ORCID Profile
0000-0003-1422-2993
Current Organisation
University of Cambridge
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Publisher: Public Library of Science (PLoS)
Date: 12-06-2020
Publisher: Springer Science and Business Media LLC
Date: 27-12-2022
DOI: 10.1186/S13059-022-02837-1
Abstract: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis ( N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
Publisher: Elsevier BV
Date: 08-2022
Publisher: Springer Science and Business Media LLC
Date: 31-05-2021
Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1186/S12966-019-0882-6
Abstract: Physical activity (PA) plays a role in the prevention of a range of diseases including obesity and cardiometabolic disorders. Large population-based descriptive studies of PA, incorporating precise measurement, are needed to understand the relative burden of insufficient PA levels and to inform the tailoring of interventions. Combined heart and movement sensing enables the study of physical activity energy expenditure (PAEE) and intensity distribution. We aimed to describe the sociodemographic correlates of PAEE and moderate-to-vigorous physical activity (MVPA) in UK adults. The Fenland study is a population-based cohort study of 12,435 adults aged 29–64 years-old in Cambridgeshire, UK. Following in idual calibration (treadmill), participants wore a combined heart rate and movement sensor continuously for 6 days in free-living, from which we derived PAEE (kJ•day − 1 •kg − 1 ) and time in MVPA ( 3 & 4 METs) in bouts greater than 1 min and 10 min. Socio-demographic information was self-reported. Stratum-specific summary statistics and multivariable analyses were performed. Women accumulated a mean (sd) 50(20) kJ•day − 1 •kg − 1 of PAEE, and 83(67) and 33(39) minutes•day − 1 of 1-min bouted and 10-min bouted MVPA respectively. By contrast, men recorded 59(23) kJ•day − 1 •kg − 1 , 124(84) and 60(58) minutes•day − 1 . Age and BMI were also important correlates of PA. Association with age was inverse in both sexes, more strongly so for PAEE than MVPA. Obese in iduals accumulated less PA than their normal-weight counterparts, whether considering PAEE or allometrically-scaled PAEE (− 10 kJ•day − 1 •kg − 1 or − 15 kJ•day − 1 •kg -2/3 in men). Higher income and manual work were associated with higher PA manual workers recorded 13–16 kJ•kg − 1 •day − 1 more PAEE than sedentary counterparts. Overall, 86% of women and 96% of men accumulated a daily average of MVPA ( 3 METs) corresponding to 150 min per week. These values were 49 and 74% if only considering bouts 10 min (15 and 31% for 4 METs). PA varied by age, sex and BMI, and was higher in manual workers and those with higher incomes. Light physical activity was the main driver of PAEE a component of PA that is currently not quantified as a target in UK guidelines.
Publisher: Informa UK Limited
Date: 09-2020
Publisher: Public Library of Science (PLoS)
Date: 19-07-2016
Publisher: Springer Science and Business Media LLC
Date: 30-03-2020
Publisher: Elsevier BV
Date: 11-2020
Publisher: BMJ
Date: 08-07-2020
DOI: 10.1136/BMJ.M2194
Abstract: To investigate the association of plasma vitamin C and carotenoids, as indicators of fruit and vegetable intake, with the risk of type 2 diabetes. Prospective case-cohort study. Populations from eight European countries. 9754 participants with incident type 2 diabetes, and a subcohort of 13 662 in iduals from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort of 340 234 participants: EPIC-InterAct case-cohort study. Incident type 2 diabetes. In a multivariable adjusted model, higher plasma vitamin C was associated with a lower risk of developing type 2 diabetes (hazard ratio per standard deviation 0.82, 95% confidence interval 0.76 to 0.89). A similar inverse association was shown for total carotenoids (hazard ratio per standard deviation 0.75, 0.68 to 0.82). A composite biomarker score (split into five equal groups), comprising vitamin C and in idual carotenoids, was inversely associated with type 2 diabetes with hazard ratios 0.77, 0.66, 0.59, and 0.50 for groups 2-5 compared with group 1 (the lowest group). Self-reported median fruit and vegetable intake was 274 g/day, 396 g/day, and 508 g/day for participants in categories defined by groups 1, 3, and 5 of the composite biomarker score, respectively. One standard deviation difference in the composite biomarker score, equivalent to a 66 (95% confidence interval 61 to 71) g/day difference in total fruit and vegetable intake, was associated with a hazard ratio of 0.75 (0.67 to 0.83). This would be equivalent to an absolute risk reduction of 0.95 per 1000 person years of follow up if achieved across an entire population with the characteristics of the eight European countries included in this analysis. These findings indicate an inverse association between plasma vitamin C, carotenoids, and their composite biomarker score, and incident type 2 diabetes in different European countries. These biomarkers are objective indicators of fruit and vegetable consumption, and suggest that diets rich in even modestly higher fruit and vegetable consumption could help to prevent development of type 2 diabetes.
Publisher: Elsevier BV
Date: 03-2020
Publisher: Wiley
Date: 03-09-2021
DOI: 10.1002/EHF2.13517
Abstract: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological s les and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 in idual studies enrolled participants of both sexes in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate s le, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P 5 × 10 −8 under an additive genetic model. HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization and (iii) develop genomic tools for disease stratification and risk prediction.
Publisher: Springer Science and Business Media LLC
Date: 31-05-2022
DOI: 10.1007/S00198-022-06435-6
Abstract: We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).
Publisher: Springer Science and Business Media LLC
Date: 09-12-2021
Publisher: American Diabetes Association
Date: 24-01-2023
DOI: 10.2337/DC22-1467
Abstract: To investigate the association between accelerometer-derived physical activity energy expenditure (PAEE) and incident type 2 diabetes (T2D) in a cohort of middle-aged adults and within subgroups. Data were from 90,096 UK Biobank participants without prevalent diabetes (mean 62 years of age 57% women) who wore a wrist accelerometer for 7 days. PAEE was derived from wrist acceleration using a population-specific method validated against doubly labeled water. Logistic regressions were used to assess associations between PAEE, its underlying intensity, and incident T2D, ascertained using hospital episode and mortality data up to November 2020. Models were progressively adjusted for demographic, lifestyle factors, and BMI. The association between PAEE and T2D was approximately linear (n = 2,018 events). We observed 19% (95% CI 17–21) lower odds of T2D per 5 kJ · kg−1 · day−1 in PAEE without adjustment for BMI and 11% (9–13) with BMI adjustment. The association was stronger in men than women and weaker in those with obesity and higher genetic susceptibility to obesity. There was no evidence of effect modification by genetic susceptibility to T2D or insulin resistance. For a given level of PAEE, odds of T2D were lower among those engaging in more moderate-to-vigorous activity. There was a strong linear relationship between PAEE and incident T2D. A difference in PAEE equivalent to an additional daily 20-min brisk walk was associated with 19% lower odds of T2D. The association was broadly similar across population subgroups, supporting physical activity for diabetes prevention in the whole population.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Springer Science and Business Media LLC
Date: 19-10-2020
DOI: 10.1186/S12992-020-00630-Y
Abstract: Non-communicable diseases (NCDs) are the leading cause of death globally. While upstream approaches to tackle NCD risk factors of poor quality diets and physical inactivity have been trialled in high income countries (HICs), there is little evidence from low and middle-income countries (LMICs) that bear a disproportionate NCD burden. Sub-Saharan Africa and the Caribbean are therefore the focus regions for a novel global health partnership to address upstream determinants of NCDs. The Global Diet and Activity research Network (GDAR Network) was formed in July 2017 with funding from the UK National Institute for Health Research (NIHR) Global Health Research Units and Groups Programme. We describe the GDAR Network as a case ex le and a potential model for research generation and capacity strengthening for others committed to addressing the upstream determinants of NCDs in LMICs. We highlight the dual equity targets of research generation and capacity strengthening in the description of the four work packages. The work packages focus on learning from the past through identifying evidence and policy gaps and priorities, understanding the present through adolescent lived experiences of healthy eating and physical activity, and co-designing future interventions with non-academic stakeholders. We present five lessons learned to date from the GDAR Network activities that can benefit other global health research partnerships. We close with a summary of the GDAR Network contribution to cultivating sustainable capacity strengthening and cutting-edge policy-relevant research as a beacon to exemplify the need for such collaborative groups.
Publisher: Human Kinetics
Date: 2020
Abstract: Background : Recent updates to physical activity guidelines highlight the importance of reducing sedentary time. However, at present, only general recommendations are possible (ie, “Sit less, move more”). There remains a need to investigate the strength, temporality, specificity, and dose–response nature of sedentary behavior associations with chronic disease, along with potential underlying mechanisms. Methods : Stemming from a recent research workshop organized by the Sedentary Behavior Council themed “Sedentary behaviour mechanisms—biological and behavioural pathways linking sitting to adverse health outcomes,” this paper (1) discusses existing challenges and scientific discussions within this advancing area of science, (2) highlights and discusses emerging areas of interest, and (3) points to potential future directions. Results : A brief knowledge update is provided, reflecting upon current and evolving thinking/discussions, and the rapid accumulation of new evidence linking sedentary behavior to chronic disease. Research “action points” are made at the end of each section—spanning from measurement systems and analytic methods, genetic epidemiology, causal mediation, and experimental studies to biological and behavioral determinants and mechanisms. Conclusion : A better understanding of whether and how sedentary behavior is causally related to chronic disease will allow for more meaningful conclusions in the future and assist in refining clinical and public health policies/recommendations.
Publisher: F1000 Research Ltd
Date: 24-05-2021
DOI: 10.12688/WELLCOMEOPENRES.15846.2
Abstract: Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent in iduals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P x10 -8 ) interactions with sex on lung function, and 21 showed suggestive interactions (P x10 -6 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV 1 ) (P=3.15x10 -15 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV 1 more in males (untransformed FEV 1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( HHIP ) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10 -6 ), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
Publisher: Springer Science and Business Media LLC
Date: 10-06-2201
DOI: 10.1007/S00125-023-05948-X
Abstract: Islet autoimmunity may progress to adult-onset diabetes. We investigated whether circulating odd-chain fatty acids (OCFA) 15:0 and 17:0, which are inversely associated with type 2 diabetes, interact with autoantibodies against GAD65 (GAD65Ab) on the incidence of adult-onset diabetes. We used the European EPIC-InterAct case–cohort study including 11,124 incident adult-onset diabetes cases and a subcohort of 14,866 randomly selected in iduals. Adjusted Prentice-weighted Cox regression estimated HRs and 95% CIs of diabetes in relation to 1 SD lower plasma phospholipid 15:0 and/or 17:0 concentrations or their main contributor, dairy intake, among GAD65Ab-negative and -positive in iduals. Interactions between tertiles of OCFA and GAD65Ab status were estimated by proportion attributable to interaction (AP). Low concentrations of OCFA, particularly 17:0, were associated with a higher incidence of adult-onset diabetes in both GAD65Ab-negative (HR 1.55 [95% CI 1.48, 1.64]) and GAD65Ab-positive (HR 1.69 [95% CI 1.34, 2.13]) in iduals. The combination of low 17:0 and high GAD65Ab positivity vs high 17:0 and GAD65Ab negativity conferred an HR of 7.51 (95% CI 4.83, 11.69), with evidence of additive interaction (AP 0.25 [95% CI 0.05, 0.45]). Low dairy intake was not associated with diabetes incidence in either GAD65Ab-negative (HR 0.98 [95% CI 0.94, 1.02]) or GAD65Ab-positive in iduals (HR 0.97 [95% CI 0.79, 1.18]). Low plasma phospholipid 17:0 concentrations may promote the progression from GAD65Ab positivity to adult-onset diabetes.
Publisher: Springer Science and Business Media LLC
Date: 13-11-2020
DOI: 10.1038/S41597-020-00716-7
Abstract: Type 2 diabetes (T2D) is a global public health challenge. Whilst the advent of genome-wide association studies has identified genetic variants associated with T2D, our understanding of its biological mechanisms and translational insights is still limited. The EPIC-InterAct project, centred in 8 countries in the European Prospective Investigations into Cancer and Nutrition study, is one of the largest prospective studies of T2D. Established as a nested case-cohort study to investigate the interplay between genetic and lifestyle behavioural factors on the risk of T2D, a total of 12,403 in iduals were identified as incident T2D cases, and a representative sub-cohort of 16,154 in iduals was selected from a larger cohort of 340,234 participants with a follow-up time of 3.99 million person-years. We describe the results from a genome-wide association analysis between more than 8.9 million SNPs and T2D risk among 22,326 in iduals (9,978 cases and 12,348 non-cases) from the EPIC-InterAct study. The summary statistics to be shared provide a valuable resource to facilitate further investigations into the genetics of T2D.
Publisher: Springer Science and Business Media LLC
Date: 2021
Publisher: American Diabetes Association
Date: 03-03-2021
DOI: 10.2337/DC20-2426
Abstract: Prospective associations between n-3 fatty acid biomarkers and type 2 diabetes (T2D) risk are not consistent in in idual studies. We aimed to summarize the prospective associations of biomarkers of α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an in idual participant-level pooled analysis. For our analysis we incorporated data from a global consortium of 20 prospective studies from 14 countries. We included 65,147 participants who had blood measurements of ALA, EPA, DPA, or DHA and were free of diabetes at baseline. De novo harmonized analyses were performed in each cohort following a prespecified protocol, and cohort-specific associations were pooled using inverse variance–weighted meta-analysis. A total of 16,693 incident T2D cases were identified during follow-up (median follow-up ranging from 2.5 to 21.2 years). In pooled multivariable analysis, per interquintile range (difference between the 90th and 10th percentiles for each fatty acid), EPA, DPA, DHA, and their sum were associated with lower T2D incidence, with hazard ratios (HRs) and 95% CIs of 0.92 (0.87, 0.96), 0.79 (0.73, 0.85), 0.82 (0.76, 0.89), and 0.81 (0.75, 0.88), respectively (all P & 0.001). ALA was not associated with T2D (HR 0.97 [95% CI 0.92, 1.02]) per interquintile range. Associations were robust across prespecified subgroups as well as in sensitivity analyses. Higher circulating biomarkers of seafood-derived n-3 fatty acids, including EPA, DPA, DHA, and their sum, were associated with lower risk of T2D in a global consortium of prospective studies. The biomarker of plant-derived ALA was not significantly associated with T2D risk.
Publisher: Elsevier BV
Date: 2021
Publisher: Public Library of Science (PLoS)
Date: 11-10-2017
Publisher: Springer Science and Business Media LLC
Date: 02-2020
Publisher: MDPI AG
Date: 21-11-2021
DOI: 10.3390/NU13114164
Abstract: Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-s le MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes (2) pathway SNPs present in enzymes’ coding regions and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84–1.27 and OR: 1.08, 95% CI: 0.86–1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.
Publisher: Research Square Platform LLC
Date: 31-03-2023
DOI: 10.21203/RS.3.RS-2720355/V1
Abstract: Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioral traits and the disease etiology of neuropsychiatric disorders. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 in iduals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits such as sleeping, smoking, feelings, alcohol intake, mental health, and psychiatric disorders. Integrating with established drug information, we validated 13 out of 13 matched combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets. This consortium effort provides a large-scale proteogenomic resource for biomedical research on human behaviors and other neuro-related phenotypes.
Publisher: Cold Spring Harbor Laboratory
Date: 05-08-2021
DOI: 10.1101/2021.08.03.21261494
Abstract: We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis -instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.
Publisher: Springer Science and Business Media LLC
Date: 30-09-2021
DOI: 10.1038/S41366-021-00970-8
Abstract: Physical activity energy expenditure (PAEE) represents the total volume of all physical activity. This can be accumulated as different underlying intensity profiles. Although volume and intensity have been studied in isolation, less is known about their joint association with health. We examined this association with body fatness in a population-based s le of middle-aged British adults. In total, 6148 women and 5320 men from the Fenland study with objectively measured physical activity from in idually calibrated combined heart rate and movement sensing and DXA-derived body fat percentage (BF%) were included in the analyses. We used linear and compositional isocaloric substitution analysis to examine associations of PAEE and its intensity composition with body fatness. Sex-stratified models were adjusted for socio-economic and dietary covariates. PAEE was inversely associated with body fatness in women (beta = −0.16 (95% CI: −0.17 −0.15) BF% per kJ day −1 kg −1 ) and men (beta = −0.09 (95% CI: −0.10 −0.08) BF% per kJ day −1 kg −1 ). Intensity composition was significantly associated with body fatness, beyond that of PAEE the reallocation of energy to vigorous physical activity ( METs) from other intensities was associated with less body fatness, whereas light activity (1.5–3 METs) was positively associated. However, light activity was the main driver of overall PAEE volume, and the relative importance of intensity was marginal compared to that of volume the difference between PAEE in tertile 1 and 2 in women was associated with 3 percentage-point lower BF%. Higher vigorous physical activity in the same group to the maximum observed value was associated with 1 percentage-point lower BF%. In this large, population-based cohort study with objective measures, PAEE was inversely associated with body fatness. Beyond the PAEE association, greater levels of intense activity were also associated with lower body fatness. This contribution was marginal relative to PAEE. These findings support current guidelines for physical activity which emphasise that any movement is beneficial, rather than specific activity intensity or duration targets.
Publisher: Cold Spring Harbor Laboratory
Date: 02-07-2020
DOI: 10.1101/2020.07.01.20144154
Abstract: Resting heart rate (RHR) is inversely associated with cardiorespiratory fitness (CRF) but few studies have investigated the nature of this relationship in large population s les. We examined the association between RHR and CRF in UK adults and explored factors that may influence this relationship. In a population-based s le of 5,143 men and 5,722 women (aged 29-65 years), mean (SD) RHR while seated, supine, and during sleep was 67.6 (9.8), 63.5 (8.9), and 56.9 (6.9) bpm, respectively. The age- and sex-adjusted association with CRF as assessed by submaximal treadmill testing was −0.26 (95%CI −0.27 −0.24), −0.31 (95%CI −0.33 −0.29), and −0.31 (95%CI −0.34 −0.29) ml O 2 kg -1 beat -1 . Sequential adjustment for objectively measured obesity and physical activity attenuated the RHR coefficient by 10% and 50%, respectively. In longitudinal analyses of 6,589 participants re-examined after 6 years, each 1 bpm increase in supine RHR was associated with 0.23 (95%CI 0.20 0.25) ml O 2 min -1 kg -1 decrease in CRF. Across all measures, RHR is inversely associated with CRF half of this association is explained by obesity and physical activity, suggesting CRF changes achieved through altered behaviour could be tracked through changes in RHR, a notion supported by longitudinal results. As well as its utility as a biomarker of CRF at population-level, serial measurements of RHR may facilitate personal goal setting/evaluation and remote patient monitoring.
Publisher: Springer Science and Business Media LLC
Date: 09-2023
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1093/JN/NXZ156
Publisher: American Diabetes Association
Date: 11-09-2020
DOI: 10.2337/DB20-0070
Abstract: Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 in iduals of erse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in in iduals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10−16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
Publisher: Public Library of Science (PLoS)
Date: 16-10-2020
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1093/JN/NXZ031
Publisher: Springer Science and Business Media LLC
Date: 11-11-2019
DOI: 10.1007/S00125-019-05016-3
Abstract: Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort ( n = 15,802) and in incident diabetes cases ( n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24 95% CI 1.03, 1.50) and incident cases (OR 1.97 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other in iduals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.
Publisher: Springer Science and Business Media LLC
Date: 23-11-2020
Publisher: Springer Science and Business Media LLC
Date: 02-03-2023
Publisher: Oxford University Press (OUP)
Date: 30-09-2022
DOI: 10.1530/EJE-22-0523
Abstract: Few prospective studies have assessed whether in iduals with subclinical thyroid dysfunction are more likely to develop diabetes, with conflicting results. In this study, we conducted a systematic review of the literature and an in idual participant data analysis of multiple prospective cohorts to investigate the association between subclinical thyroid dysfunction and incident diabetes. We performed a systematic review of the literature in Medline, Embase, and the Cochrane Library from inception to February 11, 2022. A two-stage in idual participant data analysis was conducted to compare participants with subclinical hypothyroidism and subclinical hyperthyroidism vs euthyroidism at baseline and the adjusted risk of developing diabetes at follow-up. Among 61 178 adults from 18 studies, 49% were females, mean age was 58 years, and mean follow-up time was 8.2 years. At the last available follow-up, there was no association between subclinical hypothyroidism and incidence of diabetes (odds ratio (OR) = 1.02, 95% CI: 0.88–1.17, I2 = 0%) or subclinical hyperthyroidism and incidence of diabetes (OR = 1.03, 95% CI: 0.82–1.30, I2 = 0%), in age- and sex-adjusted analyses. Time-to-event analysis showed similar results (hazard ratio for subclinical hypothyroidism: 0.98, 95% CI: 0.87–1.11 hazard ratio for subclinical hyperthyroidism: 1.07, 95% CI: 0.88–1.29). The results were robust in all sub-group and sensitivity analyses. This is the largest systematic review and in idual participant data analysis to date investigating the prospective association between subclinical thyroid dysfunction and diabetes. We did not find an association between subclinical thyroid dysfunction and incident diabetes. Our results do not support screening patients with subclinical thyroid dysfunction for diabetes. Evidence is conflicting regarding whether an association exists between subclinical thyroid dysfunction and incident diabetes. We therefore aimed to investigate whether in iduals with subclinical thyroid dysfunction are more prone to develop diabetes in the long run as compared to euthyroid in iduals. We included data from 18 international cohort studies with 61 178 adults and a mean follow-up time of 8.2 years. We did not find an association between subclinical hypothyroidism or subclinical hyperthyroidism at baseline and incident diabetes at follow-up. Our results have clinical implications as they neither support screening patients with subclinical thyroid dysfunction for diabetes nor treating them in the hope of preventing diabetes in the future.
Publisher: Cold Spring Harbor Laboratory
Date: 08-02-2019
DOI: 10.1101/542613
Abstract: Little is known about population levels of energy expenditure as national surveillance systems typically employ only crude measures. The National Diet and Nutrition Survey (NDNS) in the UK measures energy expenditure in a 10% subs le by gold-standard doubly-labelled water (DLW). DLW-subs le participants from the NDNS (383 males, 387 females) aged 4-91yrs were recruited between 2008 and 2015. Height and weight were measured, and bodyfat percentage was estimated by deuterium dilution. Absolute Total Energy Expenditure (TEE) increases steadily throughout childhood, ranging from 6.3 and 7.2 MJ/day in 4-7yr-old to 9.9 and 11.8 MJ/day for 14-16yr-old girls and boys, respectively. TEE peaked in 17-27yr-old women (10.9 MJ/day) and 28-43yr-old men (14.4 MJ/day), before decreasing gradually in old age. Physical Acitivty Energy Expenditure (PAEE) declines steadily with age from childhood (87.7 kJ/day/kg in 4-7yr olds) through to old age (38.9 kJ/day/kg in 71-91yr olds). Bodyfat percentage was strongly inversely associated with PAEE throughout life, irrespective of expressing PAEE relative to bodymass or fat-free mass. Compared to females with % bodyfat, females % recorded 28 kJ/day/kg and 17 kJ/day/kg fat-free mass less PAEE in analyses adjusted for age, geographical region, and time of assessment. Similarly, compared to males with % bodyfat, males % recorded 26 kJ/day/kg and 10 kJ/day/kg fat-free mass less PAEE. This first nationally representative study reports levels of human energy expenditure as measured by gold-standard methodology values may serve as reference for other population studies. Age, sex and body composition are main biological determinants of energy expenditure. First nationally representative study of human energy expenditure, covering the UK in the period 2008-2015 Total Energy Expenditure (MJ/day) increases steadily with age thoughout childhood and adolescence, peaks in the 3 rd decade of life in women and 4 th decade of life in men, before decreasing gradually in old age Physical Acitivty Energy Expenditure (kJ/day/kg or kJ/day/kg fat-free mass) declines steadily with age from childhood to old age, more steeply so in males Bodyfat percentage is strongly inversely associated with physical activity energy expenditure
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-05-2022
Abstract: Emerging evidence suggests accruing sedentary behavior (SB) in relatively more prolonged periods may convey additional cardiometabolic risks, but few studies have examined prospective outcomes. We examined the association of SB accumulation patterns with incident cardiovascular disease (CVD), cancer, and all‐cause mortality (ACM). Data were from 7671 EPIC‐Norfolk (European Prospective Investigation Into Cancer and Nutrition–Norfolk) cohort middle‐ to older‐aged adults who wore accelerometers on the right hip for 4 to 7 days. Cox proportional hazards regression modeled associations between 2 measures of SB accumulation and incident CVD, cancer, and ACM. These were usual SB bout duration (the midpoint of each in idual’s SB accumulation curve, fitted using nonlinear regression) and alpha (hybrid measure of bout frequency and duration, with higher values indicating relatively shorter bouts and fewer long bouts). Models were adjusted for potential confounders, then further for 24‐hour time‐use compositions. During mean follow‐up time of 6.4 years, 339 ACM, 1106 CVD, and 516 cancer events occurred. Elevated rates of incident cancer and ACM were seen with more prolonged SB accumulation (lower alpha, higher usual SB bout duration) but not CVD. For usual SB bout duration and alpha, respectively, the confounder‐adjusted hazard ratios per SD of the exposure were 1.12 (95% CI, 1.02–1.23) and 0.88 (95% CI, 0.79–0.98) with incident cancer and 1.16 (95% CI, 1.07–1.26) and 0.80 (95% CI, 0.72–0.89) with ACM (all P .05). Further adjustment for 24‐hour time use weakened associations with ACM for usual bout duration (hazard ratio, 1.06 95% CI, 0.97–1.16 P =0.209) and partially for alpha (hazard ratio, 0.87 95% CI, 0.77–0.99 P =0.029). Accruing SB in longer bout durations was associated with higher rates of incident cancer and ACM but not with incident CVD, with some evidence of direct SB accumulation effects independent of 24‐hour time use. Findings provide some support for considering SB accumulation as an adjunct target of messaging to “sit less and move more.”
Publisher: Springer Science and Business Media LLC
Date: 10-01-2020
DOI: 10.1186/S12916-019-1474-7
Abstract: Although lifestyle factors have been studied in relation to in idual non-communicable diseases (NCDs), their association with development of a subsequent NCD, defined as multimorbidity, has been scarcely investigated. The aim of this study was to investigate associations between five lifestyle factors and incident multimorbidity of cancer and cardiometabolic diseases. In this prospective cohort study, 291,778 participants (64% women) from seven European countries, mostly aged 43 to 58 years and free of cancer, cardiovascular disease (CVD), and type 2 diabetes (T2D) at recruitment, were included. Incident multimorbidity of cancer and cardiometabolic diseases was defined as developing subsequently two diseases including first cancer at any site, CVD, and T2D in an in idual. Multi-state modelling based on Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95% CI) of developing cancer, CVD, or T2D, and subsequent transitions to multimorbidity, in relation to body mass index (BMI), smoking status, alcohol intake, physical activity, adherence to the Mediterranean diet, and their combination as a healthy lifestyle index (HLI) score. Cumulative incidence functions (CIFs) were estimated to compute 10-year absolute risks for transitions from healthy to cancer at any site, CVD (both fatal and non-fatal), or T2D, and to subsequent multimorbidity after each of the three NCDs. During a median follow-up of 11 years, 1910 men and 1334 women developed multimorbidity of cancer and cardiometabolic diseases. A higher HLI, reflecting healthy lifestyles, was strongly inversely associated with multimorbidity, with hazard ratios per 3-unit increment of 0.75 (95% CI, 0.71 to 0.81), 0.84 (0.79 to 0.90), and 0.82 (0.77 to 0.88) after cancer, CVD, and T2D, respectively. After T2D, the 10-year absolute risks of multimorbidity were 40% and 25% for men and women, respectively, with unhealthy lifestyle, and 30% and 18% for men and women with healthy lifestyles. Pre-diagnostic healthy lifestyle behaviours were strongly inversely associated with the risk of cancer and cardiometabolic diseases, and with the prognosis of these diseases by reducing risk of multimorbidity.
Publisher: American Diabetes Association
Date: 10-02-2022
DOI: 10.2337/DC21-1756
Abstract: Trans fatty acids (TFAs) have harmful biologic effects that could increase the risk of type 2 diabetes (T2D), but evidence remains uncertain. We aimed to investigate the prospective associations of TFA biomarkers and T2D by conducting an in idual participant-level pooled analysis. We included data from an international consortium of 12 prospective cohorts and nested case-control studies from six nations. TFA biomarkers were measured in blood collected between 1990 and 2008 from 25,126 participants aged ≥18 years without prevalent diabetes. Each cohort conducted de novo harmonized analyses using a prespecified protocol, and findings were pooled using inverse-variance weighted meta-analysis. Heterogeneity was explored by prespecified between-study and within-study characteristics. During a mean follow-up of 13.5 years, 2,843 cases of incident T2D were identified. In multivariable-adjusted pooled analyses, no significant associations with T2D were identified for trans/trans-18:2, relative risk (RR) 1.09 (95% CI 0.94–1.25) cis/trans-18:2, 0.89 (0.73–1.07) and trans/cis-18:2, 0.87 (0.73–1.03). Trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated with T2D (RR 0.81 [95% CI 0.67–0.99], 0.86 [0.75–0.99], and 0.84 [0.74–0.96], respectively). Findings were not significantly different according to prespecified sources of potential heterogeneity (each P ≥ 0.1). Circulating in idual trans-18:2 TFA biomarkers were not associated with risk of T2D, while trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated. Findings may reflect the influence of mixed TFA sources (industrial vs. natural ruminant), a general decline in TFA exposure due to policy changes during this period, or the relatively limited range of TFA levels.
Publisher: BMJ
Date: 18-01-2023
Abstract: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). Pooled analysis. A consortium of 19 studies from 12 countries identified up to May 2020. Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate. Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis. Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate mL/min/1.73 m 2 . In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate mL/min/1.73 m 2 and % of baseline rate. 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98 P=0.009, I 2 =9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96 P=0.005, I 2 =0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06 P=0.94, I 2 =5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 v years), estimated glomerular filtration rate (60-89 v ≥90 mL/min/1.73 m 2 ), hypertension, diabetes, and coronary heart disease at baseline. Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.
Publisher: Elsevier BV
Date: 03-2022
Publisher: Springer Science and Business Media LLC
Date: 30-09-2022
DOI: 10.1038/S41586-022-05165-3
Abstract: Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control in iduals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control in iduals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated ( P 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN ) and variants (such as at GRK5 and NOS3 ). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
Publisher: Springer Science and Business Media LLC
Date: 03-09-2020
DOI: 10.1038/S41598-020-71302-5
Abstract: Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk in iduals within underweight (BMI 18.5 kg/m 2 ) or obese (BMI ≥ 30 kg/m 2 ) categories, while the highest quartile of ABSI separated 18–39% of the in iduals within each BMI category, which had 22–55% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2023
DOI: 10.1161/STROKEAHA.122.040715
Abstract: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ] P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98] P =0.0041). The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
Publisher: Research Square Platform LLC
Date: 16-12-2021
DOI: 10.21203/RS.3.RS-1129252/V1
Abstract: Even though physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Here, we combine data for up to 674,980 in iduals from 51 studies in a trans-ancestry meta-analysis of genome-wide association studies for self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA) leisure screen time (LST) sedentary commuting and sedentary behavior at work. We identify 99 loci that associate with at least one trait. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. Molecular dynamics simulations suggest that the Glu to Ala substitution encoded by rs2229456 (ACTN3) – associated with more MVPA – disrupts salt bridge interactions and makes the alpha actinin 3 filaments more flexible. In isolated type II A muscle fibers, the Ala-encoding allele is associated with lower maximal force and power during an isometric contraction, suggesting protection from exercise-induced muscle damage. Finally, Mendelian Randomization analyses show that the causal effect of LST on BMI is 2-3 times larger than the effect of body mass index (BMI) on LST, and that beneficial effects of LST and MVPA on several risk factors and diseases are mediated or confounded by BMI. Taken together, our results provide mechanistic insights into the regulation of MVPA and into the role of LST and MVPA in disease prevention. These insights may facilitate the development of tailored physical activity interventions.
Publisher: Elsevier BV
Date: 12-2021
Publisher: Public Library of Science (PLoS)
Date: 10-10-2018
Publisher: Springer Science and Business Media LLC
Date: 03-11-2021
Publisher: Elsevier BV
Date: 09-2020
DOI: 10.1093/AJCN/NQAA157
Publisher: Oxford University Press (OUP)
Date: 13-06-2021
DOI: 10.1093/EURHEARTJ/EHAB309
Abstract: The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in in iduals without previous CVD or diabetes aged 40–69 years in Europe. We derived risk prediction models using in idual-participant data from 45 cohorts in 13 countries (677 684 in iduals, 30 121 CVD events). We used sex-specific and competing risk-adjusted models, including age, smoking status, systolic blood pressure, and total- and HDL-cholesterol. We defined four risk regions in Europe according to country-specific CVD mortality, recalibrating models to each region using expected incidences and risk factor distributions. Region-specific incidence was estimated using CVD mortality and incidence data on 10 776 466 in iduals. For external validation, we analysed data from 25 additional cohorts in 15 European countries (1 133 181 in iduals, 43 492 CVD events). After applying the derived risk prediction models to external validation cohorts, C-indices ranged from 0.67 (0.65–0.68) to 0.81 (0.76–0.86). Predicted CVD risk varied several-fold across European regions. For ex le, the estimated 10-year CVD risk for a 50-year-old smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL-cholesterol of 1.3 mmol/L, ranged from 5.9% for men in low-risk countries to 14.0% for men in very high-risk countries, and from 4.2% for women in low-risk countries to 13.7% for women in very high-risk countries. SCORE2—a new algorithm derived, calibrated, and validated to predict 10-year risk of first-onset CVD in European populations—enhances the identification of in iduals at higher risk of developing CVD across Europe.
Publisher: Springer Science and Business Media LLC
Date: 09-01-2020
DOI: 10.1038/S41467-019-13690-5
Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development ( MYOZ1 , SYNPO2L ), protein homoeostasis ( BAG3 ), and cellular senescence ( CDKN1A ). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-11-2022
DOI: 10.1161/CIRCULATIONAHA.122.060700
Abstract: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Observational analyses were conducted using in idual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values or mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR mL·min –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
Publisher: Springer Science and Business Media LLC
Date: 04-08-2021
Publisher: Springer Science and Business Media LLC
Date: 12-10-2022
DOI: 10.1038/S41586-022-05275-Y
Abstract: Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge s le sizes 1 . Here, using data from a genome-wide association study of 5.4 million in iduals of erse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-s le estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller s le sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
Publisher: Impact Journals, LLC
Date: 11-01-2021
Publisher: Springer Science and Business Media LLC
Date: 17-08-2020
Publisher: Elsevier BV
Date: 09-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-03-2020
Publisher: Springer Science and Business Media LLC
Date: 28-09-2020
Publisher: Public Library of Science (PLoS)
Date: 27-04-2023
DOI: 10.1371/JOURNAL.PMED.1004221
Abstract: Self-reported adherence to the Mediterranean diet has been modestly inversely associated with incidence of type 2 diabetes (T2D) in cohort studies. There is uncertainty about the validity and magnitude of this association due to subjective reporting of diet. The association has not been evaluated using an objectively measured biomarker of the Mediterranean diet. We derived a biomarker score based on 5 circulating carotenoids and 24 fatty acids that discriminated between the Mediterranean or habitual diet arms of a parallel design, 6-month partial-feeding randomised controlled trial (RCT) conducted between 2013 and 2014, the MedLey trial (128 participants out of 166 randomised). We applied this biomarker score in an observational study, the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, to assess the association of the score with T2D incidence over an average of 9.7 years of follow-up since the baseline (1991 to 1998). We included 22,202 participants, of whom 9,453 were T2D cases, with relevant biomarkers from an original case-cohort of 27,779 participants s led from a cohort of 340,234 people. As a secondary measure of the Mediterranean diet, we used a score estimated from dietary-self report. Within the trial, the biomarker score discriminated well between the 2 arms the cross-validated C-statistic was 0.88 (95% confidence interval (CI) 0.82 to 0.94). The score was inversely associated with incident T2D in EPIC-InterAct: the hazard ratio (HR) per standard deviation of the score was 0.71 (95% CI: 0.65 to 0.77) following adjustment for sociodemographic, lifestyle and medical factors, and adiposity. In comparison, the HR per standard deviation of the self-reported Mediterranean diet was 0.90 (95% CI: 0.86 to 0.95). Assuming the score was causally associated with T2D, higher adherence to the Mediterranean diet in Western European adults by 10 percentiles of the score was estimated to reduce the incidence of T2D by 11% (95% CI: 7% to 14%). The study limitations included potential measurement error in nutritional biomarkers, unclear specificity of the biomarker score to the Mediterranean diet, and possible residual confounding. These findings suggest that objectively assessed adherence to the Mediterranean diet is associated with lower risk of T2D and that even modestly higher adherence may have the potential to reduce the population burden of T2D meaningfully. Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12613000602729 www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363860 .
Publisher: Springer Science and Business Media LLC
Date: 09-2021
Publisher: Elsevier BV
Date: 07-2020
Publisher: Springer Science and Business Media LLC
Date: 22-04-2021
DOI: 10.1038/S41467-021-22370-2
Abstract: The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 in iduals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15–18%, at least p 0.003) in the highest vs the lowest quintile for circulating long chain (20–22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.
Publisher: Springer Science and Business Media LLC
Date: 29-03-2023
DOI: 10.1038/S41586-023-05772-8
Abstract: Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being 1–6 . Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was .1 kg m –2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have lified.
Publisher: Cold Spring Harbor Laboratory
Date: 03-2022
DOI: 10.1101/2022.03.01.22271683
Abstract: Cardiorespiratory fitness is rarely measured in population studies. Most studies of fitness do not examine differences by population subgroups or seasonal trends. We used a validated submaximal exercise test to measure fitness in 5976 women and 5316 men, residing in England. We expressed fitness as maximal oxygen consumption per kilogram total body mass (VO 2 max tbm ) and fat free mass (VO 2 max ffm ). Descriptive statistics were computed across anthropometric and sociodemographic characteristics, as well as across the year. Progressive multivariable analyses were performed to examine mediation by physical activity energy expenditure (PAEE) and BMI. Mean±SD VO 2 max tbm was lower in women (35.4±7.6 ml·min -1 ·kg -1 ) than men (42.1±7.4 ml·min -1 ·kg -1 ) but VO 2 max ffm was similar (women: 59.7±11.8 ml·min -1 ·kg -1 men: 62.5±10.4 ml·min -1 ·kg -1 ). Fitness was inversely associated with age but not after adjustment for PAEE. People in more physically demanding jobs were fitter compared to those in sedentary jobs but this association was attenuated in women and reversed in men following adjustment for total PAEE. PAEE and BMI and were positively associated with fitness at all levels of adjustment when fitness was expressed relative to fat-free mass. Fitness during summer was 4% higher than the winter among women, but did not differ by season among men. Fitness was inversely associated with age but less steeply than anticipated, suggesting older generations are comparatively fitter than younger generations. PAEE and BMI were stronger determinants of the variance in fitness than any other characteristic including age. This emphasizes the importance of modifiable physical activity behaviours in public health interventions. Fitness was inversely associated with age but less steeply than anticipated, suggesting older generations are comparatively fitter than younger generations Relationships between cardiorespiratory fitness and sociodemographic characteristics were primarily mediated by physical activity. A one standard deviation difference in physical activity had the same impact on cardiorespiratory fitness as being 25 years younger
Publisher: American Diabetes Association
Date: 17-11-2021
DOI: 10.2337/DC20-1328
Abstract: Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. We conducted genome-wide association studies of plasma vitamin C among 52,018 in iduals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. We identified 11 genomic regions associated with plasma vitamin C (P & 5 × 10−8), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03 95% CI 0.96, 1.10). These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.
Publisher: Springer Science and Business Media LLC
Date: 16-03-2020
DOI: 10.1186/S12966-020-00937-4
Abstract: UK Biobank is a large prospective cohort study containing accelerometer-based physical activity data with strong validity collected from 100,000 participants approximately 5 years after baseline. In contrast, the main cohort has multiple self-reported physical behaviours from 500,000 participants with longer follow-up time, offering several epidemiological advantages. However, questionnaire methods typically suffer from greater measurement error, and at present there is no tested method for combining these erse self-reported data to more comprehensively assess the overall dose of physical activity. This study aimed to use the accelerometry sub-cohort to calibrate the self-reported behavioural variables to produce a harmonised estimate of physical activity energy expenditure, and subsequently examine its reliability, validity, and associations with disease outcomes. We calibrated 14 self-reported behavioural variables from the UK Biobank main cohort using the wrist accelerometry sub-cohort ( n = 93,425), and used published equations to estimate physical activity energy expenditure (PAEE SR ). For comparison, we estimated physical activity based on the scoring criteria of the International Physical Activity Questionnaire, and by summing variables for occupational and leisure-time physical activity with no calibration. Test-retest reliability was assessed using data from the UK Biobank repeat assessment ( n = 18,905) collected a mean of 4.3 years after baseline. Validity was assessed in an independent validation study ( n = 98) with estimates based on doubly labelled water (PAEE DLW ). In the main UK Biobank cohort ( n = 374,352), Cox regression was used to estimate associations between PAEE SR and fatal and non-fatal outcomes including all-cause, cardiovascular diseases, respiratory diseases, and cancers. PAEE SR explained 27% variance in gold-standard PAEE DLW estimates, with no mean bias. However, error was strongly correlated with PAEE DLW ( r = −.98 p 0.001), and PAEE SR had narrower range than the criterion. Test-retest reliability (Λ = .67) and relative validity (Spearman = .52) of PAEE SR outperformed two common approaches for processing self-report data with no calibration. Predictive validity was demonstrated by associations with morbidity and mortality, e.g. 14% (95%CI: 11–17%) lower mortality for in iduals meeting lower physical activity guidelines. The PAEE SR variable has good reliability and validity for ranking in iduals, with no mean bias but correlated error at in idual-level. PAEE SR outperformed uncalibrated estimates and showed stronger inverse associations with disease outcomes.
Publisher: Public Library of Science (PLoS)
Date: 02-2017
Publisher: Springer Science and Business Media LLC
Date: 09-2022
DOI: 10.1038/S41588-022-01165-1
Abstract: Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 in iduals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type II A muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2021
DOI: 10.1161/CIRCGEN.120.003288
Abstract: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the CHREBP locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the CHREBP locus and dyslipidemia. Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near CHREBP were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake. In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16–3.07] mg/dL per allele P .0001), but not significantly among the lowest SSB consumers ( P =0.81 P Diff .0001). Similar results were observed for 2 additional variants (rs35709627 and rs71556736). For triglyceride, rs55673514 was positively associated with triglyceride concentrations only among the highest SSB consumers (β, 0.06 [95% CI, 0.02–0.09] ln-mg/dL per allele, P =0.001) but not the lowest SSB consumers ( P =0.84 P Diff =0.0005). Our results identified genetic variants in the CHREBP locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in triglyceride concentrations. URL: www.clinicaltrials.gov Unique identifier: NCT00005133, NCT00005121, NCT00005487, and NCT00000479.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2008
End Date: 2014
Funder: Economic and Social Research Council
View Funded ActivityStart Date: 2013
End Date: 2019
Funder: Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2019
Funder: Medical Research Council
View Funded Activity