1.38-1.52), adjusted absolute dense area (OR = 1.34 per SD, 95% CI 1.28-1.41), and the 77-SNP PRS (OR = 1.52 per SD, 95% CI 1.45-1.59) were associated with breast cancer risk. There was no evidence of interaction of the PRS with adjusted percent density or dense area on risk of breast cancer by either the likelihood ratio (P > 0.21) or goodness of fit tests (P > 0.09), whether assessed continuously or categorically. The joint association (OR) was 2.60 in the highest categories of adjusted PD and PRS and 0.34 in the lowest categories, relative to women in the second density quartile and middle PRS quintile. CONCLUSIONS: The combined associations of the 77-SNP PRS and adjusted density measures are generally well described by multiplicative models, and both risk factors provide independent information on breast cancer risk.

15.
Int J Obes (Lond) ; 43(11): 2333-2342, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30940917

RESUMO

BACKGROUND: Many large studies have implemented wrist or thigh accelerometry to capture physical activity, but the accuracy of these measurements to infer activity energy expenditure (AEE) and consequently total energy expenditure (TEE) has not been demonstrated. The purpose of this study was to assess the validity of acceleration intensity at wrist and thigh sites as estimates of AEE and TEE under free-living conditions using a gold-standard criterion. METHODS: Measurements for 193 UK adults (105 men, 88 women, aged 40-66 years, BMI 20.4-36.6 kg m-2) were collected with triaxial accelerometers worn on the dominant wrist, non-dominant wrist and thigh in free-living conditions for 9-14 days. In a subsample (50 men, 50 women) TEE was simultaneously assessed with doubly labelled water (DLW). AEE was estimated from non-dominant wrist using an established estimation model, and novel models were derived for dominant wrist and thigh in the non-DLW subsample. Agreement with both AEE and TEE from DLW was evaluated by mean bias, root mean squared error (RMSE), and Pearson correlation. RESULTS: Mean TEE and AEE derived from DLW were 11.6 (2.3) MJ day-1 and 49.8 (16.3) kJ day-1 kg-1. Dominant and non-dominant wrist acceleration were highly correlated in free-living (r = 0.93), but less so with thigh (r = 0.73 and 0.66, respectively). Estimates of AEE were 48.6 (11.8) kJ day-1 kg-1 from dominant wrist, 48.6 (12.3) from non-dominant wrist, and 46.0 (10.1) from thigh; these agreed strongly with AEE (RMSE ~12.2 kJ day-1 kg-1, r ~ 0.71) with small mean biases at the population level (~6%). Only the thigh estimate was statistically significantly different from the criterion. When combining these AEE estimates with estimated REE, agreement was stronger with the criterion (RMSE ~1.0 MJ day-1, r ~ 0.90). CONCLUSIONS: In UK adults, acceleration measured at either wrist or thigh can be used to estimate population levels of AEE and TEE in free-living conditions with high precision.

16.
Am J Clin Nutr ; 109(4): 1216-1223, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30982858

RESUMO

BACKGROUND: Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed. OBJECTIVE: We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies. METHODS: Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-variance-weighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants. RESULTS: There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides. CONCLUSIONS: Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes.

17.
Nutrients ; 11(4)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027226

RESUMO

Selenoprotein genetic variations and suboptimal selenium (Se) levels may contribute to the risk of colorectal cancer (CRC) development. We examined the association between CRC risk and genotype for single nucleotide polymorphisms (SNPs) in selenoprotein and Se metabolic pathway genes. Illumina Goldengate assays were designed and resulted in the genotyping of 1040 variants in 154 genes from 1420 cases and 1421 controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Multivariable logistic regression revealed an association of 144 individual SNPs from 63 Se pathway genes with CRC risk. However, regarding the selenoprotein genes, only TXNRD1 rs11111979 retained borderline statistical significance after adjustment for correlated tests (PACT = 0.10; PACT significance threshold was P < 0.1). SNPs in Wingless/Integrated (Wnt) and Transforming growth factor (TGF) beta-signaling genes (FRZB, SMAD3, SMAD7) from pathways affected by Se intake were also associated with CRC risk after multiple testing adjustments. Interactions with Se status (using existing serum Se and Selenoprotein P data) were tested at the SNP, gene, and pathway levels. Pathway analyses using the modified Adaptive Rank Truncated Product method suggested that genes and gene x Se status interactions in antioxidant, apoptosis, and TGF-beta signaling pathways may be associated with CRC risk. This study suggests that SNPs in the Se pathway alone or in combination with suboptimal Se status may contribute to CRC development.

18.
J Clin Lipidol ; 13(3): 492-501, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30910668

RESUMO

BACKGROUND: Evidence on the causal link between plasma triglyceride (TG) levels and risk for cardiovascular disease (CVD) has recently emerged. Individuals with the metabolic syndrome have an increased risk for acquiring elevated TG levels later in life. Moreover, common DNA sequence variations in genes affecting TG levels identify individuals at risk for elevated plasma TG levels. OBJECTIVE: We evaluated whether a 3-single nucleotide polymorphism (SNP) TG gene risk score (GRS) and a metabolic risk score (MetRS) both improved CVD risk prediction. METHODS: A 3-SNP GRS and MetRS were generated in the EPIC-Norfolk cohort (n = 20,074) based on 3 SNPs in LPL and APOA5 or the number of Metabolic Syndrome criteria present (maximum 5), respectively. The associations between the 3-SNP GRS, MetRS, TG levels, and CVD risk were evaluated. RESULTS: The 3-SNP GRS and MetRS were both linearly associated with plasma TG levels, that is, +0.25 mmol/L [95% CI 0.22-0.27] per allele change (P < .001) and +0.72 mmol/L [95% CI 0.70-0.73] per increase of number of metabolic syndrome risk score points (P < .001), respectively. We observed a positive association between the 3-SNP GRS and the risk of CVD with an adjusted hazard ratio (HR) of 1.35 [95% CI 1.04-1.74] for the highest versus the lowest GRS, which was independent of the MetRS. For the MetRS, the adjusted HR was 2.03 [95% CI 1.73-2.40] for the highest versus the lowest MetRS. CONCLUSION: Both the 3-SNP GRS and the MetRS are associated with increased plasma TG levels and increased risk for CVD.

19.
Int J Cancer ; 145(9): 2349-2359, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30694528

RESUMO

Published associations between dietary folate and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status. This nested case-control analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC) investigated associations between pre-diagnostic serum folate, homocysteine, vitamins B6 and B12 and the risk of urothelial cell carcinomas of the bladder (UCC). A total of 824 patients with newly diagnosed UCC were matched with 824 cohort members. Serum folate, homocysteine, and vitamins B6 and B12 were measured. Odds ratios (OR) and 95% confidence intervals (CI) for total, aggressive, and non-aggressive UCC were estimated using conditional logistic regression with adjustment for smoking status, smoking duration and intensity, and other potential confounders. Additionally, statistical interaction with smoking status was assessed. A halving in serum folate concentrations was moderately associated with risk of UCC (OR: 1.18; 95% CI: 0.98-1.43), in particular aggressive UCC (OR: 1.34; 95% CI: 1.02-1.75; p-heterogeneity = 0.19). Compared to never smokers in the highest quartile of folate concentrations, this association seemed only apparent among current smokers in the lowest quartile of folate concentrations (OR: 6.26; 95% CI: 3.62-10.81, p-interaction = 0.07). Dietary folate was not associated with aggressive UCC (OR: 1.26; 95% CI: 0.81-1.95; p-heterogeneity = 0.14). No association was observed between serum homocysteine, vitamins B6 and B12 and risk of UCC. This study suggests that lower serum folate concentrations are associated with increased UCC risk, in particular aggressive UCC. Residual confounding by smoking cannot be ruled out and these findings require confirmation in future studies with multiple measurements.

20.
Redox Biol ; 20: 349-353, 2018 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-30391827

RESUMO

Elevated intraocular pressure (IOP) is an important risk factor for glaucoma. Mechanisms involved in its homeostasis are not well understood, but associations between metabolic factors and IOP have been reported. To investigate the relationship between levels of circulating metabolites and IOP, we performed a metabolome-wide association using a machine learning algorithm, and then employing Mendelian Randomization models to further explore the strength and directionality of effect of the metabolites on IOP. We show that O-methylascorbate, a circulating Vitamin C metabolite, has a significant IOP-lowering effect, consistent with previous knowledge of the anti-hypertensive and anti-oxidative role of ascorbate compounds. These results enhance understanding of IOP control and may potentially benefit future IOP treatment and reduce vision loss from glaucoma.

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