How do lifestyle factors modify the association between genetic predisposition and obesity-related phenotypes? A 4-way decomposition analysis using UK Biobank.

BACKGROUND: Obesity and central obesity are multifactorial conditions with genetic and non-genetic (lifestyle and environmental) contributions. There is incomplete understanding of whether lifestyle modifies the translation from respective genetic risks into phenotypic obesity and central obesity, and to what extent genetic predisposition to obesity and central obesity is mediated via lifestyle factors. METHODS: This is a cross-sectional study of 201,466 (out of approximately 502,000) European participants from UK Biobank and tested for interactions and mediation role of lifestyle factors (diet quality; physical activity levels; total energy intake; sleep duration, and smoking and alcohol intake) between genetic risk for obesity and central obesity. BMI-PRS and WHR-PRS are exposures and obesity and central obesity are outcomes. RESULTS: Overall, 42.8% of the association between genetic predisposition to obesity and phenotypic obesity was explained by lifestyle: 0.9% by mediation and 41.9% by effect modification. A significant difference between men and women was found in central obesity; the figures were 42.1% (association explained by lifestyle), 1.4% (by mediation), and 40.7% (by modification) in women and 69.6% (association explained by lifestyle), 3.0% (by mediation), and 66.6% (by modification) in men. CONCLUSIONS: A substantial proportion of the association between genetic predisposition to obesity/central obesity and phenotypic obesity/central obesity was explained by lifestyles. Future studies with repeated measures of obesity and lifestyle would be needed to clarify causation.

Testing for associations between HbA1c levels, polygenic risk and brain health in UK Biobank (N = 39 283).

AIM: To investigate whether continuous HbA1c levels and HbA1c-polygenic risk scores (HbA1c-PRS) are significantly associated with worse brain health independent of type 2 diabetes (T2D) diagnosis (vs. not), by examining brain structure and cognitive test score phenotypes. METHODS: Using UK Biobank data (n = 39 283), we tested whether HbA1c levels and/or HbA1c-PRS were associated with cognitive test scores and brain imaging phenotypes. We adjusted for confounders of age, sex, Townsend deprivation score, level of education, genotyping chip, eight genetic principal components, smoking, alcohol intake frequency, cholesterol medication, body mass index, T2D and apolipoprotein (APOE) e4 dosage. RESULTS: We found an association between higher HbA1c levels and poorer performance on symbol digit substitution scores (standardized beta [ß] = -0.022, P = .001) in the fully adjusted model. We also found an association between higher HbA1c levels and worse brain MRI phenotypes of grey matter (GM; fully-adjusted ß = -0.026, P < .001), whole brain volume (ß = -0.072, P = .0113) and a general factor of frontal lobe GM (ß = -0.022, P < .001) in partially and fully adjusted models. HbA1c-PRS were significantly associated with GM volume in the fully adjusted model (ß = -0.010, P = .0113); however, when adjusted for HbA1c levels, the association was not significant. CONCLUSIONS: Our findings suggest that measured HbA1c is associated with poorer cognitive health, and that HbA1c-PRS do not add significant information to this.

Psychosocial predictors of COVID-19 infection in UK biobank (N = 104 201).

BACKGROUND: Since the outbreak of COVID-19, data on its psychosocial predictors are limited. We therefore aimed to explore psychosocial predictors of COVID-19 infection at the UK Biobank (UKB). METHODS: This was a prospective cohort study conducted among UKB participants. RESULTS: The sample size was N = 104 201, out of which 14 852 (14.3%) had a positive COVID-19 test. The whole sample analysis showed significant interactions between sex and several predictor variables. Among females, absence of college/university degree [odds ratio (OR) 1.55, 95% confidence interval (CI) 1.45-1.66] and socioeconomic deprivation (OR 1.16 95% CI 1.11-1.21) were associated with higher odds of COVID-19 infection, while history of psychiatric consultation (OR 0.85 95% CI 0.77-0.94) with lower odds. Among males, absence of college/university degree (OR 1.56, 95% CI 1.45-1.68) and socioeconomic deprivation (OR 1.12, 95% CI 1.07-1.16) were associated with higher odds, while loneliness (OR 0.87, 95% CI 0.78-0.97), irritability (OR 0.91, 95% CI 0.83-0.99) and history of psychiatric consultation (OR 0.85, 95% CI 0.75-0.97) were associated with lower odds. CONCLUSION: Sociodemographic factors predicted the odds of COVID-19 infection equally among male and female participants, while psychological factors had differential impacts.

Artificial intelligence for dementia-Applied models and digital health.

INTRODUCTION: The use of applied modeling in dementia risk prediction, diagnosis, and prognostics will have substantial public health benefits, particularly as "deep phenotyping" cohorts with multi-omics health data become available. METHODS: This narrative review synthesizes understanding of applied models and digital health technologies, in terms of dementia risk prediction, diagnostic discrimination, prognosis, and progression. Machine learning approaches show evidence of improved predictive power compared to standard clinical risk scores in predicting dementia, and the potential to decompose large numbers of variables into relatively few critical predictors. RESULTS: This review focuses on key areas of emerging promise including: emphasis on easier, more transparent data sharing and cohort access; integration of high-throughput biomarker and electronic health record data into modeling; and progressing beyond the primary prediction of dementia to secondary outcomes, for example, treatment response and physical health. DISCUSSION: Such approaches will benefit also from improvements in remote data measurement, whether cognitive (e.g., online), or naturalistic (e.g., watch-based accelerometry).

Dose-response association between device-measured physical activity and incident dementia: a prospective study from UK Biobank.

BACKGROUND: Previous cohort studies have investigated the relationship between self-reported physical activity (PA) and dementia. Evidence from objective device-measured PA data is lacking. This study aimed to explore the association of device-measured PA with the risk of dementia incidence and common subtypes (Alzheimer's disease [AD] and vascular dementia) using the UK Biobank study. METHODS: 84,854 participants (55.8% women), invited to participate in the device-measured PA between 2013 and 2015, were included in this prospective cohort study. Wrist accelerometers were used to measure light, moderate, vigorous, moderate-to-vigorous PA (MVPA) and total PA intensity and duration (MET/min/week). Incident dementia (fatal and non-fatal) was extracted from hospital episodes records for incidence and death register for mortality. Incidence follow-up was carried out until the end of March 2021in England and Scotland and the end of March 2018 in Wales. Mortality data were available until February 2021. Nonlinear associations were first investigated using penalised cubic splines fitted in the Cox proportional hazard models. In addition, using MVPA, five categories were created. Associations of these categories with the outcomes were investigated using Cox proportional hazard models. Analyses were adjusted for sociodemographic, lifestyle and health-related factors. RESULTS: After a median follow-up of 6.3 years, 678 individuals were diagnosed with dementia. Evidence of nonlinearity was observed for all PA modes and all-cause dementia. For categories of MVPA, there was a significant trend towards a low risk of overall dementia when higher levels of MVPA were achieved (HRtrend 0.66 [95% CI 0.62 to 0.70]. The lowest risk was identified in individuals who performed more than 1200 MET/min/week, those who had 84% (95% CI 0.12 to 0.21) lower risk of incident dementia compared to those who performed < 300 MET/min/week. CONCLUSIONS: Participants with higher PA levels had a lower risk of incident dementia than those less active, independently of sociodemographic, lifestyle factors and comorbidity. Considering that the majority of previous studies have reported this association using self-reported data, our findings highlight the strong inverse association between PA objectively measured and incident dementia.

Associations between major psychiatric disorder polygenic risk scores and blood-based markers in UK biobank.

Major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD) have both shared and discrete genetic risk factors, and are associated with peripheral abnormalities. The relationships between such genetic architectures and blood-based markers are, however, unclear. We investigated relationships between polygenic risk scores (PRS) for these disorders and peripheral markers in the UK Biobank cohort. We calculated polygenic risk scores for n = 367,329 (MDD PRS), n = 366,465 (SCZ PRS), and n = 366,383 (BD PRS) UK Biobank cohort subjects. We then examined associations between disorder PRS and 58 inflammatory/immune, hematological, bone, cardiovascular, hormone, liver, renal and diabetes-associated blood markers using two generalized linear regression models: 'minimally adjusted' controlling for variables such as age and sex, and 'fully adjusted' including additional lifestyle covariates: BMI, alcohol and smoking status, and medication intake. There were 38/58 MDD PRS, 32/58 SCZ PRS, and 20/58 BD PRS-blood marker associations detected for our minimally adjusted model. Of these, 13/38 (MDD PRS), 14/32 (SCZ PRS), and 10/20 (BD PRS) associations remained significant after controlling for lifestyle factors. Many were disorder-specific, with 8/13 unique MDD PRS associations identified. Several disorder-specific associations for MDD and SCZ were immune-related, with mostly positive and negative associations identified for MDD and SCZ PRS respectively. This study suggests that MDD, SCZ and BD have both shared and distinct peripheral markers associated with disorder-specific genetic risk. The results also implicate inflammatory dysfunction in MDD and SCZ, albeit with differences in patterns between the two conditions, and enrich our understanding of potential underlying pathophysiological mechanisms in major psychiatric disorders.

Correction: The genomic basis of mood instability: identification of 46 loci in 363,705 UK Biobank participants, genetic correlation with psychiatric disorders, and association with gene expression and function.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

The genomic basis of mood instability: identification of 46 loci in 363,705 UK Biobank participants, genetic correlation with psychiatric disorders, and association with gene expression and function.

Genome-wide association studies (GWAS) of psychiatric phenotypes have tended to focus on categorical diagnoses, but to understand the biology of mental illness it may be more useful to study traits which cut across traditional boundaries. Here, we report the results of a GWAS of mood instability as a trait in a large population cohort (UK Biobank, n = 363,705). We also assess the clinical and biological relevance of the findings, including whether genetic associations show enrichment for nervous system pathways. Forty six unique loci associated with mood instability were identified with a SNP heritability estimate of 9%. Linkage Disequilibrium Score Regression (LDSR) analyses identified genetic correlations with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia, anxiety, and Post Traumatic Stress Disorder (PTSD). Gene-level and gene set analyses identified 244 significant genes and 6 enriched gene sets. Tissue expression analysis of the SNP-level data found enrichment in multiple brain regions, and eQTL analyses highlighted an inversion on chromosome 17 plus two brain-specific eQTLs. In addition, we used a Phenotype Linkage Network (PLN) analysis and community analysis to assess for enrichment of nervous system gene sets using mouse orthologue databases. The PLN analysis found enrichment in nervous system PLNs for a community containing serotonin and melatonin receptors. In summary, this work has identified novel loci, tissues and gene sets contributing to mood instability. These findings may be relevant for the identification of novel trans-diagnostic drug targets and could help to inform future stratified medicine innovations in mental health.

Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank.

Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10-7 versus rg = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10-4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.

Carotid Intima-Media Thickness: Novel Loci, Sex-Specific Effects, and Genetic Correlations With Obesity and Glucometabolic Traits in UK Biobank.

OBJECTIVE: Atherosclerosis is the underlying cause of most cardiovascular disease, but mechanisms underlying atherosclerosis are incompletely understood. Ultrasound measurement of the carotid intima-media thickness (cIMT) can be used to measure vascular remodeling, which is indicative of atherosclerosis. Genome-wide association studies have identified many genetic loci associated with cIMT, but heterogeneity of measurements collected by many small cohorts have been a major limitation in these efforts. Here, we conducted genome-wide association analyses in UKB (UK Biobank; N=22 179), the largest single study with consistent cIMT measurements. Approach and Results: We used BOLT-LMM software to run linear regression of cIMT in UKB, adjusted for age, sex, and genotyping chip. In white British participants, we identified 5 novel loci associated with cIMT and replicated most previously reported loci. In the first sex-specific analyses of cIMT, we identified a locus on chromosome 5, associated with cIMT in women only and highlight VCAN as a good candidate gene at this locus. Genetic correlations with body mass index and glucometabolic traits were also observed. Two loci influenced risk of ischemic heart disease. CONCLUSIONS: These findings replicate previously reported associations, highlight novel biology, and provide new directions for investigating the sex differences observed in cardiovascular disease presentation and progression.

Comparison of Conventional Lipoprotein Tests and Apolipoproteins in the Prediction of Cardiovascular Disease.

BACKGROUND: Total cholesterol and high-density lipoprotein cholesterol (HDL-C) measurements are central to cardiovascular disease (CVD) risk assessment, but there is continuing debate around the utility of other lipids for risk prediction. METHODS: Participants from UK Biobank without baseline CVD and not taking statins, with relevant lipid measurements (n=346 686), were included in the primary analysis. An incident fatal or nonfatal CVD event occurred in 6216 participants (1656 fatal) over a median of 8.9 years. Associations of nonfasting lipid measurements (total cholesterol, HDL-C, non-HDL-C, direct and calculated low-density lipoprotein cholesterol [LDL-C], and apolipoproteins [Apo] A1 and B) with CVD were compared using Cox models adjusting for classical risk factors, and predictive utility was determined by the C-index and net reclassification index. Prediction was also tested in 68 649 participants taking a statin with or without baseline CVD (3515 CVD events). RESULTS: ApoB, LDL-C, and non-HDL-C were highly correlated (r>0.90), while HDL-C was strongly correlated with ApoA1 (r=0.92). After adjustment for classical risk factors, 1 SD increase in ApoB, direct LDL-C, and non-HDL-C had similar associations with composite fatal/nonfatal CVD events (hazard ratio, 1.23, 1.20, 1.21, respectively). Associations for 1 SD increase in HDL-C and ApoA1 were also similar (hazard ratios, 0.81 [both]). Adding either total cholesterol and HDL-C, or ApoB and ApoA, to a CVD risk prediction model (C-index, 0.7378) yielded similar improvement in discrimination (C-index change, 0.0084; 95% CI, 0.0065, 0.0104, and 0.0089; 95% CI, 0.0069, 0.0109, respectively). Once total and HDL-C were in the model, no further substantive improvement was achieved with the addition of ApoB (C-index change, 0.0004; 95% CI, 0.0000, 0.0008) or any measure of LDL-C. Results for predictive utility were similar for a fatal CVD outcome, and in a discordance analysis. In participants taking a statin, classical risk factors (C-index, 0.7118) were improved by non-HDL-C (C-index change, 0.0030; 95% CI, 0.0012, 0.0048) or ApoB (C-index change, 0.0030; 95% CI, 0.0011, 0.0048). However, adding ApoB or LDL-C to a model already containing non-HDL-C did not further improve discrimination. CONCLUSIONS: Measurement of total cholesterol and HDL-C in the nonfasted state is sufficient to capture the lipid-associated risk in CVD prediction, with no meaningful improvement from addition of apolipoproteins, direct or calculated LDL-C.

The associations of sugar-sweetened, artificially sweetened and naturally sweet juices with all-cause mortality in 198,285 UK Biobank participants: a prospective cohort study.

BACKGROUND: Recent efforts to address the obesity epidemic have focused on sugar consumption, especially sugar-sweetened beverages. However, sugar takes many forms, is only one contributor to overall energy consumption and is correlated with other health-related lifestyle factors. The objective was to investigate the associations with all-cause mortality of sugar- and artificially sweetened beverages and naturally sweet juices. METHODS: Setting: UK Biobank, UK. Participants joined the UK Biobank study from 2006 to 2010 and were followed up until 2016; 198,285 men and women aged 40-69 years were eligible for this study (40% of the UK Biobank), of whom 3166 (1.6%) died over a mean of 7 years follow-up. DESIGN: prospective population-based cohort study. Exposure variables: dietary consumption of sugar-sweetened beverages, artificially sweetened beverages, naturally sweet juices (100% fruit/vegetable juices) and total sugar intake, self-reported via 24-h dietary assessment tool completed between 2009 and 2012. MAIN OUTCOME: all-cause mortality. Cox regression analyses were used to study the association between the daily intake of the above beverages and all-cause mortality. Models were adjusted for sociodemographic, economic, lifestyle and dietary confounders. RESULTS: Total energy intake, total sugar intake and percentage of energy derived from sugar were comparable among participants who consumed > 2/day sugar-sweetened beverages and > 2/day fruit/vegetable juices (10,221 kJ/day versus 10,381 kJ/day; 183 g versus 190 g; 30.6% versus 31.0%). All-cause mortality was associated with total sugar intake (highest quintile adj. HR 1.28, 95% CI 1.06-1.55) and intake of sugar-sweetened beverages (> 2/day adj. HR 1.84, 95% CI 1.42-2.37) and remained so in sensitivity analyses. An association between artificially sweetened beverage intake and mortality did not persist after excluding deaths in the first 2 years of follow-up (landmark analysis) nor after excluding participants with recent weight loss. Furthermore, the inverse association between fruit/vegetable juice intake and mortality did not persist after additional adjustment for a diet quality score. CONCLUSIONS: Higher mortality is associated with sugar-sweetened beverages specifically. The lack of an adverse association with fruit/vegetable juices suggests that source of sugar may be important and the association with artificially sweetened beverage may reflect reverse causation.

Associations between vascular risk factors and brain MRI indices in UK Biobank.

AIMS: Several factors are known to increase risk for cerebrovascular disease and dementia, but there is limited evidence on associations between multiple vascular risk factors (VRFs) and detailed aspects of brain macrostructure and microstructure in large community-dwelling populations across middle and older age. METHODS AND RESULTS: Associations between VRFs (smoking, hypertension, pulse pressure, diabetes, hypercholesterolaemia, body mass index, and waist-hip ratio) and brain structural and diffusion MRI markers were examined in UK Biobank (N = 9722, age range 44-79 years). A larger number of VRFs was associated with greater brain atrophy, lower grey matter volume, and poorer white matter health. Effect sizes were small (brain structural R2 ≤1.8%). Higher aggregate vascular risk was related to multiple regional MRI hallmarks associated with dementia risk: lower frontal and temporal cortical volumes, lower subcortical volumes, higher white matter hyperintensity volumes, and poorer white matter microstructure in association and thalamic pathways. Smoking pack years, hypertension and diabetes showed the most consistent associations across all brain measures. Hypercholesterolaemia was not uniquely associated with any MRI marker. CONCLUSION: Higher levels of VRFs were associated with poorer brain health across grey and white matter macrostructure and microstructure. Effects are mainly additive, converging upon frontal and temporal cortex, subcortical structures, and specific classes of white matter fibres. Though effect sizes were small, these results emphasize the vulnerability of brain health to vascular factors even in relatively healthy middle and older age, and the potential to partly ameliorate cognitive decline by addressing these malleable risk factors.

Do physical activity, commuting mode, cardiorespiratory fitness and sedentary behaviours modify the genetic predisposition to higher BMI? Findings from a UK Biobank study.

OBJECTIVE: To investigate whether the association between a genetic profile risk score for obesity (GPRS-obesity) (based on 93 SNPs) and body mass index (BMI) was modified by physical activity (PA), cardiorespiratory fitness, commuting mode, walking pace and sedentary behaviours. METHODS: For the analyses we used cross-sectional baseline data from 310,652 participants in the UK Biobank study. We investigated interaction effects of GPRS-obesity with objectively measured and self-reported PA, cardiorespiratory fitness, commuting mode, walking pace, TV viewing, playing computer games, PC-screen time and total sedentary behaviour on BMI. Body mass index (BMI) was the main outcome measure. RESULTS: GPRS-obesity was associated with BMI (ß:0.54 kg.m-2 per standard deviation (SD) increase in GPRS, [95% CI: 0.53; 0.56]; P = 2.1 × 10-241). There was a significant interaction between GPRS-obesity and objectively measured PA (P[interaction] = 3.3 × 10-11): among inactive individuals, BMI was higher by 0.58 kg.m-2 per SD increase in GPRS-obesity (p = 1.3 × 10-70) whereas among active individuals the relevant BMI difference was less (ß:0.33 kg.m-2, p = 6.4 × 10-41). We observed similar patterns for fitness (Unfit ß:0.72 versus Fit ß:0.36 kg.m-2, P[interaction] = 1.4 × 10-11), walking pace (Slow ß:0.91 versus Brisk ß:0.38 kg.m-2, P[interaction] = 8.1 × 10-27), discretionary sedentary behaviour (High ß:0.64 versus Low ß:0.48 kg.m-2, P[interaction] = 9.1 × 10-12), TV viewing (High ß:0.62 versus Low ß:0.47 kg.m-2, P[interaction] = 1.7 × 10-11), PC-screen time (High ß:0.82 versus Low ß:0.54 kg.m-2, P[interaction] = 0.0004) and playing computer games (Often ß:0.69 versus Low ß:0.52 kg.m-2, P[interaction] = 8.9 × 10-10). No significant interactions were found for commuting mode (car, public transport, active commuters). CONCLUSIONS: Physical activity, sedentary behaviours and fitness modify the extent to which a set of the most important known adiposity variants affect BMI. This suggests that the adiposity benefits of high PA and low sedentary behaviour may be particularly important in individuals with high genetic risk for obesity.

Association of central adiposity with psoriasis, psoriatic arthritis and rheumatoid arthritis: a cross-sectional study of the UK Biobank.

OBJECTIVES: To determine the independent association of central adiposity, assessed by waist circumference, with odds of psoriasis, PsA and RA prevalence after controlling for general adiposity (BMI). METHODS: A cross-sectional study of UK Biobank participants aged 40-70 years was performed. Logistic regression was used to calculate the odds of psoriasis, PsA and RA occurrence compared with controls without these conditions by waist circumference, adjusting for covariates: age, sex, smoking status, socioeconomic deprivation and self-reported physical activity (Model 1), followed additionally by BMI (Model 2). RESULTS: A total of 502 417 participants were included; 5074 with psoriasis (1.02%), 905 with PsA (0.18%), 5532 with RA (1.11%) and 490 906 controls without these conditions. Adjusted odds ratios (ORs) (Model 1) for psoriasis, PsA and RA, per s.d. (13.5 cm) higher waist circumference were 1.20 (95% CI 1.16, 1.23), 1.30 (95% CI 1.21, 1.39) and 1.21 (95% CI 1.17, 1.24), respectively (all P < 0.001). These ORs remained significant after further adjustment for BMI (Model 2) in psoriasis [OR 1.19 (95% CI 1.12, 1.27), P < 0.001] and RA [OR 1.19 (95% CI 1.12, 1.26), P < 0.001], but not in PsA [OR 1.11 (95% CI 0.95, 1.29), P = 0.127]. CONCLUSION: Central adiposity as measured by waist circumference is associated with greater odds of psoriasis and RA prevalence after adjustment for confounders and for BMI. Our findings add support for central adiposity as a long-term clinically relevant component of these conditions.

Association of Total and Differential Leukocyte Counts With Cardiovascular Disease and Mortality in the UK Biobank.

OBJECTIVE: Elevated white blood cell count is associated with a higher risk of cardiovascular disease (CVD). We aimed to investigate whether specific leukocyte subpopulations, which may more closely indicate a specific inflammatory pathway, are specifically associated with CVD. APPROACH AND RESULTS: Participants (478 259) from UK Biobank with data for white blood cell count were included. Death because of CVD (n=1377) and non-CVD causes (n=8987) occurred during median follow-up time of 7.0 years (interquartile range, 6.3-7.6). In Cox models, deciles of leukocyte counts (lymphocytes, monocytes, neutrophils, eosinophils, and basophils) were examined using the fifth decile as the referent group. Models were stratified by sex and adjusted for a range of classical risk factors. A sensitivity analysis excluded participants with baseline comorbidites and the first 2 years of follow-up. Men (hazard ratio [HR], 1.59; 95% confidence interval, 1.22-2.08) and women (HR, 2.15; 95% confidence interval, 1.38-3.35) in the highest decile of neutrophil count were at higher risk of CVD mortality and nonfatal CVD (men HR, 1.28; 95% confidence interval, 1.16-1.42 and women HR, 1.21; 95% confidence interval, 1.06-1.38). In the sensitivity analysis, the power to investigate CVD mortality was limited, but for both sexes combined, the linear HRs for a 1×109/L cell count increase in white blood cell count and neutrophils, respectively, was 1.05 (1.03-1.07) and 1.07 (1.04-1.11). CONCLUSIONS: Among circulating leukocyte subpopulations, neutrophil count in men was most consistently associated with fatal and nonfatal CVD. Further studies of interventions that lower circulating neutrophils, such as canakinumab, are required to investigate causality.

The association of grip strength with health outcomes does not differ if grip strength is used in absolute or relative terms: a prospective cohort study.

BACKGROUND: higher grip strength is associated with better health outcomes. The optimal way to report grip strength (i.e. absolute vs. relative) for prediction, however, remains to be established. METHODS: in participants (aged 37-73 at baseline) from the UK Biobank, we examined the associations of grip strength, expressed in absolute terms (kilograms) and relative to anthropometric variables, with mortality and disease incidence, after exclusion of the first 2 years of follow-up, and compared risk predictions scores of handgrip strength when differentially expressed. RESULTS: of the 356 721 participants included in the analysis 6,234 died (1.7%) and 4,523 developed CVD (1.3%) over a mean follow-up of 5.0 years (ranging from 3.3 to 7.8) for mortality and 4.1 years (ranging from 2.4 to 7.0) for disease incidence data. As expected, baseline higher grip strength was associated with lower risk of all-cause and cause specific mortality and incidence. These associations did not meaningfully differ when grip-strength was expressed in absolute terms, vs. relative to height, weight, fat-free mass, BMI, fat-free mass index and fat-free mass, or as z-scores. Similarly the different ways of expressing grip strength had little effect on the ability of grip strength to improve risk prediction, based on C-index change, of an office-based risk score. CONCLUSIONS: the ability of grip strength to predict mortality is not altered by changing how it is expressed.

Dose-response associations of cardiorespiratory fitness with all-cause mortality and incidence and mortality of cancer and cardiovascular and respiratory diseases: the UK Biobank cohort study.

OBJECTIVE: To investigate the association of cardiorespiratory fitness with all-cause mortality, and cardiovascular disease (CVD), respiratory disease, chronic obstructive pulmonary disease (COPD) and cancer mortality and incidence. DESIGN: Prospective population-based study. SETTING: UK Biobank. PARTICIPANTS: Of the 5 02 628 (5.5% response rate) participants recruited by UK Biobank, we included 73 259 (14.6%) participants with available data in this analysis. Of these, 1374 participants died and 4210 developed circulatory diseases, 1293 respiratory diseases and 4281 cancer, over a median of 5.0 years (IQR 4.3-5.7) follow-up. MAIN OUTCOME MEASURES: All-cause mortality and circulatory disease, respiratory disease, COPD and cancer (such as colorectal, lung, breast and prostate) mortality/incidence. Fitness was estimated using a submaximal cycle ergometer test. RESULTS: The HR for all-cause mortality for each metabolic equivalent of task (MET) higher fitness was 0.96 (95% CI 0.93 to 0.98). Similar results were observed for incident circulatory disease (HR 0.96 [0.95 to 0.97]), respiratory disease (HR 0.96 [0.94 to 0.98]), COPD (HR 0.90 [0.86 to 0.95) and colorectal cancer (HR 0.96 [0.92 to 1.00]). Nonlinear analysis revealed that a high level of fitness (>10METs) was associated with a greater incidence of atrial fibrillation (HR 1.24 [1.07 to 1.44]) and prostate cancer (HR 1.16 [1.02 to 1.32]) compared with average fitness. All results were adjusted for sociodemographic, lifestyle and dietary factors, body composition, and morbidity at baseline and excluded events in the first 2 years of follow-up. CONCLUSIONS: Higher cardiorespiratory fitness was associated with lower risk of premature mortality and incidence of CVD, respiratory disease and colorectal cancer.

The impact of confounding on the associations of different adiposity measures with the incidence of cardiovascular disease: a cohort study of 296 535 adults of white European descent.

Aims: The data regarding the associations of body mass index (BMI) with cardiovascular (CVD) risk, especially for those at the low categories of BMI, are conflicting. The aim of our study was to examine the associations of body composition (assessed by five different measures) with incident CVD outcomes in healthy individuals. Methods and results: A total of 296 535 participants (57.8% women) of white European descent without CVD at baseline from the UK biobank were included. Exposures were five different measures of adiposity. Fatal and non-fatal CVD events were the primary outcome. Low BMI (≤18.5 kg m-2) was associated with higher incidence of CVD and the lowest CVD risk was exhibited at BMI of 22-23 kg m-2 beyond, which the risk of CVD increased. This J-shaped association attenuated substantially in subgroup analyses, when we excluded participants with comorbidities. In contrast, the associations for the remaining adiposity measures were more linear; 1 SD increase in waist circumference was associated with a hazard ratio of 1.16 [95% confidence interval (CI) 1.13-1.19] for women and 1.10 (95% CI 1.08-1.13) for men with similar magnitude of associations for 1 SD increase in waist-to-hip ratio, waist-to-height ratio, and percentage body fat mass. Conclusion: Increasing adiposity has a detrimental association with CVD health in middle-aged men and women. The association of BMI with CVD appears more susceptible to confounding due to pre-existing comorbidities when compared with other adiposity measures. Any public misconception of a potential 'protective' effect of fat on CVD risk should be challenged. Take home figureThe obesity paradox is mainly due to the effect of confounding on BMI and disappears on other adiposity measures.

Associations of Dietary Protein Intake With Fat-Free Mass and Grip Strength: A Cross-Sectional Study in 146,816 UK Biobank Participants.

Adequate dietary protein intake is important for the maintenance of fat-free mass (FFM) and muscle strength, but optimal requirements remain unknown. Our aim in the current study was to explore the associations of protein intake with FFM and grip strength. We used baseline data from the UK Biobank (a study of 146,816 participants aged 40-69 years with data collected across the United Kingdom in 2007-2010) to examine the associations of protein intake with FFM and grip strength. Protein intake was positively associated with FFM (men: 5.1% (95% confidence interval (CI): 5.0, 5.2); women: 7.7% (95% CI: 7.7, 7.8)) and grip strength (men: 0.076 kg/kg (95% CI: 0.074, 0.078); women: 0.074 kg/kg (95% CI: 0.073, 0.076)) per 0.5-g/kg/day (grams per kg of body mass per day) increment in protein intake. FFM and grip strength were higher with higher intakes across the full range of intakes (i.e., highest in persons who reported consuming ≥2.00 g/kg/day) independently of sociodemographic factors, other dietary measures, physical activity, and comorbidity. FFM and grip strength were lower with age, but this association did not differ by category of protein intake (P > 0.05). The current recommendation for all adults (ages 40-69 years) to maintain a protein intake of 0.8 g/kg/day may need to be increased to optimize FFM and grip strength.