HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.

BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target. METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis. FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials). INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition. FUNDING: The funding sources are cited at the end of the paper.

Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12.

BACKGROUND: Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants. OBJECTIVE: To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation. METHODS: 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10(-5)) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays. RESULTS: Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10(-6), preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10(-6)). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10(-6)). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10(-7)). CONCLUSIONS: This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.

Adherence to physical activity guidelines in older adults, using objectively measured physical activity in a population-based study.

BACKGROUND: Physical activity (PA) levels in older adults decline with age. The prevalence and correlates of adherence to current UK PA guidelines in older adults has not been studied using objectively measured PA, which can examine precisely whether PA is carried out in bouts of specified length and intensity. METHODS: Free living men and women aged 70-93 years from 25 towns in the United Kingdom, participating in parallel on-going population based cohort studies were invited (by post) to wear a GT3x accelerometer over the hip for one week in 2010-12. Adherence to UK PA guidelines was defined as ≥150 minutes/week of moderate or vigorous PA (MVPA) in bouts of ≥10 minutes; the effect of different intensities and durations were examined. RESULTS: 1593 men and 857 women participated (responses 51% and 29% respectively). 15% men and 10% women achieved ≥150 minutes/week of MVPA (defined as >1040 cpm) in bouts lasting ≥10 minutes. With MVPA defined as >1952 cpm, prevalences were 7% and 3% respectively. Those adhering to guidelines were younger, had fewer chronic health conditions, less depression, less severe mobility limitations, but higher exercise self-efficacy and exercise outcomes expectations. They rated their local environment more highly for social activities and leisure facilities, having somewhere nice to go for a walk and feeling safe after dark, They left the house on more days per week, were more likely to use active transport (cycle or walk) and to walk a dog regularly. CONCLUSIONS: Few older adults attain current PA guidelines. Health promotion to extend the duration of moderate-intensity activity episodes to 10 minutes or more could yield important health gains among older adults. However future studies will need to clarify whether attaining guideline amounts of PA in spells lasting 10 minutes or more is critical for reducing chronic disease risks as well as improving cardiometabolic risk factors.

Predictors of patterns of change in health-related quality of life in older women over 7 years: evidence from a prospective cohort study.

BACKGROUND: the evaluation of the determinants of change over time in health-related quality of life (HR-QoL) in older people is limited. This study aims to identify patterns of change in HR-QoL over 7 years and their determinants using data from the British Women's Heart and Health Study, a representative sample of older women (n = 4286). METHODS: longitudinal latent class analysis was used to identify subpopulations of women with similar HR-QoL trajectories from 1999-2000 to 2007. HR-QoL was measured using the EQ-5D. Multivariate multinomial logistic regression was used to model the association of identified trajectories with baseline predictors after multiple imputation of missing data. RESULTS: four distinct EQ-5D trajectories were suggested: high (19% of women), high decline (22%), intermediate (42%) and low decline (16%). Prevalent arthritis (OR = 13.4; 95% CI: 8.8, 20.5), diabetes (OR = 4.6; 95% CI: 1.5, 14.2) and obesity (OR = 3.9; 95% CI: 2.5, 6.0) were the strongest predicting health conditions of adverse changes in HR-QoL and physical activity the strongest predicting lifestyle factor (OR = 2.8; 95% CI: 2.0, 3.9). CONCLUSIONS: findings suggest that older women without obesity or pre-existing health conditions who undertake more physical activity are more likely to experience high HR-QoL, reinforcing the importance of these factors for healthy ageing.

Effect of changes in moderate or vigorous physical activity on changes in health-related quality of life of elderly British women over seven years.

PURPOSE: This study investigates the effect of changes in moderate or vigorous physical activity (MVPA) on trajectories in health-related quality of life (HR-QoL) over 7 years in British elderly women. METHODS: A total of 1,926 women from the British Women's Heart and Health Study with information on MVPA and HR-QoL [measured using Euro quality of life 5 dimension (EQ-5D)] at baseline and at 7 years of follow-up were included in the analysis. Baseline and 7-year follow-up MVPA values were categorised into 3 groups, generating 9 categories of change in MVPA. Logistic regression was used to obtain odds ratios (ORs) of maintaining or improving HR-QoL according to different patterns of change in MVPA level. RESULTS: Women who remained inactive over the 7 years of follow-up had the largest reduction in their EQ-5D scores. Compared to these women, women that increased their MPVA level from "inactive" to "low" or to "moderate-high" were more likely to maintain or improve their HR-QoL over 7 years (ORs 1.65 or 2.70, respectively, p value for trend <0.001). After adjustment for baseline EQ-5D score and a wide range of potential confounders, results remained largely unchanged, though precision of the estimates generally decreased. CONCLUSIONS: Our findings suggest that relatively regular MVPA, even taken up later in life, can help older women prevent a decline in HR-QoL and even improve their enjoyment of life.

Inflammation, coagulation and risk of locomotor disability in elderly women: findings from the British Women's Heart and Health Study.

This study investigated associations between chronic inflammation and coagulation and incident locomotor disability using prospective data from the British Women's Heart and Health Study. Locomotor disability was assessed using self-reported questionnaires in 1999/2000, and 3 and 7 years later. Scores for inflammation and coagulation were obtained from summation of quartile categories of all available biomarkers from blood samples taken at baseline. 534 women developed locomotor disability after 3 years, 260 women after 7 years, while 871 women remained free of locomotor disability over the whole study period. After adjustment for demographic characteristics, lifestyle factors and health conditions, we found associations between inflammation and incident locomotor disability after three (OR per unit increase in score = 1.08, 95 % confidence interval (CI): 1.03, 1.13) and 7 years (OR = 1.10, 95 % CI: 1.03, 1.18) and between coagulation and incident locomotor disability after 3 (OR = 1.06, 95 % CI: 0.98, 1.14) and 7 years (OR = 1.09, 95 % CI: 1.00, 1.18). This corresponds to ORs between 1.8 and 2.4 comparing women with highest to lowest inflammation or coagulation scores. These results support the role of inflammation and coagulation in the development of locomotor disability in elderly women irrespective of their lifestyle factors and underlying age-related chronic diseases.

The association between graded physical activity in postmenopausal British women, and the prevalence and incidence of hip and wrist fractures.

BACKGROUND: physical activity is promoted for older women as a means of maintaining health and avoiding falls and fractures. Findings relating physical activity of older women to risk of falls and fracture are contradictory. The association between level of physical activity and prevalent and incident hip and wrist fractures was examined in a large representative sample of postmenopausal British women. METHODS: data from the British Women's Heart and Health Study, a cohort study of 4286 postmenopausal women aged 60-79, from 23 UK towns were used. Information on physical activity, anthropometry, falls and hip and wrist fractures from baseline examination and questionnaire (1999-2001) and follow-up questionnaire (2007) were available. Cross-sectional baseline prevalence data were analysed using logistic regression and cohort incidence data using a Cox proportional hazards model examining the association of physical activity with fracture outcomes. RESULTS: 3003 (70%) women, with complete baseline data, were studied. 13.6% had previously fractured a wrist and 1.3% a hip. Analyses unadjusted for confounders showed moderate protective associations between activity and fracture risk. After adjustment for confounders there was a weak trend towards fewer hip fractures (adjusted OR 0.13 [0.01, 1.18]) and more wrist fractures (adjusted OR 1.35 [0.76, 2.48]), amongst most active compared with inactive women. The crude incidence rate of wrist and/or hip fracture was 7.0 [5.9, 8.2] per 1000 person-years. No evidence was found for an association between physical activity and combined incident hip and/or wrist fracture (adjusted rate ratio inactive versus most active 1.69 [0.67, 4.24]). CONCLUSION: no clear associations between graded physical activity and hip/wrist fractures were seen but estimates were imprecise. Physical activities are heterogeneous and individual fracture types and mechanisms differ. Very large prospective observational studies are required to disentangle the precise effects of different activity patterns on different fracture types.

Influence of area and individual lifecourse deprivation on health behaviours: findings from the British Women's Heart and Health Study.

BACKGROUND: Variable findings have been reported on the contribution of census-based measures of area deprivation over and above that of individual socioeconomic position (SEP) on health outcomes. This study aims to examine the association between residence in a deprived area and health behaviours (diet, smoking and physical inactivity), and how this association is influenced by lifecourse SEP of individuals. DESIGN: A population-based longitudinal study of women aged 60-79 years in 1999-2001 recruited from one general practice in each of 23 British towns. METHODS: Three thousand five hundred twenty-two women were included in the analyses. Area deprivation scores were derived from postcode for residence and lifecourse SEP scores were calculated using 10 individual level indicators of childhood and adult circumstances. To allow direct comparisons of effect of area deprivation and individual SEP, we standardized both measures by generating relative indices of inequality. RESULTS: Both area deprivation and lifecourse SEP were independent predictors of eating fruit and vegetables [odds ratio (OR): 2.87, 95% confidence interval (CI): 2.22-3.72; comparing highest with lowest area Index of Multiple Deprivation of inequality (OR: 3.07, 95% CI: 2.33-4.06) for lifecourse SEP index of inequality] and exercise habits (OR: 2.39, 95% CI: 1.86-3.06 area deprivation; OR: 2.7, 95% CI: 2.07-3.51 individual SEP). Area deprivation was a stronger predictor of smoking behaviour (OR: 2.34, 95% CI: 1.91-3.08) than individual lifecourse SEP (OR: 1.51, 95% CI: 1.17-1.95). CONCLUSION: Most health behaviours among older women were independently associated with both living in deprived areas and individual lifecourse SEP. This suggests that additional health promotion approaches focusing on improving environments would have potential to improve health behaviour.

Investigating associations between the built environment and physical activity among older people in 20 UK towns.

BACKGROUND: Policy initiatives such as WHO Age Friendly Cities recognise the importance of the urban environment for improving health of older people, who have both low physical activity (PA) levels and greater dependence on local neighbourhoods. Previous research in this age group is limited and rarely uses objective measures of either PA or the environment. METHODS: We investigated the association between objectively measured PA (Actigraph GT3x accelerometers) and multiple dimensions of the built environment, using a cross-sectional multilevel linear regression analysis. Exposures were captured by a novel foot-based audit tool that recorded fine-detail neighbourhood features relevant to PA in older adults, and routine data. RESULTS: 795 men and 638 women aged 69-92 years from two national cohorts, covering 20 British towns, were included in the analysis. Median time in moderate to vigorous PA (MVPA) was 27.9 (lower quartile: 13.8, upper quartile: 50.4) minutes per day. There was little evidence of associations between any of the physical environmental domains (eg, road and path quality defined by latent class analysis; number of bus stops; area aesthetics; density of shops and services; amount of green space) and MVPA. However, analysis of area-level income deprivation suggests that the social environment may be associated with PA in this age group. CONCLUSIONS: Although small effect sizes cannot be discounted, this study suggests that older individuals are less affected by their local physical environment and more by social environmental factors, reflecting both the functional heterogeneity of this age group and the varying nature of their activity spaces.

Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals.

BACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing. CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.

Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis.

BACKGROUND: Increased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis. METHODS: We first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy. FINDINGS: In the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04-1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08-1·29), 1·10 (1·00-1·22), and 1·05 (0·92-1·20), respectively, per 1 SD increment in plasma urate. INTERPRETATION: Conventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions. FUNDING: UK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council.

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

A qualitative geographical information systems approach to explore how older people over 70 years interact with and define their neighbourhood environment.

A growing body of literature explores the relationship between the built environment and health, and the methodological challenges of understanding these complex interactions across the lifecourse. The impact of the neighbourhood environment on health and behaviour amongst older adults has received less attention, despite this age group being potentially more vulnerable to barriers in their surrounding social and physical environment. A qualitative geographical information systems (QGIS) approach was taken to facilitate the understanding of how older people over 70 in 5 UK towns interact with their local neighbourhood. The concept of neighbourhood changed seasonally and over the lifecourse, and was associated with social factors such as friends, family, or community activities, rather than places. Spaces stretched further than the local, which is problematic for older people who rely on variable public transport provision. QGIS techniques prompted rich discussions on interactions with and the meanings of 'place' in older people.

Why do thin people have elevated all-cause mortality? Evidence on confounding and reverse causality in the association of adiposity and COPD from the British Women's Heart and Health Study.

Low adiposity has been linked to elevated mortality from several causes including respiratory disease. However, this could arise from confounding or reverse causality. We explore the association between two measures of adiposity (BMI and WHR) with COPD in the British Women's Heart and Health Study including a detailed assessment of the potential for confounding and reverse causality for each adiposity measure. Low BMI was found to be associated with increased COPD risk while low WHR was not (OR = 2.2; 95% CI 1.3-3.1 versus OR = 1.2; 95% CI 0.7-1.6). Potential confounding variables (e.g. smoking) and markers of ill-health (e.g. unintentional weight loss) were found to be higher in low BMI but not in low WHR. Women with low BMI have a detrimental profile across a broad range of health markers compared to women with low WHR, and women with low WHR do not appear to have an elevated COPD risk, lending support to the hypothesis that WHR is a less confounded measure of adiposity than BMI. Low adiposity does not in itself appear to increase the risk of respiratory disease, and the apparent adverse consequences of low BMI may be due to reverse causation and confounding.

Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium.

OBJECTIVES: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. PARTICIPANTS: Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). PRIMARY OUTCOME MEASURES: Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. RESULTS: The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. CONCLUSIONS: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.

Area-level deprivation and overall and cause-specific mortality: 12 years' observation on British women and systematic review of prospective studies.

BACKGROUND: Prospective studies have suggested a negative impact of area deprivation on overall mortality, but its effect on cause-specific mortality and the mechanisms that account for this association remain unclear. We investigate the association of area deprivation, using Index of Multiple deprivation (IMD), with overall and cause-specific mortality, contextualising findings within a systematic review. METHODS AND FINDINGS: We used data from 4,286 women from the British Women's Heart Health Study (BWHHS) recruited at 1999-2001 to examine the association of IMD with overall and cause-specific mortality using Cox regression models. One standard deviation (SD) increase in the IMD score had a hazard ratio (HR) of 1.21 (95% CI: 1.13-1.30) for overall mortality after adjustment for age and lifecourse individual deprivation, which was attenuated to 1.15 (95% CI: 1.04-1.26) after further inclusion of mediators (health behaviours, biological factors and use of statins and blood pressure-lowering medications). A more pronounced association was observed for respiratory disease and vascular deaths. The meta-analysis, based on 20 published studies plus the BWHHS (n=21), yielded a summary relative risk (RR) of 1.15 (95% CI: 1.11-1.19) for area deprivation (top [least deprived; reference] vs. bottom tertile) with overall mortality in an age and sex adjusted model, which reduced to 1.06 (95% CI: 1.04-1.08) in a fully adjusted model. CONCLUSIONS: Health behaviours mediate the association between area deprivation and cause-specific mortality. Efforts to modify health behaviours may be more successful if they are combined with measures that tackle area deprivation.

Population genomics of cardiometabolic traits: design of the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium.

Substantial advances have been made in identifying common genetic variants influencing cardiometabolic traits and disease outcomes through genome wide association studies. Nevertheless, gaps in knowledge remain and new questions have arisen regarding the population relevance, mechanisms, and applications for healthcare. Using a new high-resolution custom single nucleotide polymorphism (SNP) array (Metabochip) incorporating dense coverage of genomic regions linked to cardiometabolic disease, the University College-London School-Edinburgh-Bristol (UCLEB) consortium of highly-phenotyped population-based prospective studies, aims to: (1) fine map functionally relevant SNPs; (2) precisely estimate individual absolute and population attributable risks based on individual SNPs and their combination; (3) investigate mechanisms leading to altered risk factor profiles and CVD events; and (4) use Mendelian randomisation to undertake studies of the causal role in CVD of a range of cardiovascular biomarkers to inform public health policy and help develop new preventative therapies.

Integration of genetics into a systems model of electrocardiographic traits using HumanCVD BeadChip.

BACKGROUND: Electrocardiographic traits are important, substantially heritable determinants of risk of arrhythmias and sudden cardiac death. METHODS AND RESULTS: In this study, 3 population-based cohorts (n=10,526) genotyped with the Illumina HumanCVD Beadchip and 4 quantitative electrocardiographic traits (PR interval, QRS axis, QRS duration, and QTc interval) were evaluated for single-nucleotide polymorphism associations. Six gene regions contained single nucleotide polymorphisms associated with these traits at P<10(-6), including SCN5A (PR interval and QRS duration), CAV1-CAV2 locus (PR interval), CDKN1A (QRS duration), NOS1AP, KCNH2, and KCNQ1 (QTc interval). Expression quantitative trait loci analyses of top associated single-nucleotide polymorphisms were undertaken in human heart and aortic tissues. NOS1AP, SCN5A, IGFBP3, CYP2C9, and CAV1 showed evidence of differential allelic expression. We modeled the effects of ion channel activity on electrocardiographic parameters, estimating the change in gene expression that would account for our observed associations, thus relating epidemiological observations and expression quantitative trait loci data to a systems model of the ECG. CONCLUSIONS: These association results replicate and refine the mapping of previous genome-wide association study findings for electrocardiographic traits, while the expression analysis and modeling approaches offer supporting evidence for a functional role of some of these loci in cardiac excitation/conduction.

Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure.

BACKGROUND: Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure. METHODS: We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730-rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730-rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided. RESULTS: Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730-rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 × 10(-6)) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 × 10(-11)). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730-rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42). CONCLUSIONS: Our data show a stronger association of rs1051730-rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure.

Survival with treated and well-controlled blood pressure: findings from a prospective cohort study.

AIM: To compare survival and incident cardiovascular disease between normotensive, untreated hypertensive, treated and poorly-controlled hypertensive and treated and well-controlled hypertensive adults. METHODS AND RESULTS: Data from the British Regional Heart Study (men) and British Women's Heart and Health Study (women) were used (N = 6476). Blood pressure and treatment were assessed at baseline (1998-2001) when participants were aged 60-79 years and participants were followed up for a median of 8 years. Date and cause of death were obtained from death certificates and non-fatal cardiovascular disease events were obtained from repeat detailed medical record reviews. Of the whole cohort 52% of women and 49% of men had untreated hypertension and a further 22% and 18%, respectively, had poorly treated hypertension. Just 3% of women and 4% of men had treated and well controlled hypertension and 23% and 29%, respectively, were normotensive. Compared to normotensive individuals, incident cardiovascular disease (fatal and non-fatal) was increased in those with poorly-controlled hypertension (Hazard Ratio (HR): 1.88; 95%CI: 1.53, 2.30), those with untreated hypertension (HR 1.46; 95%CI 1.22, 1.75) and those who were well-controlled hypertension (HR 1.38; 95%CI 0.94, 2.03). Adjustment for baseline differences in mean blood pressure between the groups resulted in attenuation of the increased risk in the poorly-controlled (1.52 (1.18, 1.97) and untreated groups (1.21 (0.97, 1.52), but did not change the association in the well-controlled group. All-cause mortality was also increased in all three hypertension groups but estimates were imprecise with wide confidence intervals. CONCLUSIONS: Half of women and men aged 60-79 in Britain had untreated hypertension and only a very small proportion of those with diagnosed and treated hypertension were well controlled. Those with hypertension, irrespective of whether this was treated and controlled or not, were at greater risk of future cardiovascular disease than those who are normotensive.