Association of variants in the PCSK1 gene with obesity in the EPIC-Norfolk study

Recently, the rs6232 (N221D) and rs6235 (S690T) SNPs in the PCSK1 gene were associated with obesity in a meta-analysis comprising more than 13 000 individuals of European ancestry. Each additional minor allele of rs6232 or rs6235 was associated with a 1.34- or 1.22-fold increase in the risk of obesity, respectively. So far, only one relatively small study has aimed to replicate these findings, but could not confirm the association of the rs6235 SNP and did not study the rs6232 variant. In the present study, we examined the associations of the rs6232 and rs6235 SNPs with obesity in a population-based cohort consisting of 20 249 individuals of European descent from Norfolk, UK. Logistic regression and generalized linear models were used to test the associations of the risk alleles with obesity and related quantitative traits, respectively. Neither of the SNPs was significantly associated with obesity, BMI or waist circumference under the additive genetic model (P > 0.05). However, we observed an interaction between rs6232 and age on the level of BMI (P = 0.010) and risk of obesity (P = 0.020). The rs6232 SNP was associated with BMI (P = 0.021) and obesity (P = 0.022) in the younger individuals [less than median age (59 years)], but not among the older age group (P = 0.81 and P = 0.68 for BMI and obesity, respectively). In conclusion, our data suggest that the PCSK1 rs6232 and rs6235 SNPs are not major contributors to common obesity in the general population. However, the effect of rs6232 may be age-dependent

The association between a biomarker score for fruit and vegetable intake and incident type 2 diabetes: the EPIC-Norfolk study.

BACKGROUND/OBJECTIVES: Biomarkers for a mixed fruit and vegetable (FV) diet are needed to provide a better understanding of the association between FV intake and type 2 diabetes. We aimed to examine the prospective association between a composite score comprised of three biomarkers of FV intake in free-living populations and incident diabetes. SUBJECTS/METHODS: A total of 318 incident diabetes cases and 926 controls from the EPIC (European Prospective Investigation of Cancer)-Norfolk study aged 40-79 years at baseline (1993-1997), completed 7-day prospective food diary and had plasma vitamin C and carotenoid measures. A composite biomarker score (CB-score) comprising the sum of plasma vitamin C, beta-carotene and lutein was derived. Odds ratios (ORs) and 95% confidence intervals (CIs) for incident diabetes were estimated using multivariable logistic regression. RESULTS: A strong inverse association was found between the CB-score and incident diabetes. The ORs (95% CI) of diabetes comparing quartiles Q2, Q3 and Q4 of the CB-score with Q1 (reference category) were 0.70 (0.49, 1.00), 0.34 (0.23, 0.52) and 0.19 (0.12, 0.32), respectively, and 0.49 (0.40, 0.58) per s.d. change in CB-score in a model adjusted for demographic and lifestyle factors. The association was marginally attenuated after additionally adjusting for body mass index and waist circumference (0.60 (0.49 and 0.74) per s.d. change in CB-score). CONCLUSIONS: A combination of biomarkers representing the intake of a mixed FV diet was strongly inversely associated with incident diabetes. These findings provide further support for measuring dietary biomarkers in studies of diet-disease associations and highlight the importance of consuming FV for the prevention of diabetes.The EPIC Norfolk study is supported by programme grants from the Medical Research Council UK and Cancer Research UK. The sponsors did not participate in the design or conduct of this study; in the collection, management, analysis, or interpretation of data; in the writing of the manuscript; or in the preparation, review, approval, or decision to submit this manuscript for publication. We acknowledge support from the MRC Epidemiology Unit (MC_UU_12015/5).This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ejcn.2014.24

Diurnal Profiles of Physical Activity and Postures Derived From Wrist-Worn Accelerometry in UK Adults

Background: Wrist-worn accelerometry is the commonest objective method for measuring physical activity in large-scale epidemiological studies. Research-grade devices capture raw triaxial acceleration which, in addition to quantifying movement, facilitates assessment of orientation relative to gravity. No population-based study has yet described the interrelationship and variation of these features by time and personal characteristics. Methods: 2,043 United Kingdom adults (35–65 years) wore an accelerometer on the non-dominant wrist and a chest-mounted combined heart-rate-and-movement sensor for 7 days free-living. From raw (60 Hz) wrist acceleration, we derived movement (non-gravity acceleration) and pitch and roll (forearm) angles relative to gravity. We inferred physical activity energy expenditure (PAEE) from combined sensing and sedentary time from approximate horizontal arm angle coupled with low movement. Results: Movement differences by time-of-day and day-of-week were associated with forearm angles; more movement in downward forearm positions. Mean (SD) movement was similar between sexes ∼31 (42) mg, despite higher PAEE in men. Women spent longer with the forearm pitched >0°, above horizontal (53% vs 36%), and less time at <0° (37% vs 53%). Diurnal pitch was 2.5–5° above and 0–7.5°below horizontal during night and daytime, respectively; corresponding roll angles were ∼0° (hand flat) and ∼20° (thumb-up). Differences were more pronounced in younger participants. All diurnal profiles indicated later wake-times on weekends. Daytime pitch was closer to horizontal on weekdays; roll was similar. Sedentary time was higher (17 vs 15 hours/day) in obese vs normal-weight individuals. Conclusions: More movement occurred in forearm positions below horizontal, commensurate with activities including walking. Findings suggest time-specific population differences in behaviors by age, sex, and BMI.The authors were supported by the UK Medical Research Council (MC_UU_12015/3) and the NIHR Biomedical Research Centre in Cambridge (IS-BRC-1215-20014). We would also like to thank EPSRC and GlaxoSmithKline for their support through graduate fellowships (iCase 17100053)

The hardness of perfect phylogeny, feasible register assignment and other problems on thin colored graphs

AbstractIn this paper, we consider the complexity of a number of combinatorial problems; namely, Intervalizing Colored Graphs (DNA physical mapping), Triangulating Colored Graphs (perfect phylogeny), (Directed) (Modified) Colored Cutwidth, Feasible Register Assignment and Module Allocation for graphs of bounded pathwidth. Each of these problems has as a characteristic a uniform upper bound on the tree or path width of the graphs in “yes”-instances. For all of these problems with the exceptions of Feasible Register Assignment and Module Allocation, a vertex or edge coloring is given as part of the input. Our main results are that the parameterized variant of each of the considered problems is hard for the complexity classes W[t] for all t∈N. We also show that Intervalizing Colored Graphs, Triangulating Colored Graphs, and Colored Cutwidth are NP-Complete

Network Harmonisation of Physical Activity Variables Through Indirect Validation

Harmonisation of data for pooled analysis relies on the principle of inferential equivalence between variables from different sources. Ideally, this is achieved using models of the direct relationship with gold standard criterion measures, but the necessary validation study data are often unavailable. This study examines an alternative method of network harmonisation using indirect models. Starting methods were self-report or accelerometry, from which we derived indirect models of relationships with doubly labelled water (DLW)-based physical activity energy expenditure (PAEE) using sets of two bridge equations via one of three intermediate measures. Coefficients and performance of indirect models were compared to corresponding direct models (linear regression of DLW-based PAEE on starting methods). Indirect model beta coefficients were attenuated compared to direct model betas (10-63%), narrowing the range of PAEE values; attenuation was greater when bridge equations were weak. Directly and indirectly harmonised models had similar error variance but most indirectly derived values were biased at group-level. Correlations with DLW-based PAEE were identical after harmonisation using continuous linear but not categorical models. Wrist acceleration harmonised to DLW-based PAEE via combined accelerometry and heart rate sensing had lowest error variance (24.5%) and non-significant mean bias 0.9 (95%CI: -1.6; 3.4) kJ•day-1•kg-1. Associations between PAEE and BMI were similar for directly and indirectly harmonised values, but most fell outside the confidence interval of the criterion PAEE-to-BMI association. Indirect models can be used for harmonisation. Performance depends on the measurement properties of original data, variance explained by available bridge equations, and similarity of population characteristics.This work was funded by UK Medical Research Council (MC_UU_12015/3) and the NIHR Biomedical Research Centre in Cambridge (IS-BRC-1215-20014). UK Biobank is acknowledged for contributing to the costs of the fieldwork. Newcastle University and MedImmune are acknowledged for contributing to the costs of the doubly labelled water measurements. The funders had no role in the design, conduct, analysis, and decision to publish results from this study

Fracture Risk in Relation to Serum 25-Hydroxyvitamin D and Physical Activity: Results from the EPIC-Norfolk Cohort Study.

Vitamin D deficiency and physical inactivity have been associated with bone loss and fractures, but their combined effect has scarcely been studied either in younger or older adults. Therefore, we aimed to assess the associations between physical activity, age and 25-hydroxyvitamin D (25(OH)D) status separately and in combination with the incidence of fracture risk in the EPIC-Norfolk cohort study. Baseline (1993-1998) self-reported physical activity and serum 25(OH)D concentrations at follow-up (1998-2000) were collected in 14,624 men and women (aged 42-82 y between 1998 and 2000). Fracture incidence was ascertained up to March 2015. Cox proportional hazard model was used to determine HRs of fractures by plasma 25(OH)D (90 nmol/L), age (65 y) and physical activity (inactive and active) categories, by follow-up time per 20 nmol/L increase in serum 25(OH)D and to explore age-25(OH)D and physical activity-25(OH)D interactions. The age-, sex-, and month-adjusted HRs (95% CIs) for all fractures (1183 fractures) by increasing vitamin D category were not significantly different. With additional adjustment for body mass index, smoking status, alcohol intake, supplement use and history of fractures, the fracture risk was 29% lower in those participants with 50 to 70 nmol/L compared with those in the lowest quintile (<30 nmol/L). Physical inactivity based on a single baseline assessment was not associated with fracture risk. Vitamin D status appeared inversely related to fractures in middle aged adults. In older adults, the relationship between vitamin D status and fracture risk was observed to be J-shaped. Clinical and public health practice in vitamin D supplementation could partially explain these findings, although definitive conclusions are difficult due to potential changes in exposure status over the long follow up period.This work was supported by Medical Research Council (MRC) - MKS/S16 (RG19715) / Sponsor Funding Ref: G9502233; Cancer Research UK (CRUK) - MKS/R07 (RG14230) / Sponsor Funding Ref: SP2024/0201; and Cancer Research UK (CRUK) - MKS/T21 (RG23772) / Sponsor Funding Ref: SP2024/0204. CJA received a Grant FPU13/00421 from the Government of Spain “Ministerio de Educación, Cultura y Deporte”

Long Term Prognostic Impact of Sex-specific Longitudinal Changes in Blood Pressure. The EPIC-Norfolk Prospective Population Cohort Study

AIMS: We aimed to determine the sex differences in longitudinal systolic and diastolic blood pressure (SBP and DBP) trajectories in mid-life and delineate the associations between these and mortality (all-cause, cardiovascular, and non-cardiovascular) and incident cardiovascular disease (CVD) in old age. METHODS AND RESULTS: Participants were selected from the European Prospective Investigation into Cancer, Norfolk (EPIC-Norfolk) cohort study. Sex-specific trajectories were determined using group-based trajectory models using three clinic BP measurements acquired between 1993 and 2012 (mean exposure ∼12.9 years). Multivariable Cox regressions determined the associations between trajectories and incident outcomes over the follow-up (median follow-up 9.4 years). A total of 2897 men (M) and 3819 women (F) were included. At baseline, women were younger (F-55.5, M-57.1), had a worse cardiometabolic profile and were less likely to receive primary CVD prevention including antihypertensive treatment (F-36.0%, M-42.0%). Over the exposure period, women had lower SBP trajectories while men exhibited more pronounced SBP decreases over this period. Over the follow-up period, women had lower mortality (F-11.9%, M-20.5%) and CVD incidence (F-19.8%, M-29.6%). Compared to optimal SBP (≤120 mmHg) and DBP (≤70 mmHg) trajectories, hypertensive trajectories were associated with increased mortality and incident CVD in both men and women during follow-up at univariable level. These associations were nevertheless not maintained upon extensive confounder adjustment including antihypertensive therapies. CONCLUSION: We report sex disparities in CVD prevention which may relate to worse cardiometabolic profiles and less pronounced longitudinal SBP decreases in women. Effective anti-hypertensivetherapy may offset the adverse outcomes associated with prolonged exposure to high blood pressure

Dietary determinants of changes in waist circumference adjusted for body mass index - a proxy measure of visceral adiposity

Background Given the recognized health effects of visceral fat, the understanding of how diet can modulate changes in the phenotype “waist circumference for a given body mass index (WCBMI)”, a proxy measure of visceral adiposity, is deemed necessary. Hence, the objective of the present study was to assess the association between dietary factors and prospective changes in visceral adiposity as measured by changes in the phenotype WCBMI. Methods and Findings We analyzed data from 48,631 men and women from 5 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Anthropometric measurements were obtained at baseline and after a median follow-up time of 5.5 years. WCBMI was defined as the residuals of waist circumference regressed on body mass index, and annual change in WCBMI (¿WCBMI, cm/y) was defined as the difference between residuals at follow-up and baseline, divided by follow-up time. The association between energy, energy density (ED), macronutrients, alcohol, glycemic index (GI), glycemic load (GL), fibre and ¿WCBMI was modelled using centre-specific adjusted linear regression, and random-effects meta-analyses to obtain pooled estimates. Men and women with higher ED and GI diets showed significant increases in their WCBMI, compared to those with lower ED and GI [1 kcal/g greater ED predicted a ¿WCBMI of 0.09 cm (95% CI 0.05 to 0.13) in men and 0.15 cm (95% CI 0.09 to 0.21) in women; 10 units greater GI predicted a ¿WCBMI of 0.07 cm (95% CI 0.03 to 0.12) in men and 0.06 cm (95% CI 0.03 to 0.10) in women]. Among women, lower fibre intake, higher GL, and higher alcohol consumption also predicted a higher ¿WCBMI. Conclusions Results of this study suggest that a diet with low GI and ED may prevent visceral adiposity, defined as the prospective changes in WCBMI. Additional effects may be obtained among women of low alcohol, low GL, and high fibre intake