Prospective associations between diet quality, dietary components, and risk of cardiometabolic multimorbidity in older British men.

PURPOSE: Cardiometabolic multimorbidity (CMM) is a major public health challenge. This study investigated the prospective relationships between diet quality, dietary components, and risk of CMM in older British men. METHODS: We used data from the British Regional Heart Study of 2873 men aged 60-79 free of myocardial infarction (MI), stroke, and type 2 diabetes (T2D) at baseline. CMM was defined as the coexistence of two or more cardiometabolic diseases, including MI, stroke, and T2D. Sourcing baseline food frequency questionnaire, the Elderly Dietary Index (EDI), which was a diet quality score based on Mediterranean diet and MyPyramid for Older Adults, was generated. Cox proportional hazards regression and multi-state model were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During a median follow-up of 19.3 years, 891 participants developed first cardiometabolic disease (FCMD), and 109 developed CMM. Cox regression analyses found no significant association between baseline EDI and risk of CMM. However, fish/seafood consumption, a dietary component of the EDI score, was inversely associated with risk of CMM, with HR 0.44 (95% CI 0.26, 0.73) for consuming fish/seafood 1-2 days/week compared to less than 1 day/week after adjustment. Further analyses with multi-state model showed that fish/seafood consumption played a protective role in the transition from FCMD to CMM. CONCLUSIONS: Our study did not find a significant association of baseline EDI with CMM but showed that consuming more fish/seafood per week was associated with a lower risk of transition from FCMD to CMM in older British men.

Haematological variables and risk of future venous thromboembolism in the British Regional Heart Study on men. Combined D-dimer and APTT as a predictive test for thromboembolism?

We examined the associations between haematological and inflammatory variables with future venous thromboembolism (VTE), in 3494 men aged 60-79 years, with no previous history of VTE or myocardial infarction, who were not receiving oral anticoagulants. After a mean follow-up period of 18 years, there were 149 confirmed cases of fatal or non-fatal VTE (deep vein thrombosis and/or pulmonary embolism). Among classical cardiovascular risk factors, only obesity and cigarette smoking were associated with VTE risk. After adjustment for age, obesity and smoking, VTE risk was associated with coagulation factor VIII, factor IX, von Willebrand factor (VWF), activated partial thromboplastin time (APTT), and fibrin D-dimer. Hazard ratios (95% CI) for top to bottom quarters (bottom to top for APTT), were respectively 2.17 (1.37, 3.44), 2.15 (1.30, 3.53), 2.02 (1.27, 3.22), 2.43 (1.47, 4.02) and 3.62 (2.18, 6.08). The 11% of men with both the shortest APTT and highest D-dimer combined had a 5.02 (2.37, 10.62) higher risk of VTE. VTE risk was not associated with fibrinogen, factor VII or activated protein C resistance; full blood count variables or with inflammatory markers, plasma viscosity, C-reactive protein or interleukin-6. The combination of D-dimer and APTT merits evaluation as an adjunct to VTE risk prediction scores.

Associations between inflammation, coagulation, cardiac strain and injury, and subclinical vascular disease with frailty in older men: a cross-sectional study.

BACKGROUND: Inflammation, coagulation activation, endothelial dysfunction and subclinical vascular disease are cross-sectionally associated with frailty. Cardiac-specific biomarkers are less-well characterised. We assessed associations between these and frailty, in men with, and without, cardiovascular disease (CVD). METHODS: Cross-sectional analysis of 1096 men without, and 303 with, CVD, aged 71-92, from the British Regional Heart Study. Multinominal logistic regression was performed to examine the associations between frailty status (robust/pre-frail/frail) and, separately, C-reactive protein (CRP), interleukin-6 (IL-6), tissue plasminogen activator (tPA), D-dimer, von Willebrand factor (vWF), high-sensitivity cardiac troponin-T (hs-cTnT), N-terminal pro B-type natriuretic peptide (NT-proBNP) (all natural log-transformed), and, in men without CVD, carotid intima-media thickness (CIMT), carotid-femoral pulse wave velocity (cfPWV), carotid distensibility coefficient (DC), and ankle-brachial pressure index (ABPI), adjusted for age, renal function, BMI, social class, smoking, polypharmacy, cognition, multimorbidity and systolic blood pressure. Explanatory variables with p < 0.05 were carried forward into mutually-adjusted analysis. RESULTS: In men without CVD, higher CRP, IL-6, vWF, tPA, hs-cTnT, NT-proBNP, cfPWV, and lower DC were significantly associated with frailty; mutually-adjusted, log IL-6 (OR for frailty = 2.02, 95%CI 1.38-2.95), log hs-cTnT (OR = 1.95, 95%CI 1.24-3.05) and DC (OR = 0.92, 95%CI 0.86-0.99) retained associations. In men with CVD, higher CRP, IL-6, and hs-cTnT, but not vWF, tPA, NT-proBNP or D-dimer, were significantly associated with frailty; mutually-adjusted, log hs-cTnT (OR 3.82, 95%CI 1.84-7.95) retained a significant association. CONCLUSIONS: In older men, biomarkers of myocardial injury are associated with frailty. Inflammation is associated with frailty in men without CVD. Carotid artery stiffness is associated with frailty in men without CVD, independently of these biomarkers.

Poor oral health and the association with diet quality and intake in older people in two studies in the UK and USA.

We aimed to investigate the associations of poor oral health cross-sectionally with diet quality and intake in older people. We also examined whether change in diet quality is associated with oral health problems. Data from the British Regional Heart Study (BRHS) comprising British males aged 71-92 years and the Health, Aging and Body Composition (HABC) Study comprising American males and females aged 71-80 years were used. Dental data included tooth loss, periodontal disease, dry mouth and self-rated oral health. Dietary data included diet quality (based on Elderly Dietary Index (BRHS) and Healthy Eating Score (HABC Study)) and several nutrients. In the BRHS, change in diet quality over 10 years (1998-2000 to 2010-2012) was also assessed. In the BRHS, tooth loss, fair/poor self-rated oral health and accumulation of oral health problems were associated with poor diet quality, after adjustment. Similar associations were reported for high intake of processed meat. Poor oral health was associated with the top quartile of percentage of energy content from saturated fat (self-rated oral health, OR 1·34, 95 % CI 1·02, 1·77). In the HABC Study, no significant associations were observed for diet quality after adjustment. Periodontal disease was associated with the top quartile of percentage of energy content from saturated fat (OR 1·48, 95 % CI 1·09, 2·01). In the BRHS, persistent low diet quality was associated with higher risk of tooth loss and accumulation of oral health problems. Older individuals with oral health problems had poorer diets and consumed fewer nutrient-rich foods. Persistent poor diet quality was associated with oral health problems later in life.

Vitamin D deficiency is associated with orthostatic hypotension in older men: a cross-sectional analysis from the British Regional Heart Study.

BACKGROUND: orthostatic hypotension (OH) that occurs within, or at, 1 minute of standing is associated with higher risk of falls, myocardial infarction, syncope and mortality, compared to OH that occurs after 1 minute of standing. Whether vitamin D deficiency increases the risk of OH is controversial. METHODS: this was a cross-sectional analysis of 3,620 older, community-dwelling men. Multinomial, multiple logistic regression models were used to calculate the risk of OH across categories of vitamin D status (deficient [<25 nmol/l], insufficient [≥25-<50 nmol/l] and sufficient [≥50 nmol/l]) and parathyroid hormone quintile. RESULTS: men with vitamin D deficiency were more likely to have OH that occurred within 1 minute of standing in univariate logistic regression (OR 1.88, 95% CI 1.40-2.53) and multinomial, multiple logistic regression (OR 1.51, 95% CI 1.06-2.15), compared to men with sufficient levels of vitamin D. Vitamin D insufficiency was not associated with the risk of OH. Elevated parathyroid hormone was not associated with risk of OH. CONCLUSION: the absence of an association between vitamin D insufficiency and risk of OH and the presence of an association between vitamin D deficiency and risk of OH suggest that there may be a threshold effect; it is only below a particular level of vitamin D that risk of OH is increased. In this cohort, the threshold was <25 nmol/l. Future work should investigate whether treating vitamin D deficiency can improve postural blood pressure or if preventing vitamin D deficiency reduces the incidence of OH.

Associations between inflammation, cardiovascular biomarkers and incident frailty: the British Regional Heart Study.

INTRODUCTION: cardiovascular disease (CVD) and chronic inflammation are implicated in the development of frailty. Longitudinal analyses of inflammatory markers, biomarkers of cardiac dysfunction and incidence of frailty are limited. METHODS: in the British Regional Heart Study, 1,225 robust or pre-frail men aged 71-92 years underwent a baseline examination, with questionnaire-based frailty assessment after 3 years. Frailty definitions were based on the Fried phenotype. Associations between incident frailty and biomarkers of cardiac dysfunction (high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro B-type natriuretic peptide (NT-proBNP)) and inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6)) were examined, by tertile, with the lowest as reference. RESULTS: follow-up data were available for 981 men. Ninety one became frail. Adjusted for age, pre-frailty, prevalent and incident CVD, comorbidity, polypharmacy and socioeconomic status, IL-6 (third tertile OR 2.36, 95% CI 1.07-5.17) and hs-cTnT (third tertile OR 2.24, 95% CI 1.03-4.90) were associated with increased odds of frailty. CRP (third tertile OR 1.83, 95% CI 0.97-4.08) and NT-proBNP (second tertile OR 0.48, 95% CI 0.23-1.01) showed no significant association with incident frailty. The top tertiles of CRP, IL-6, hscTnT and NT-proBNP were strongly associated with mortality prior to follow-up. CONCLUSION: IL-6 is associated with incident frailty, supporting the prevailing argument that inflammation is involved in the pathogenesis of frailty. Cardiomyocyte injury may be associated with frailty risk. Associations between elevated CRP and frailty cannot be fully discounted; NT-proBNP may have a non-linear relationship with incident frailty. CRP, IL-6, hs-cTnT and NT-proBNP are vulnerable to survivorship bias.

Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research.

Healthier diet quality and dietary patterns are associated with lower risk of mobility limitation in older men.

PURPOSE: To investigate associations between diet quality, dietary patterns and mobility limitation 15 years later in a population-based sample of older British men. METHODS: We used longitudinal data from 1234 men from the British Regional Heart Study, mean age 66 years at baseline. Mobility limitation was defined as difficulty going up- or downstairs or walking 400 yards as a result of a long-term health problem. Dietary intake was measured using a food frequency questionnaire data from which the Healthy Diet Indicator (HDI), the Elderly Dietary Index (EDI), and three a posteriori dietary patterns were derived. The a posteriori dietary patterns were identified using principal components analysis: (1) high fat/low fibre, (2) prudent and (3) high sugar. RESULTS: Men with greater adherence to the EDI or HDI were less likely to have mobility limitation at follow-up, top vs bottom category odds ratio for the EDI OR 0.50, 95% CI 0.34, 0.75, and for the HDI OR 0.55, 95% CI 0.35, 0.85, after adjusting for age, social class, region of residence, smoking, alcohol consumption and energy intake. Men with a higher score for the high-fat/low-fibre pattern at baseline were more likely to have mobility limitation at follow-up, top vs bottom quartile odds ratio OR 3.28 95% CI 2.05, 5.24. These associations were little changed by adjusting for BMI and physical activity. CONCLUSION: Our study provides evidence that healthier eating patterns could contribute to prevention or delay of mobility limitation in older British men.

Physical frailty in older men: prospective associations with diet quality and patterns.

BACKGROUND: increasing numbers of older adults are living with frailty and its adverse consequences. We investigated relationships between diet quality or patterns and incident physical frailty in older British men and whether any associations were influenced by inflammation. METHODS: prospective study of 945 men from the British Regional Heart Study aged 70-92 years with no prevalent frailty. Incident frailty was assessed by questionnaire after 3 years of follow-up. Frailty was defined as having at least three of: low grip strength, low physical activity, slow walking speed, unintentional weight loss and feeling of low energy, all based on self-report. The Healthy Diet Indicator (HDI) based on WHO dietary guidelines and the Elderly Dietary Index (EDI) based on a Mediterranean-style dietary intake were computed from questionnaire data and three dietary patterns were identified using principal components analysis: prudent, high fat/low fibre and high sugar. RESULTS: men in the highest EDI category and those who followed a prudent diet were less likely to become frail [top vs bottom category odds ratio (OR) (95% CI) 0.49 (0.30, 0.82) and 0.53 (0.30, 0.92) respectively] after adjustment for potential confounders including BMI and prevalent cardiovascular disease. No significant association was seen for the HDI. By contrast those who had a high fat low fibre diet pattern were more likely to become frail [OR (95% CI) 2.54 (1.46, 4.40)]. These associations were not mediated by C-reactive protein (marker of inflammation). CONCLUSIONS: the findings suggest adherence to a Mediterranean-style diet is associated with reduced risk of developing frailty in older people.

Objectively measured physical activity, sedentary behaviour and all-cause mortality in older men: does volume of activity matter more than pattern of accumulation?

OBJECTIVES: To understand how device-measured sedentary behaviour and physical activity are related to all-cause mortality in older men, an age group with high levels of inactivity and sedentary behaviour. METHODS: Prospective population-based cohort study of men recruited from 24 UK General Practices in 1978-1980. In 2010-2012, 3137 surviving men were invited to a follow-up, 1655 (aged 71-92 years) agreed. Nurses measured height and weight, men completed health and demographic questionnaires and wore an ActiGraph GT3x accelerometer. All-cause mortality was collected through National Health Service central registers up to 1 June 2016. RESULTS: After median 5.0 years' follow-up, 194 deaths occurred in 1181 men without pre-existing cardiovascular disease. For each additional 30 min in sedentary behaviour, or light physical activity (LIPA), or 10 min in moderate to vigorous physical activity (MVPA), HRs for mortality were 1.17 (95% CI 1.10 to 1.25), 0.83 (95% CI 0.77 to 0.90) and 0.90 (95% CI 0.84 to 0.96), respectively. Adjustments for confounders did not meaningfully change estimates. Only LIPA remained significant on mutual adjustment for all intensities. The HR for accumulating 150 min MVPA/week in sporadic minutes (achieved by 66% of men) was 0.59 (95% CI 0.43 to 0.81) and 0.58 (95% CI 0.33 to 1.00) for accumulating 150 min MVPA/week in bouts lasting ≥10 min (achieved by 16% of men). Sedentary breaks were not associated with mortality. CONCLUSIONS: In older men, all activities (of light intensity upwards) were beneficial and accumulation of activity in bouts ≥10 min did not appear important beyond total volume of activity. Findings can inform physical activity guidelines for older adults.

Association Between 20-Year Trajectories of Nonoccupational Physical Activity From Midlife to Old Age and Biomarkers of Cardiovascular Disease: A 20-Year Longitudinal Study of British Men.

The trajectories of physical activity (PA) from midlife into old age and their associations with established and novel cardiovascular disease (CVD) risk factors in later life remain unclear. This study examined associations between 20-year nonoccupational PA trajectories and a range of CVD biomarkers at ages 60-79 years. We used data from a sample of 3,331 men (mean baseline age = 50.2 ± 5.8 years) recruited in 1978-1980, with follow-up after 12, 16, and 20 years, reporting habitual nonoccupational PA at each wave. At the 20-year follow-up, surviving men attended a physical examination and provided a fasting blood sample. Group-based trajectory modeling was used to identify trajectories. Adjusted regression analyses examined the association between trajectory-group membership and several cardiometabolic, cardiac, and inflammatory markers at follow-up. Three distinct 20-year trajectories were identified: low/decreasing (21.3%), light/stable (51.8%), and moderate/increasing (27.0%). Compared with the low/decreasing group, membership in the light/stable and moderate/increasing trajectory groups was associated with a more favorable cardiometabolic profile and lower levels of inflammation and endothelial dysfunction. Although following a moderate-increasing PA trajectory was most favorable, more modest but sustained doses of PA into old age may be sufficient to lower CVD risk.

Trajectories of self-reported physical activity and predictors during the transition to old age: a 20-year cohort study of British men.

BACKGROUND: Maintenance of physical activity (PA) during later life is associated with optimal health; however, the long-term trajectories of PA into old age and their predictors have not been extensively researched using latent class methods. This study aimed to identify trajectories of self-reported PA and their predictors in men transitioning from midlife to old age. METHODS: 7735 men (aged 40-59 years) recruited in 1978-80 were followed up after 12, 16 and 20 years, reporting PA, health status, lifestyle behaviours and socio-demographic characteristics. Group-based trajectory modelling identified the trajectories of PA and associations with time-stable and time-varying covariates. We considered a range of sociodemographic and health and lifestyle factors as potential covariates. RESULTS: 4952 men (mean baseline age 49.1 ± 5.6 years) providing PA data at ≥3 time points were included in analyses. Three distinct 20-year trajectories were identified: low decreasing (24.6%, n = 1218), light stable (51.1%, n = 2530) and moderate increasing (24.3%, n = 1204). Being older, having a manual occupation, having never married or had children, residing in the midlands or North of England, suffering from a range of health conditions, being a smoker/ex-smoker and never consuming breakfast cereal or alcohol were independently associated with reduced odds of belonging to the moderate increasing trajectory group compared to the low decreasing group. Of the time-varying covariates considered, leaving employment was associated with a decrease in PA in the low decreasing group (ß -0.306, p < 0.001) but an increase in the light stable (ß 0.324, p < 0.001) and moderate increasing groups (ß 0.847, p < 0.001). Developing cardiovascular-related conditions was associated with a decrease in PA in the low decreasing (ß -0.408, p < 0.001) and light stable groups (ß -0.118, p < 0.001) but no association was observed in the moderate increasing group (ß -0.060, p = 0.313). CONCLUSIONS: Three distinct trajectories of PA were identified in men transitioning from midlife to old age, of which nearly a quarter had persistently low levels of PA. Promotion efforts may need to focus attention prior to middle age and consider a number of sociodemographic, health and lifestyle factors to sustain PA into old age. The effects of retirement and development of cardiovascular disease may vary according to PA trajectories.

Socioeconomic disadvantage across the life-course and oral health in older age: findings from a longitudinal study of older British men.

Background: The influence of life-course socioeconomic disadvantage on oral health at older ages is not well-established. We examined the influence of socioeconomic factors in childhood, middle-age and older age on oral health at older ages, and tested conceptual life-course models (sensitive period, accumulation of risk, social mobility) to determine which best described observed associations. Methods: A representative cohort of British men aged 71-92 in 2010-12 included socioeconomic factors in childhood, middle-age and older age. Oral health assessment at 71-92 years (n = 1622) included tooth count, periodontal disease and self-rated oral health (excellent/good, fair/poor) (n = 2147). Life-course models (adjusted for age and town of residence) were compared with a saturated model using Likelihood-ratio tests. Results: Socioeconomic disadvantage in childhood, middle-age and older age was associated with complete tooth loss at 71-92 years-age and town adjusted odds ratios (95% CI) were 1.39 (1.02-1.90), 2.26 (1.70-3.01), 1.83 (1.35-2.49), respectively. Socioeconomic disadvantage in childhood and middle-age was associated with poor self-rated oral health; adjusted odds ratios (95% CI) were 1.48 (1.19-1.85) and 1.45 (1.18-1.78), respectively. A sensitive period for socioeconomic disadvantage in middle-age provided the best model fit for tooth loss, while accumulation of risk model was the strongest for poor self-rated oral health. None of the life-course models were significant for periodontal disease measures. Conclusion: Socioeconomic disadvantage in middle-age has a particularly strong influence on tooth loss in older age. Poor self-rated oral health in older age is influenced by socioeconomic disadvantage across the life-course. Addressing socioeconomic factors in middle and older ages are likely to be important for better oral health in later life.

Objectively measured physical activity and kidney function in older men; a cross-sectional population-based study.

Background: kidney function declines in older adults and physical activity levels are low. We investigated whether higher levels of physical activity and lower levels of sedentary behaviour were associated with lower odds of low kidney function in older men. Methods: cross-sectional study of 1,352 men from the British Regional Heart Study, mean (standard deviation) age 78.5 (4.6) year. Physical activity and sedentary behaviour were measured using Actigraph GT3X accelerometers. Kidney function was measured by estimated Glomerular filtration rate (eGFR) using the chronic kidney disease-EPI creatinine-cystatin equation. Associations between physical (in)activity and kidney function were investigated using regression models. Results: higher levels of physical activity and lower levels of sedentary behaviour were associated with reduced odds ratios (ORs) for lower eGFR (<45 versus ≥45 ml/min per 1.73 m2) after adjustment for covariates. Each additional 1,000 steps, 30 min of light physical activity and 10 min of moderate/vigorous physical activity per day were associated with a lower odds (95% confidence interval (CI)) of a low eGFR; OR 0.81 (0.73, 0.91), OR 0.87 (0.78, 0.97) and OR 0.84 (0.76, 0.92), respectively. Each additional 30 min of sedentary behaviour per day was associated with a higher odds of a low eGFR (1.16 95% CI 1.06, 1.27). Associations between moderate/vigorous physical activity and lower kidney function persisted after adjustment for light physical activity or sedentary behaviour. Conclusion: physical activity is associated with kidney function in older men and could be of public health importance in this group who are at increased risk of poor kidney function and low physical activity. More evidence is needed on whether the association is causal.

Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers.

We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00 × 10(-10)), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38 × 10(-5)). An interaction test confirmed that these estimates differed from each other (P = 4.95 × 10(-13)). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.

Copeptin and the risk of incident stroke, CHD and cardiovascular mortality in older men with and without diabetes: The British Regional Heart Study.

AIMS/HYPOTHESIS: This study aimed to examine the association between copeptin (a surrogate marker of arginine vasopressin) and incident stroke, CHD and cardiovascular mortality in older men with and without diabetes. METHODS: We conducted a prospective study of 3536 men aged 60-79 years who were followed for an average of 13 years. During this period, there were 437 major CHD events (fatal and non-fatal myocardial infarction [MI]), 323 stroke events (fatal and non-fatal) and 497 cardiovascular disease (CVD) deaths. Prevalent diabetes was defined on the basis of a history of doctor-diagnosed diabetes or fasting blood glucose ≥7.0 mmol or HbA1c ≥6.5% (48 mmol/mol) (n = 428). RESULTS: No association was seen between copeptin and incident stroke or CVD mortality in men without diabetes after adjustment for conventional cardiovascular risk factors, renal dysfunction, and insulin and N-terminal pro B-type natriuretic peptide levels. In contrast, elevated copeptin levels were associated with an increased risk of stroke and CVD mortality in men with diabetes after these adjustments. Compared with those in the lowest tertile of copeptin, men in the top tertile had adjusted relative HRs for stroke and CVD death of 2.34 (95% CI 1.04, 5.27) and 2.21 (1.12, 4.36), respectively. The risk of stroke and CVD mortality remained increased after the exclusion of men with prevalent stroke or MI. Higher levels of copeptin were associated with increased risk of CHD in the diabetic and non-diabetic groups, but these associations were attenuated after exclusion of individuals with a previous stroke or MI. CONCLUSIONS/INTERPRETATION: Copeptin was independently associated with an increased risk of incident stroke and CVD mortality in men with diabetes, but not in men without diabetes. Targeting the arginine vasopressin system might have beneficial effects on CVD mortality and stroke risk in older men with diabetes.

Lung function and airway obstruction: associations with circulating markers of cardiac function and incident heart failure in older men-the British Regional Heart Study.

AIMS: The association between lung function and cardiac markers and heart failure (HF) has been little studied in the general older population. We have examined the association between lung function and airway obstruction with cardiac markers N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT) and risk of incident HF in older men. METHODS AND RESULTS: Prospective study of 3242 men aged 60-79 years without prevalent HF or myocardial infarction followed up for an average period of 13 years, in whom 211 incident HF cases occurred. Incident HF was examined in relation to % predicted FEV1 and FVC. The Global Initiative on Obstructive Lung Diseases spirometry criteria were used to define airway obstruction. Reduced FEV1, but not FVC in the normal range, was significantly associated with increased risk of HF after adjustment for established HF risk factors including inflammation. The adjusted HRs comparing men in the 6-24th percentile with the highest quartile were 1.91 (1.24 to 2.94) and 1.30 (0.86 to 1.96) for FEV1 and FVC, respectively. FEV1 and FVC were inversely associated with NT-proBNP and cTnT, although the association between FEV1 and incident HF remained after adjustment for NT-proBNP and cTnT. Compared with normal subjects (FEV1/FVC ≥0.70 and FVC≥80%), moderate or severe (FEV1/FVC <0.70 and FEV1 <80%) airflow obstruction was independently associated with HF ((adjusted relative risk 1.59 (1.08 to 2.33)). Airflow restriction (FEV1/FVC ≥0.70 and FVC <80%) was not independently associated with HF. CONCLUSIONS: Reduced FEV1 reflecting airflow obstruction is associated with cardiac dysfunction and increased risk of incident HF in older men.

Variant rs10911021 that associates with coronary heart disease in type 2 diabetes, is associated with lower concentrations of circulating HDL cholesterol and large HDL particles but not with amino acids.

AIMS: An intergenic locus on chromosome 1 (lead SNP rs10911021) was previously associated with coronary heart disease (CHD) in type 2 diabetes (T2D). Using data from the UCLEB consortium we investigated the relationship between rs10911021 and CHD in T2D, whether rs10911021 was associated with levels of amino acids involved in the γ-glutamyl cycle or any conventional risk factors (CRFs) for CHD in the T2D participants. METHODS: Four UCLEB studies (n = 6531) had rs10911021 imputation, CHD in T2D, CRF and metabolomics data determined using a nuclear magnetic resonance based platform. RESULTS: The expected direction of effect between rs10911021 and CHD in T2D was observed (1377 no CHD/160 CHD; minor allele OR 0.80, 95 % CI 0.60-1.06) although this was not statistically significant (p = 0.13). No association between rs10911021 and CHD was seen in non-T2D participants (11218 no CHD/1274 CHD; minor allele OR 1.00 95 % CIs 0.92-1.10). In T2D participants, while no associations were observed between rs10911021 and the nine amino acids measured, rs10911021 was associated with HDL-cholesterol (p = 0.0005) but the minor "protective" allele was associated with lower levels (-0.034 mmol/l per allele). Focusing more closely on the HDL-cholesterol subclasses measured, we observed that rs10911021 was associated with six large HDL particle measures in T2D (all p < 0.001). No significant associations were seen in non-T2D subjects. CONCLUSIONS: Our findings are consistent with a true association between rs10911021 and CHD in T2D. The protective minor allele was associated with lower HDL-cholesterol and reductions in HDL particle traits. Our results indicate a complex relationship between rs10911021 and CHD in T2D.

Validity of questionnaire-based assessment of sedentary behaviour and physical activity in a population-based cohort of older men; comparisons with objectively measured physical activity data.

BACKGROUND: Older adults are the most inactive age group and self-reporting of activities may be complicated by age-related reductions in structured activities and misclassification or recall biases. We investigate the validity of simple questionnaires about sedentary behaviour (SB), (including the widely used proxy television (TV) viewing), and physical activity (PA) in comparison with objective measures. METHODS: Community dwelling men aged 71-93 years, from a UK population-based cohort wore a GT3X accelerometer over the right hip for 7 days and self-completed a questionnaire including information about SB (TV, reading, computer use and car use) and PA (leisure and sporting domains). RESULTS: 1566/3137 surviving men (mean age 79 years) attended. 1377 ambulatory men provided questionnaire and accelerometer data. Questionnaires under-estimated mean daily sedentary time; 317 minutes total SB (TV, computer use, reading or driving), 176 minutes (TV) vs 619 minutes (objectively measured). Correlations between objective measures and self-reports were 0.18 (total SB) and 0.17 (TV), both P < 0.001. Objective SB levels were similar across the lowest three quartiles of self-reported SB but raised in the highest quartile. Correlations between steps/day or moderate to vigorous PA with self-reported total PA were both 0.49, P < 0.001 and measured PA levels were progressively higher at higher levels of self-reported PA. CONCLUSIONS: Among older men, simple SB questions performed poorly for identifying total SB time, although simple PA questions were associated with a graded increase with objectively measured PA. Future studies of health effects of SB in older men would benefit from objective measures of SB.