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Tasnime Akbaraly,
Séverine Sabia,
Gareth Hagger-Johnson,
Adam G Tabak,
Martin J Shipley,
Markus Jokela,
Eric J Brunner,
Mark Hamer,
G David Batty,
Archana Singh-Manoux, Mika Kivimaki
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ABSTRACT: The impact of diet on specific age-related diseases has been studied extensively, but few investigations have adopted a more holistic approach to determine the association of diet with overall health at older ages. We examined whether diet, assessed in midlife, using dietary patterns and adherence to the Alternative Healthy Eating Index (AHEI), is associated with aging phenotypes, identified after a mean 16-year follow-up.
Data were drawn from the Whitehall II cohort study of 5350 adults (age 51.3±5.3 years, 29.4% women). Diet was assessed at baseline (1991-1993). Mortality, chronic diseases, and functioning were ascertained from hospital data, register linkage, and screenings every 5 years and were used to create 5 outcomes at follow-up: ideal aging (free of chronic conditions and high performance in physical, mental, and cognitive functioning tests; 4%), nonfatal cardiovascular event (7.3%), cardiovascular death (2.8%), noncardiovascular death (12.7%), and normal aging (73.2%).
Low adherence to the AHEI was associated with an increased risk of cardiovascular and noncardiovascular death. In addition, participants with a "Western-type" diet (characterized by high intakes of fried and sweet food, processed food and red meat, refined grains, and high-fat dairy products) had lower odds of ideal aging (odds ratio for top vs bottom tertile: 0.58; 95% confidence interval, 0.36-0.94; P=.02), independently of other health behaviors.
By considering healthy aging as a composite of cardiovascular, metabolic, musculoskeletal, respiratory, mental, and cognitive function, the present study offers a new perspective on the impact of diet on aging phenotypes.
The American journal of medicine 05/2013; 126(5):411-419.e3. · 4.47 Impact Factor
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ABSTRACT: OBJECTIVE
To assess the association of a "metabolically healthy obese" phenotype with mortality using five definitions of metabolic health.RESEARCH DESIGN AND METHODS
Adults (n = 5,269; 71.7% men) aged 39-62 years in 1991 through 1993 provided data on BMI and metabolic health, defined using data from the Adult Treatment Panel-III (ATP-III); criteria from two studies; and the Matsuda and homeostasis model assessment (HOMA) indices. Cross-classification of BMI categories and metabolic status (healthy/unhealthy) created six groups. Cox proportional hazards regression models were used to analyze associations with all-cause and cardiovascular disease (CVD) mortality during a median follow-up of 17.7 years.RESULTSA total of 638 individuals (12.1% of the cohort) were obese, of whom 9-41% were metabolically healthy, depending on the definition. Regardless of the definition, compared with metabolically healthy, normal-weight individuals, both the metabolically healthy obese (hazard ratios [HR] ranged from 1.81 [95% CI 1.16-2.84] for ATP-III to 2.30 [1.13-4.70] for the Matsuda index) and the metabolically abnormal obese (HRs ranged from 1.57 [1.08-2.28] for the Matsuda index to 2.05 [1.44-2.92] for criteria defined in a separate study) had an increased risk of mortality. The only exception was the lack of excess risk using the HOMA criterion for the metabolically healthy obese (1.08; 0.67-1.74). Among the obese, the risk of mortality did not vary as a function of metabolic health apart from when using the HOMA criterion (1.93; 1.15-3.22). Similar results were obtained for cardiovascular mortality.CONCLUSIONS
For most definitions of metabolic health, both metabolically healthy and unhealthy obese patients carry an elevated risk of mortality.
Diabetes care 05/2013; · 8.09 Impact Factor
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Sonja I Berndt,
Stefan Gustafsson,
Reedik Magi,
Andrea Ganna,
Eleanor Wheeler,
Mary F Feitosa,
Anne E Justice,
Keri L Monda,
Damien C Croteau-Chonka,
Felix R Day, [......],
Joel N Hirschhorn,
Cecilia M Lindgren,
Andrew P Morris,
David Meyre,
Andre Scherag,
Mark I McCarthy,
Elizabeth K Speliotes,
Kari E North,
Ruth J F Loos,
Erik Ingelsson
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ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Nature Genetics 04/2013; · 35.53 Impact Factor
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Tauseef A Khan,
Tina Shah,
David Prieto,
Weili Zhang,
Jackie Price,
Gerald R Fowkes,
Jackie Cooper,
Philippa J Talmud,
Steve E Humphries,
Johan Sundstrom, [......],
Meena Kumari,
Liam Smeeth,
Kay-Tee Khaw,
Michael Nalls,
James Meschia,
Kai Sun,
Rutai Hui,
Ian Day,
Aroon D Hingorani,
Juan P Casas
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ABSTRACT: BACKGROUND: At the APOE gene, encoding apolipoprotein E, genotypes of the ε2/ε3/ε4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk. METHODS: We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT). RESULTS: The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84-1.43) for ε2/ε2; 0.85 (95% CrI: 0.78-0.92) for ε2/ε3; 1.05 (95% CrI: 0.89-1.24) for ε2/ε4; 1.05 (95% CrI: 0.99-1.12) for ε3/ε4; and 1.12 (95% CrI: 0.94-1.33) for ε4/ε4 using the ε3/ε3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 × 10(-152)), apolipoprotein B (P-trend: 8.7 × 10(-06)) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 × 10(-26)) and HDL-C (P-trend: 1.6 × 10(-12)). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear. CONCLUSIONS: In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE ε2/ε2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.
International Journal of Epidemiology 04/2013; 42(2):475-492. · 6.41 Impact Factor
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Tina Shah,
Delilah Zabaneh,
Tom Gaunt,
Daniel I Swerdlow,
Sonia Shah,
Philippa J Talmud,
Ian N Day,
John Whittaker,
Michael V Holmes,
Reecha Sofat,
Steve E Humphries, Mika Kivimaki,
Meena Kumari,
Aroon D Hingorani,
Juan P Casas
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ABSTRACT: BACKGROUND: -The inflammatory cytokine interleukin-6 (IL-6), a possible risk factor for coronary heart disease, has an estimated heritability of over 60%, but to date few genetic variants influencing IL-6 levels are known. METHODS AND RESULTS: -We used the IBC HumanCVD BeadChip in the Whitehall II (WHII, N=4,911) and British Women's Heart and Health Studies (BWHHS, N=3,445) to identify single nucleotide polymorphisms (SNPs) associated with circulating IL-6 levels. Twenty-two SNPs from seven loci (IL6R/TDRD10, HLA-DRB1, BUD13, SEZ6L, IL1RN, TRIB3 and ABO) were associated with IL-6 (p<10(-5)), though none were in the IL6 gene itself. With the exception of TRIB3, all loci have been previously reported in genome-wide association studies for autoimmune and cardiovascular diseases. Fourteen SNPs in the IL6R region in high linkage disequilibrium (r(2)>0.9) with a non-synonymous variant, rs2228145, were also associated with IL-6 and CRP concentration (p<10(-5)). An IL-6 specific weighted allele score explained 2% of the variance of log IL-6 levels (p = 2.44 x 10(-22)) in WHII and 1% (p = 1.9 x 10(-8)) in BWHHS. CONCLUSIONS: -Multiple common genetic variants of modest effect influence IL-6 concentration. Several loci contain SNPs exhibiting overlapping associations with autoimmune and cardiovascular disorders and other circulating biomarkers. Genetic variants associated with IL-6 provide important tools for probing the causal relevance of IL-6 signalling in a range of cardiometabolic diseases.
Circulation Cardiovascular Genetics 03/2013; · 6.11 Impact Factor
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Tamuno Alfred,
Yoav Ben-Shlomo,
Rachel Cooper,
Rebecca Hardy,
Ian J Deary,
Jane Elliott,
Sarah E Harris,
Elina Hyppönen, Mika Kivimaki,
Meena Kumari,
Jane Maddock,
Chris Power,
John M Starr,
Diana Kuh,
Ian N M Day
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ABSTRACT: Several investigations have observed positive associations between good nutritional status, as indicated by micronutrients, and cognitive measures; however, these associations may not be causal. Genetic polymorphisms that affect nutritional biomarkers may be useful for providing evidence for associations between micronutrients and cognitive measures. As part of the Healthy Ageing across the Life Course (HALCyon) program, men and women aged between 44 and 90 y from 6 UK cohorts were genotyped for polymorphisms associated with circulating concentrations of iron [rs4820268 transmembrane protease, serine 6 (TMPRSS6) and rs1800562 hemochromatosis (HFE)], vitamin B-12 [(rs492602 fucosyltransferase 2 (FUT2)], vitamin D ([rs2282679 group-specific component (GC)] and β-carotene ([rs6564851 beta-carotene 15,15'-monooxygenase 1 (BCMO1)]. Meta-analysis was used to pool within-study effects of the associations between these polymorphisms and the following measures of cognitive capability: word recall, phonemic fluency, semantic fluency, and search speed. Among the several statistical tests conducted, we found little evidence for associations. We found the minor allele of rs1800562 was associated with poorer word recall scores [pooled β on z-score for carriers vs. noncarriers: -0.05 (95% CI: -0.09, -0.004); P = 0.03, n = 14,105] and poorer word recall scores for the vitamin D-raising allele of rs2282679 [pooled β per T allele: -0.03 (95% CI: -0.05, -0.003); P = 0.03, n = 16,527]. However, there was no evidence for other associations. Our findings provide little evidence to support associations between these genotypes and cognitive capability in older adults. Further investigations are required to elucidate whether the previous positive associations from observational studies between circulating measures of these micronutrients and cognitive performance are due to confounding and reverse causality.
Journal of Nutrition 03/2013; · 3.92 Impact Factor
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Philippa J Talmud,
Sonia Shah,
Ros Whittall,
Marta Futema,
Philip Howard,
Jackie A Cooper,
Seamus C Harrison,
Kawah Li,
Fotios Drenos,
Frederik Karpe,
H Andrew W Neil,
Olivier S Descamps,
Claudia Langenberg,
Nicholas Lench, Mika Kivimaki,
John Whittaker,
Aroon D Hingorani,
Meena Kumari,
Steve E Humphries
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ABSTRACT: BACKGROUND: Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles. METHODS: In November, 2011, we assembled a sample of patients with familial hypercholesterolaemia from three UK-based sources and compared them with a healthy control sample from the UK Whitehall II (WHII) study. We also studied patients from a Belgian lipid clinic (Hôpital de Jolimont, Haine St-Paul, Belgium) for validation analyses. We genotyped participants for 12 common LDL-C-raising alleles identified by the Global Lipid Genetics Consortium and constructed a weighted LDL-C-raising gene score. We compared the gene score distribution among patients with familial hypercholesterolaemia with no confirmed mutation, those with an identified mutation, and controls from WHII. FINDINGS: We recruited 321 mutation-negative UK patients (451 Belgian), 319 mutation-positive UK patients (273 Belgian), and 3020 controls from WHII. The mean weighted LDL-C gene score of the WHII participants (0·90 [SD 0·23]) was strongly associated with LDL-C concentration (p=1·4 × 10(-77); R(2)=0·11). Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1·0 [SD 0·21]) than did WHII controls (p=4·5 × 10(-16)), as did the mutation-negative Belgian patients (0·99 [0·19]; p=5·2 × 10(-20)). The score was also higher in UK (0·95 [0·20]; p=1·6 × 10(-5)) and Belgian (0·92 [0·20]; p=0·04) mutation-positive patients than in WHII controls. 167 (52%) of 321 mutation-negative UK patients had a score within the top three deciles of the WHII weighted LDL-C gene score distribution, and only 35 (11%) fell within the lowest three deciles. INTERPRETATION: In a substantial proportion of patients with familial hypercholesterolaemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease. FUNDING: British Heart Foundation, Pfizer, AstraZeneca, Schering-Plough, National Institute for Health Research, Medical Research Council, Health and Safety Executive, Department of Health, National Heart Lung and Blood Institute, National Institute on Aging, Agency for Health Care Policy Research, John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health, Unilever, and Departments of Health and Trade and Industry.
The Lancet 02/2013; · 38.28 Impact Factor
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ABSTRACT: BACKGROUND: It has been suggested that dietary patterns are associated with future risk of depressive symptoms. However, there is a paucity of prospective data that have examined the temporality of this relation. OBJECTIVE: We examined whether adherence to a healthy diet, as defined by using the Alternative Healthy Eating Index (AHEI), was prospectively associated with depressive symptoms assessed over a 5-y period. DESIGN: Analyses were based on 4215 participants in the Whitehall II Study. AHEI scores were computed in 1991-1993 and 2003-2004. Recurrent depressive symptoms were defined as having a Center for Epidemiologic Studies Depression Scale score ≥16 or self-reported use of antidepressants in 2003-2004 and 2008-2009. RESULTS: After adjustment for potential confounders, the AHEI score was inversely associated with recurrent depressive symptoms in a dose-response fashion in women (P-trend < 0.001; for 1 SD in AHEI score; OR: 0.59; 95% CI: 0.47, 0.75) but not in men. Women who maintained high AHEI scores or improved their scores during the 10-y measurement period had 65% (OR: 0.35%; 95% CI: 0.19%, 0.64%) and 68% (OR: 0.32%; 95% CI: 0.13%, 0.78%) lower odds of subsequent recurrent depressive symptoms than did women who maintained low AHEI scores. Among AHEI components, vegetable, fruit, trans fat, and the ratio of polyunsaturated fat to saturated fat components were associated with recurrent depressive symptoms in women. CONCLUSION: In the current study, there was a suggestion that poor diet is a risk factor for future depression in women.
American Journal of Clinical Nutrition 01/2013; · 6.67 Impact Factor
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Sonia Shah,
Juan-Pablo Casas,
Fotios Drenos,
John Whittaker,
John Deanfield,
Daniel I Swerdlow,
Michael V Holmes, Mika Kivimaki,
Claudia Langenberg,
Nick Wareham, [......],
Damiano Baldassarre,
Fabrizio Veglia,
Elena Tremoli,
Bruna Gigante,
Ulf de Faire,
Meena Kumari,
Philippa J Talmud,
Anders Hamsten,
Steve E Humphries,
Aroon D Hingorani
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ABSTRACT: BACKGROUND: -Carotid intima-media thickness (CIMT), a subclinical measure of atherosclerosis, is associated with risk of coronary heart disease (CHD) events. Statins reduce progression of CIMT and CHD risk in proportion to the reduction in low-density lipoprotein cholesterol (LDL-C). However, interventions targeting triglycerides or high density lipoprotein cholesterol (HDL-C) have produced inconsistent effects on CIMT and CHD risk, making it uncertain whether such agents are ineffective for CHD prevention or whether CIMT is an inadequate marker of HDL-C or triglyceride-mediated effects. We aimed to determine the causal association between the three major blood lipid fractions and common CIMT using Mendelian randomisation (MR) analysis. METHODS AND RESULTS: -Gene scores specific for LDL-C, HDL-C and triglycerides were derived based on single nucleotide polymorphisms (SNPs) from a gene-centric array in around 5000 individuals (Cardiochip scores) and from a genome-wide association meta-analysis in over 100,000 individuals (Global Lipids Genetic Consortium (GLGC) scores). These were used as instruments in an MR analysis in two prospective cohort studies. A genetically-predicted 1 mmol/L higher LDL-C concentration was associated with a higher common CIMT by 0.03 mm (95% CI=0.01-0.04) and 0.04 mm (95% CI=0.02-0.06) based on the Cardiochip and GLGC scores, respectively. HDL-C and triglycerides were not causally associated with CIMT. CONCLUSIONS: -Our findings confirm a causal relationship between LDL-C and CIMT but not with HDL-C and triglycerides. At present, the suitability of CIMT as a surrogate marker in trials of cardiovascular therapies targeting HDL-C and triglycerides is questionable and requires further study.
Circulation Cardiovascular Genetics 12/2012; · 6.11 Impact Factor
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ABSTRACT: The goal of cardiovascular disease (CVD) research using linked bespoke studies and electronic health records (CALIBER) is to provide evidence to inform health care and public health policy for CVDs across different stages of translation, from discovery, through evaluation in trials to implementation, where linkages to electronic health records provide new scientific opportunities. The initial approach of the CALIBER programme is characterized as follows: (i) Linkages of multiple electronic heath record sources: examples include linkages between the longitudinal primary care data from the Clinical Practice Research Datalink, the national registry of acute coronary syndromes (Myocardial Ischaemia National Audit Project), hospitalization and procedure data from Hospital Episode Statistics and cause-specific mortality and social deprivation data from the Office of National Statistics. Current cohort analyses involve a million people in initially healthy populations and disease registries with ∼10(5) patients. (ii) Linkages of bespoke investigator-led cohort studies (e.g. UK Biobank) to registry data (e.g. Myocardial Ischaemia National Audit Project), providing new means of ascertaining, validating and phenotyping disease. (iii) A common data model in which routine electronic health record data are made research ready, and sharable, by defining and curating with meta-data >300 variables (categorical, continuous, event) on risk factors, CVDs and non-cardiovascular comorbidities. (iv) Transparency: all CALIBER studies have an analytic protocol registered in the public domain, and data are available (safe haven model) for use subject to approvals. For more information, e-mail s.denaxas@ucl.ac.uk.
International Journal of Epidemiology 12/2012; · 6.41 Impact Factor
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Seamus C Harrison,
Delilah Zabaneh,
Folkert W Asselbergs,
Fotios Drenos,
Gregory T Jones,
Sonia Shah,
Karl Gertow,
Bengt Sennblad,
Rona J Strawbridge,
Bruna Gigante, [......],
Jan D Blankensteijn,
Nicholas J Wareham,
Gerry Fowkes,
Ionna Tzoulaki,
Jacqueline F Price,
Elena Tremoli,
Aroon D Hingorani,
Per Eriksson,
Anders Hamsten,
Steve E Humphries
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ABSTRACT: BACKGROUND: Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. METHODS: Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). RESULTS: rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08-0.18 mm, P = 8.2 × 10(-8)). A proxy SNP (rs4916251, R(2) = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case-control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03-1.17, p = 2.8 × 10(-3), I(2) = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. CONCLUSIONS: Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.
Atherosclerosis 11/2012; · 3.79 Impact Factor
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Tom R Gaunt,
Sonia Shah,
Christopher P Nelson,
Fotios Drenos,
Peter S Braund,
Ismail Adeniran,
Lasse Folkersen,
Debbie A Lawlor,
Juan-Pablo Casas,
Antoinette Amuzu, [......],
Maciej Tomaszewski,
Paul R Burton,
Martin D Tobin,
Steve E Humphries,
Philippa J Talmud,
Peter W Macfarlane,
Aroon D Hingorani,
Nilesh J Samani,
Meena Kumari,
Ian N M Day
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ABSTRACT: BACKGROUND: -Electrocardiographic (ECG) traits are important, substantially heritable, determinants of risk of arrhythmias and sudden cardiac death. METHODS AND RESULTS: -In this study, three population-based cohorts (n=10,526) genotyped with the Illumina HumanCVD Beadchip and four quantitative ECG traits (PR interval, QRS axis, QRS duration and QTc interval) were evaluated for single nucleotide polymorphism (SNP) associations. Six gene regions contained SNPs 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 QTL analyses of top associated SNPs were undertaken in human heart and aortic tissues. NOS1AP, SCN5A, IGFBP3, CYP2C9 and CAV1 showed evidence of differential allelic expression. We modelled the effects of ion channel activity on ECG parameters, estimating the change in gene expression that would account for our observed associations, thus relating epidemiological observations and eQTL data to a systems model of the ECG. CONCLUSIONS: -These association results replicate and refine the mapping of previous genome-wide association study (GWAS) findings for ECG traits, whilst the expression analysis and modelling approaches offer supporting evidence for a functional role of some of these loci in cardiac excitation/conduction.
Circulation Cardiovascular Genetics 11/2012; · 6.11 Impact Factor
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ABSTRACT: BACKGROUND:Increases in life expectancy make it important to remain healthy for as long as possible. Our objective was to examine the extent to which healthy behaviours in midlife, separately and in combination, predict successful aging. METHODS:We used a prospective cohort design involving 5100 men and women aged 42-63 years. Participants were free of cancer, coronary artery disease and stroke when their health behaviours were assessed in 1991-1994 as part of the Whitehall II study. We defined healthy behaviours as never smoking, moderate alcohol consumption, physical activity (≥ 2.5 h/wk moderate physical activity or ≥ 1 h/wk vigorous physical activity), and eating fruits and vegetables daily. We defined successful aging, measured over a median 16.3-year follow-up, as good cognitive, physical, respiratory and cardiovascular functioning, in addition to the absence of disability, mental health problems and chronic disease (coronary artery disease, stroke, cancer and diabetes). RESULTS:At the end of follow-up, 549 participants had died and 953 qualified as aging successfully. Compared with participants who engaged in no healthy behaviours, participants engaging in all 4 healthy behaviours had 3.3 times greater odds of successful aging (95% confidence interval [CI] 2.1-5.1). The association with successful aging was linear, with the odds ratio (OR) per increment of healthy behaviour being 1.3 (95% CI 1.2-1.4; population-attributable risk for 1-4 v. 0 healthy behaviours 47%). When missing data were considered in the analysis, the results were similar to those of our main analysis. INTERPRETATION:Although individual healthy behaviours are moderately associated with successful aging, their combined impact is substantial. We did not investigate the mechanisms underlying these associations, but we saw clear evidence of the importance of healthy behaviours for successful aging.
Canadian Medical Association Journal 10/2012; · 8.22 Impact Factor
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Folkert W Asselbergs,
Yiran Guo,
Erik P A van Iperen,
Suthesh Sivapalaratnam,
Vinicius Tragante,
Matthew B Lanktree,
Leslie A Lange,
Berta Almoguera,
Yolande E Appelman,
John Barnard, [......],
Nilesh J Samani,
Alex P Reiner,
Robert A Hegele,
John J P Kastelein,
Aroon D Hingorani,
Philippa J Talmud,
Hakon Hakonarson,
Clara C Elbers,
Brendan J Keating,
Fotios Drenos
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ABSTRACT: Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
The American Journal of Human Genetics 10/2012; · 10.60 Impact Factor
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Sonia Shah,
Juan P Casas,
Tom R Gaunt,
Jackie Cooper,
Fotios Drenos,
Delilah Zabaneh,
Daniel I Swerdlow,
Tina Shah,
Reecha Sofat,
Jutta Palmen,
Meena Kumari, Mika Kivimaki,
Shah Ebrahim,
George Davey Smith,
Debbie A Lawlor,
Philippa J Talmud,
John Whittaker,
Ian N M Day,
Aroon D Hingorani,
Steve E Humphries
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ABSTRACT: AimsThe aim of this study was to quantify the collective effect of common lipid-associated single nucleotide polymorphisms (SNPs) on blood lipid levels, cardiovascular risk, use of lipid-lowering medication, and risk of coronary heart disease (CHD) events.Methods and resultsAnalysis was performed in two prospective cohorts: Whitehall II (WHII; N = 5059) and the British Women's Heart and Health Study (BWHHS; N = 3414). For each participant, scores were calculated based on the cumulative effect of multiple genetic variants influencing total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Compared with the bottom quintile, individuals in the top quintile of the LDL-C genetic score distribution had higher LDL-C {mean difference of 0.85 [95% confidence interval, (CI) = 0.76-0.94] and 0.63 [95% CI = 0.50-0.76] mmol/l in WHII and BWHHS, respectively}. They also tended to have greater odds of having 'high-risk' status (Framingham 10-year cardiovascular disease risk >20%) [WHII: odds ratio (OR) = 1.36 (0.93-1.98), BWHHS: OR = 1.49 (1.14-1.94)]; receiving lipid-lowering treatment [WHII: OR = 2.38 (1.57-3.59), BWHHS: OR = 2.24 (1.52-3.29)]; and CHD events [WHII: OR = 1.43 (1.02-2.00), BWHHS: OR = 1.31 (0.99-1.72)]. Similar associations were observed for the TC score in both studies. The TG score was associated with high-risk status and medication use in both studies. Neither HDL nor TG scores were associated with the risk of coronary events. The genetic scores did not improve discrimination over the Framingham risk score.Conclusion
At the population level, common SNPs associated with LDL-C and TC contribute to blood lipid variation, cardiovascular risk, use of lipid-lowering medications and coronary events. However, their effects are too small to discriminate future lipid-lowering medication requirements or coronary events.
European Heart Journal 09/2012; · 10.48 Impact Factor
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Seán J Costelloe,
Julia S El-Sayed Moustafa,
Fotios Drenos,
Jutta Palmen,
Li Qiao,
Stephen Whiting,
Michael Thomas, Mika Kivimaki,
Meena Kumari,
Aroon D Hingorani,
Ioanna Tzoulaki,
Järvelin Marjo-Riitta,
Ruokonen Aimo,
Anna-Liisa Hartikainen,
Anneli Pouta,
Robin G Walters,
Alexandra I F Blakemore,
Steve E Humphries,
Lachlan J M Coin,
Philippa J Talmud
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ABSTRACT: Background- Copy number variants (CNVs) are a major form of genomic variation, which may be implicated in complex disease phenotypes. However, investigation of the role of CNVs in coronary heart disease (CHD) traits has been limited. Methods and Results- We examined the use of the cnvHap algorithm for CNV detection, using data for 2500 men from the Second Northwick Park Heart Study (NPHS-II). An Illumina custom chip, including 722 single-nucleotide polymorphisms covering 76 coronary heart disease-trait genes, was used. Common CNVs were significantly associated (at P<0.05, after correction) with coronary heart disease phenotypes in 5 genes. Novel associations of CNVs in toll-like receptor-4 with apolipoprotein AI were replicated (P<0.05) in the Whitehall II cohort (4887 subjects), whereas newly described associations of CNVs in sterol regulatory element-binding protein with apolipoprotein AI and associations of interleukin-6 signal transducer with apolipoprotein B were replicated in the data from 3546 subjects from the North Finnish Birth Cohort 1966 (P<0.05). Conclusions- This study supports the use of CNV detection algorithms such as cnvHap as potential tools for the identification of novel CNVs, some of which show significant association and replication with coronary heart disease risk phenotypes. However, the functional basis for these associations requires further substantiation.
Circulation Cardiovascular Genetics 09/2012; 5(5):555-60. · 6.11 Impact Factor
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ABSTRACT: Inflammatory processes are putative mechanisms underlying the cardioprotective effects of physical activity. An inverse association between physical activity and inflammation has been demonstrated, but no long-term prospective data are available. We therefore examined the association between physical activity and inflammatory markers over a 10-year follow-up period.
Participants were 4289 men and women (mean age, 49.2 years) from the Whitehall II cohort study. Self-reported physical activity and inflammatory markers (serum high-sensitivity C-reactive protein and interleukin-6) were measured at baseline (1991) and follow-up (2002). Forty-nine percent of the participants adhered to standard physical activity recommendations for cardiovascular health (2.5 h/wk moderate to vigorous physical activity) across all assessments. Physically active participants at baseline had lower C-reactive protein and interleukin-6 levels, and this difference remained stable over time. Compared with participants who rarely adhered to physical activity guidelines over the 10-year follow-up, the high-adherence group displayed lower log(e) C-reactive protein (β=-0.07; 95% confidence interval, -0.12 to -0.02) and log(e) interleukin-6 (β=-0.07; 95% confidence interval, -0.10 to -0.03) at follow-up after adjustment for a range of covariates. Compared with participants who remained stable, those who reported an increase in physical activity of at least 2.5 h/wk displayed lower log(e) C-reactive protein (β coefficient=-0.05; 95% confidence interval, -0.10 to -0.001) and log(e) interleukin-6 (β coefficient=-0.06; 95% confidence interval, -0.09 to -0.03) at follow-up.
Regular physical activity is associated with lower markers of inflammation over 10 years of follow-up and thus may be important in preventing the proinflammatory state seen with aging.
Circulation 08/2012; 126(8):928-33. · 14.74 Impact Factor
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Robert A Scott,
Vasiliki Lagou,
Ryan P Welch,
Eleanor Wheeler,
May E Montasser,
Jian'an Luan,
Reedik Mägi,
Rona J Strawbridge,
Emil Rehnberg,
Stefan Gustafsson, [......],
Nabila Bouatia-Naji,
Mark I McCarthy,
Paul W Franks,
James B Meigs,
Tanya M Teslovich,
Jose C Florez,
Claudia Langenberg,
Erik Ingelsson,
Inga Prokopenko,
Inês Barroso
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ABSTRACT: Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
Nature Genetics 08/2012; 44(9):991-1005. · 35.53 Impact Factor
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ABSTRACT: To examine the personality trait conscientiousness as a risk factor for mortality and to identify candidate explanatory mechanisms.
Participants in the Whitehall II cohort study (N=6800, aged 34 to 55 at recruitment in 1985) completed two self-reported items measuring conscientiousness in 1991-1993 ('I am overly conscientious' and 'I am overly perfectionistic', Cronbach's α=.72), the baseline for this study. Age, socio-economic status (SES), social support, health behaviours, physiological variables and minor psychiatric morbidity were also recorded at baseline. The vital status of participants was then monitored for a mean of 17 years. All-cause and cause-specific mortality was ascertained through linkage to a national mortality register until January 2010.
Each 1 standard deviation decrease in conscientiousness was associated with a 10% increase in all-cause (hazard ratio [HR]=1.10, 95% CI 1.003, 1.20) mortality. Patterns were similar for cardiovascular (HR=1.17, 95% CI 0.98, 1.39) and cancer mortality (HR=1.10, 95% CI 0.96, 1.25), not reaching statistical significance. The association with all-cause mortality was attenuated by 5% after adjustment for SES, 13% for health behaviours, 14% for cardiovascular risk factors, 5% for minor psychiatric morbidity, 29% for all variables. Repeating analyses with each item separately and excluding participants who died within five years of personality assessment did not change the results materially.
Low conscientiousness in midlife is a risk factor for all-cause mortality. This association is only partly explained by health behaviours, SES, cardiovascular disease risk factors and minor psychiatric morbidity in midlife.
Journal of psychosomatic research 08/2012; 73(2):98-103. · 2.91 Impact Factor
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ABSTRACT: BACKGROUND: There are few longitudinal data on physical activity patterns from mid-life into older age. The authors examined associations of self-reported physical activity, adiposity and socio-demographic factors in mid-life with objectively assessed measures of activity in older age. METHODS: Participants were 394 healthy men and women drawn from the Whitehall II population-based cohort study. At the baseline assessment in 1997 (mean age 54 years), physical activity was assessed through self-report and quantified as metabolic equivalent of task hours/week. At the follow-up in 2010 (mean age 66 years), physical activity was objectively measured using accelerometers worn during waking hours for seven consecutive days (average daily wear time 891±68 min/day). RESULTS: Self-reported physical activity at baseline was associated with objectively assessed activity at follow-up in various activity categories, including light-, moderate- and vigorous-intensity activity (all ps<0.04). Participants in the highest compared with lowest quartile of self-reported activity level at baseline recorded on average 64.1 (95% CI 26.2 to 102.1) counts per minute more accelerometer-assessed activity at follow-up and 9.0 (2.0-16.0) min/day more moderate-to-vigorous daily activity, after adjusting for baseline covariates. Lower education, obesity and self-perceived health status were also related to physical activity at follow-up. Only age and education were associated with objectively measured sedentary time at follow-up. CONCLUSION: Physical activity behaviour in middle age was associated with objectively measured physical activity in later life after 13 years of follow-up, suggesting that the habits in adulthood are partly tracked into older age.
Journal of epidemiology and community health 07/2012; · 3.04 Impact Factor
