The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
Inflammation plays an important role in the cause of cardiovascular diseases and may contribute to the association linking an unhealthy diet to chronic age-related diseases. However, to date the long-term associations between diet and inflammation have been poorly described. Our aim was to assess the extent to which adherence to a healthy diet and dietary improvements over a 6-year exposure period prevented subsequent chronic inflammation over a 5-year follow-up in a large British population of men and women.
Data were drawn from 4600 adults (mean ± standard deviation, age 49.6 ± 6.1 years, 28% were women) from the prospective Whitehall cohort II study. Adherence to a healthy diet was measured using Alternative Healthy Eating Index (AHEI) scores in 1991-1993 (50.7 ± 11.9 points) and 1997-1999 (51.6 ± 12.4 points). Chronic inflammation, defined as average levels of serum interleukin-6 from 2 measures 5 years apart, was assessed in 1997-1999 and 2002-2004.
After adjustment for sociodemographic factors, health behaviors, and health status, participants who maintained a high AHEI score (ie, a healthy diet, n = 1736, 37.7%) and those who improved this score over time (n = 681, 14.8%) showed significantly lower mean levels of interleukin-6 (1.84 pg/mL, 95% confidence interval [CI], 1.71-1.98 and 1.84 pg/mL, 95% CI, 1.70-1.99, respectively) than those who had a low AHEI score (n = 1594, 34.6%) over the 6-year exposure period (2.01 pg/mL, 95% CI, 1.87-2.17).
These data suggest that maintaining and improving adherence to healthy dietary recommendations may reduce the risk of long-term inflammation.
Alternative Healthy Eating Index; Diet quality indices; Inflammatory marker; Interleukin-6; Middle-aged population; Nutritional Epidemiology; Prospective cohort
Metabolic syndrome (MetS) is a potentially reversible cause of disability in the elderly people. The published literature suggests that the MetS–disability association is likely to be complex, depending on co-existing risk factors and with possible variation for each of the specific MetS components. Further evidence is needed to understand the specific consequences of the MetS as a whole and as a function of its components.
Prospective analyses included data from 6,141 participants (60.9% women) aged 65 and older from the Three-City cohort. Mixed logistic models were used to determine associations between MetS (National Cholesterol Education Program Adult Treatment Panel III criteria) and 7-year incident disability measured as social restriction, mobility limitations (Rosow and Breslau scale), and limitations in instrumental and basic activities of daily living.
MetS was associated with incident social restriction (odds ratio = 1.55, 95% CI: 1.14–2.09), limited mobility (odds ratio = 1.52, 95% CI: 1.21–1.90), and instrumental activities of daily living limitations (odds ratio = 1.62, 95% CI: 1.24–2.10) after adjustment for a range of potential sociodemographic, health behavior, and health status confounders at baseline. These associations were independent of chronic conditions, including cardiovascular disease and dementia. There was evidence of associations between MetS components: central obesity, high triglycerides, and elevated fasting glucose and incidence of limitations in mobility and instrumental activities of daily living.
Our results suggest that the increased risk of mobility and instrumental activities of daily living limitations in the elderly people associated with MetS is over and above that associated with its components.
Metabolism; Frailty; Epidemiology.
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.
We found that a single nucleotide polymorphism in the CHRNA5-A3-B4 gene cluster, which is known to influence smoking heaviness, is associated with lower body mass index (BMI) in current smokers, but higher BMI in never smokers. This difference in effects suggests that the variant influences BMI both via pathways other than smoking, and via the weight-reducing effects of smoking, in opposite directions. The overall effect on BMI would therefore be undetectable in an unstratified genome-wide association study, indicating that novel associations may be obscured by hidden population sub-structure.
Accelerometers, initially waist-worn but increasingly wrist-worn, are used to assess physical activity free from reporting-bias. However, its acceptability by study participants is unclear. Our objective is to assess factors associated with non-consent to a wrist-mounted accelerometer in older adults.
Data are from 4880 Whitehall II study participants (1328 women, age range = 60–83), requested to wear a wrist-worn accelerometer 24 h every day for 9 days in 2012/13. Sociodemographic, behavioral, and health-related factors were assessed by questionnaire and weight, height, blood pressure, cognitive and motor function were measured during a clinical examination.
210 participants had contraindications and 388 (8.3%) of the remaining 4670 participants did not consent. Women, participants reporting less physical activity and less favorable general health were more likely not to consent. Among the clinical measures, cognitive impairment (Odds Ratio = 2.21, 95% confidence interval: 1.22–4.00) and slow walking speed (Odds Ratio = 1.38, 95% confidence interval: 1.02–1.86) were associated with higher odds of non-consent.
The rate of non-consent in our study of older adults was low. However, key markers of poor health at older ages were associated with non-consent, suggesting some selection bias in the accelerometer data.
The extent to which social relationships influence cognitive aging is unclear. In this study, we investigated the association of midlife quality of close relationships with subsequent cognitive decline. Participants in the Whitehall II Study (n = 5,873; ages 45–69 years at first cognitive assessment) underwent executive function and memory tests 3 times over a period of 10 years (1997–1999 to 2007–2009). Midlife negative and positive aspects of close relationships were assessed twice using the Close Persons Questionnaire during the 8 years preceding cognitive assessment. Negative aspects of close relationships, but not positive aspects, were associated with accelerated cognitive aging. Participants in the top third of reported negative aspects of close relationships experienced a faster 10-year change in executive function (−0.04 standard deviation, 95% confidence interval: −0.08, −0.01) than those in the bottom third, which was comparable with 1 extra year of cognitive decline for participants aged 60 years after adjustment for sociodemographic and health status. Longitudinal analysis found no evidence of reverse causality. This study highlights the importance of differentiating aspects of social relationships to evaluate their unique associations with cognitive aging.
aging; cognitive decline; longitudinal studies; social relationships
To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach.
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.
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.
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.
Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.
Mendelian randomisation; Smoking; Depression; Anxiety
We examined whether midlife body mass index (BMI) and waist circumference (WC) predict successful ageing.
Design and Methods
BMI/WC were assessed in 4869 persons (mean age 51.2, range 42–63 in 1991/93) and survival and successful ageing (alive, no chronic disease at age >60 years, not in the worst age- and sex-standardized quintile of cognitive, physical, respiratory, and cardiovascular, and mental health) ascertained over a 16-year follow-up, analysed using logistic regression adjusted for socio-demographic factors and health behaviours.
507 participants died, 1008 met the criteria for successful ageing. Those with BMI≥30 kg/m2 had lower odds of successful ageing (Odds Ratio (OR)=0.37; 95% Confidence Interval (CI): 0.27, 0.50) and survival (OR=0.55; 95% CI: 0.41, 0.74) compared to BMI between 18.5–25 kg/m2. Those with a large waist circumference (≥102/88 cm in men/women) had lower odds of successful ageing (OR=0.41; 95% CI: 0.31, 0.54) and survival (OR=0.57; 95% CI: 0.44, 0.73) compared to those with a small waist (<94/80 cm in men/women). Analysis with finer categories showed lower odds of successful ageing starting at BMI ≥23.5 kg/m2 and waist circumference 82/68 cm in men/women.
Optimal midlife BMI and waist circumference for successful ageing might be substantially below the current thresholds used to define obesity.
obesity; body mass index; waist circumference; ageing
We examined the effect of salivary cortisol on cognitive performance and decline in 3229 adults (79% men), mean age 61 years. Six saliva samples over the day along with a cognition test battery were administered twice in 5 years. In fully-adjusted cross-sectional analyses from 2002 to 2004, higher waking cortisol was associated with higher reasoning score (β = 0.08, 95% confidence interval: 0.01, 0.15) but this finding was not replicated using data from 2007 to 2009. Over the mean 5 years follow-up there was decline in all cognitive tests but this decline did not vary as a function of cortisol levels; the exception was among APOE e4 carriers where a flatter diurnal slope and higher bedtime cortisol were associated with faster decline in verbal fluency. Changes in cortisol measures between 2002/2004 and 2007/2009 or chronically elevated levels were not associated with cognitive performance in 2007/2009. These results, based on a large sample of community-dwelling adults suggest that variability in hypothalamic-pituitary-adrenal function is not a strong contributor to cognitive aging.
Cortisol; Glucocorticoid; Cognitive decline
Mendelian randomization studies on fibrinogen commonly use a single genetic variant as an instrument, but this may explain only a small proportion of the total phenotypic variance. We examined the contribution of multiple common single nucleotide polymorphisms (SNPs) and haplotypes in the entire fibrinogen gene cluster to plasma fibrinogen levels in two prospective cohorts, for use as instruments in future Mendelian randomization studies. Genotypes for 20 SNPs were determined in 2,778 middle-age (49–64 years) men from the Second-Northwick-Park-Heart Study (NPHS-II). These were replicated in 3,705 men from the Whitehall-II study (WH-II). Plasma fibrinogen levels were determined six times in NPHS-II and three times in WH-II. The minor alleles of four SNPs from the FGB gene, two from the FGA gene, and one from the FGG gene were associated with higher plasma fibrinogen levels. SNP rs1800790 (−455G >A) commonly used in Mendelian randomization studies was associated with R2 = 1.22% of the covariate adjusted residual variance in fibrinogen level. A variable selection procedure identified one additional SNP: rs2070011 (FGA) altogether explaining R2 = 1.45% of the residual variance in fibrinogen level. Using these SNPs no evidence for causality between the fibrinogen levels and coronary heart diseases was found in instrumental variables analysis. In the replication cohort, WH-II, the effects of the two SNPs on fibrinogen levels were consistent with the NPHS-II results. There is statistical evidence for several functional sites in the fibrinogen gene cluster that determine an individual’s plasma fibrinogen levels. Thus, a combination of several SNPs will provide a stronger instrument for fibrinogen Mendelian randomization studies.
Fibrinogen gene; Tagging SNPs; Haplotypes; Mendelian randomization
Lower IQ individuals have an increased risk of psychological disorders, mental health problems, and suicide; similarly, children with low IQ scores are more likely to have behavioural, emotional and anxiety disorders. However, very little is known about the impact of parental IQ on the mental health outcomes of their children.
To determine whether maternal and paternal IQ score is associated with offspring conduct, emotional and attention scores.
Members of 1958 National Child Development Study and their offspring. Of 2,984 parent-offspring pairs, with non-adopted children aged 4+ years, 2,202 pairs had complete data on all variables of interest and were included in the analyses.
Offspring conduct, emotional and attention scores based on Behavioural Problems Index for children aged 4-6 years or the Rutter A scale for children aged 7 and over.
There was little evidence of any association of parental IQ with conduct or emotional problems in younger (aged 4-6) children. However, among children aged 7+, there was strong evidence from age- and sex-adjusted models to support a decrease in conduct, emotional and attention problems in those whose parents had higher IQ scores. These associations were linear across the full IQ range. Individual adjustments for socioeconomic status and child’s own IQ had limited impact while adjustments for Home Observation for Measurement of the Environment (HOME) scores and parental malaise attenuated associations with mother’s IQ but, again, had little impact on associations with father’s IQ. Strong associations were no longer evident in models that simultaneously adjusted for all four potential mediating variables.
Children whose parents score poorly on IQ tests may have an increased risk of conduct, emotional and attention problems. Home environment, parental malaise, and child’s own IQ may have a role in explaining these associations.
Recent experimental evidence suggests that socioeconomic characteristics of neighbourhoods influence cardiovascular health, but observational studies which examine deprivation across a wide range of cardiovascular diseases (CVDs) are lacking.
Record-linkage cohort study of 1.93 million people to examine the association between small-area socioeconomic deprivation and 12 CVDs. Health records covered primary care, hospital admissions, a myocardial infarction registry and cause-specific mortality in England (CALIBER). Patients were aged ≥30 years and were initially free of CVD. Cox proportional hazard models stratified by general practice were used.
During a median follow-up of 5.5 years 114,859 people had one of 12 initial CVD presentations. In women the hazards of all CVDs except abdominal aortic aneurysm increased linearly with higher small-area socioeconomic deprivation (adjusted HR for most vs. least deprived ranged from 1.05, 95%CI 0.83–1.32 for abdominal aortic aneurysm to 1.55, 95%CI 1.42–1.70 for heart failure; I2 = 81.9%, τ2 = 0.01). In men heterogeneity was higher (HR ranged from 0.89, 95%CI 0.75–1.06 for cardiac arrest to 1.85, 95%CI 1.67–2.04 for peripheral arterial disease; I2 = 96.0%, τ2 = 0.06) and no association was observed with stable angina, sudden cardiac death, subarachnoid haemorrhage, transient ischaemic attack and abdominal aortic aneurysm. Lifetime risk difference between least and most deprived quintiles was most marked for peripheral arterial disease in women (4.3% least deprived, 5.8% most deprived) and men (4.6% least deprived, 7.8% in most deprived); but it was small or negligible for sudden cardiac death, transient ischaemic attack, abdominal aortic aneurysm and ischaemic and intracerebral haemorrhage, in both women and men.
Associations of small-area socioeconomic deprivation with 12 types of CVDs were heterogeneous, and in men absent for several diseases. Findings suggest that policies to reduce deprivation may impact more strongly on heart failure and peripheral arterial disease, and might be more effective in women.
Participation in weight loss programs is often associated with improved wellbeing alongside reduced cardio-metabolic risk. In contrast, population-based analyses have found no evidence of psychological benefits of weight loss, but this may be due to inclusion of healthy-weight individuals. We therefore examined cardio-metabolic and psychological changes following weight loss in a cohort of overweight/obese adults.
Data were from 1,979 overweight and obese adults (BMI ≥25 kg/m2; age ≥50 y), free of long-standing illness or clinical depression at baseline, from the English Longitudinal Study of Ageing. Participants were grouped according to four-year weight change into those losing ≥5% weight, those gaining ≥5%, and those whose weight was stable within 5%. Logistic regression examined changes in depressed mood (eight-item Center for Epidemiologic Studies Depression score ≥4), low wellbeing (Satisfaction With Life Scale score <20), hypertension (systolic blood pressure ≥140 mmHg or anti-hypertensives), and high triglycerides (≥1.7 mmol/l), controlling for demographic variables, weight loss intention, and baseline characteristics.
The proportion of participants with depressed mood increased more in the weight loss than weight stable or weight gain groups (+289%, +86%, +62% respectively; odds ratio [OR] for weight loss vs. weight stable = 1.78 [95% CI 1.29–2.47]). The proportion with low wellbeing also increased more in the weight loss group (+31%, +22%, −4%), but the difference was not statistically significant (OR = 1.16 [0.81–1.66]). Hypertension and high triglyceride prevalence decreased in weight losers and increased in weight gainers (−28%, 4%, +18%; OR = 0.61 [0.45–0.83]; −47%, −13%, +5%; OR = 0.41 [0.28–0.60]). All effects persisted in analyses adjusting for illness and life stress during the weight loss period.
Weight loss over four years in initially healthy overweight/obese older adults was associated with reduction in cardio-metabolic risk but no psychological benefit, even when changes in health and life stresses were accounted for. These results highlight the need to investigate the emotional consequences of weight loss.
Peripheral inflammatory markers are elevated in patients with dementia. In order to assess their etiologic role, we examined whether interleukin-6 (IL-6) and C-reactive protein (CRP) measured in midlife predict concurrently assessed cognition and subsequent cognitive decline.
Mean value of IL-6 and CRP, assessed on 5,217 persons (27.9% women) in 1991–1993 and 1997–1999 in the Whitehall II longitudinal cohort study, were categorized into tertiles to examine 10-year decline (assessments in 1997–1999, 2002–2004, and 2007–2009) in standardized scores (mean = 0, SD = 1) of memory, reasoning, and verbal fluency using mixed models. Mini-Mental State Examination (MMSE) was administered in 2002–2004 and 2007–2009; decline ≥3 points was modeled with logistic regression. Analyses were adjusted for baseline age, sex, education, and ethnicity; further analyses were also adjusted for smoking, obesity, Framingham cardiovascular risk score, and chronic diseases (cancer, coronary heart disease, stroke, diabetes, and depression).
In cross-sectional analysis, reasoning was 0.08 SD (95% confidence interval [CI] −0.14, −0.03) lower in participants with high compared to low IL-6. In longitudinal analysis, 10-year decline in reasoning was greater (ptrend = 0.01) among participants with high IL-6 (−0.35; 95% CI −0.37, −0.33) than those with low IL-6 (−0.29; 95% CI −0.31, −0.27). In addition, participants with high IL-6 had 1.81 times greater odds ratio of decline in MMSE (95% CI 1.20, 2.71). CRP was not associated with decline in any test.
Elevated IL-6 but not CRP in midlife predicts cognitive decline; the combined cross-sectional and longitudinal effects over the 10-year observation period corresponded to an age effect of 3.9 years.
Although basic research on neuroimmune interactions suggests that inflammatory processes may play a role in the development of fatigue, population-based evidence on this association is limited. This study examined whether plasma C-reactive protein (CRP) and interleukin-6 (IL-6), biomarkers of systemic inflammation, predict fatigue onset.
The Whitehall II study is a large-scale cohort study conducted in 20 civil service departments in London. Plasma CRP and IL-6 were measured in 4847 non-fatigued participants at Phase 3 (1991-1993, ages 39-63 years). Fatigue was assessed using the Vitality Subscale of the 36-item Short Form Health Survey (SF-36) at Phase 3 and Phase 4 (1995-1996).
During a mean follow-up of 3.1 years, 957 new fatigue cases (19.7%) were identified using the pre-established cutoff score 50 or less on the Vitality Subscale. CRP values were dichotomized as low (<1.0 mg/L) or high (≥1.0 mg/L) using the Centers for Disease Control/American Heart Association recommendations. Similarly, IL-6 values were also dichotomized as low (<1.5 pg/mL) or high (≥1.5 pg/mL). After full adjustment for sociodemographic and biobehavioral covariates, the odds ratios for new-onset fatigue were 1.28 (95% confidence interval 1.09-1.49, P=0.003) for high CRP and 1.24 (1.06-1.45, P=0.008) for high IL-6. Similar results were found when CRP and IL-6 were treated as continuous variables.
Plasma CRP and IL-6 were prospectively associated with new-onset fatigue, supporting the hypothesis that low-grade inflammation has a role in the development of fatigue.
C-reactive protein; fatigue; inflammation; interleukin-6; prospective cohort study
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.
A 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 [HRs] 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.
For most definitions of metabolic health, both metabolically healthy and unhealthy obese patients carry an elevated risk of mortality.
Identifying modifiable risk factors for cognitive decline may inform prevention of dementia.
To examine the combined impact of cigarette smoking and heavy alcohol consumption on cognitive decline from midlife.
Prospective cohort study (Whitehall II cohort) with three clinical examinations in 1997/99, 2002/04 and 2007/09. Participants were 6473 adults (72% men), mean age 55.76 years (s.d. = 6.02) in 1997/99. Four cognitive tests, assessed three times over 10 years, combined into a global z-score (mean 0, s.d. = 1).
Age-related decline in the global cognitive score was faster in individuals who were smoking heavy drinkers than in non-smoking moderate alcohol drinkers (reference group). The interaction term (P = 0.04) suggested that the combined effects of smoking and alcohol consumption were greater than their individual effects. Adjusting for age, gender, education and chronic diseases, 10-year decline in global cognition was –0.42 z-scores (95% CI –0.45 to –0.39) for the reference group. In individuals who were heavy alcohol drinkers who also smoked the decline was –0.57 z-scores (95% CI –0.67 to –0.48); 36% faster than the reference group.
Individuals who were smokers who drank alcohol heavily had a 36% faster cognitive decline, equivalent to an age-effect of 2 extra years over 10-year follow-up, compared with individuals who were non-smoking moderate drinkers.
Our study aimed to investigate the combined effects of moderate-to-vigorous physical activity and leisure time sitting on the long-term risk of obesity and clustering of metabolic risk factors.
The duration of moderate and vigorous physical activity and of leisure time sitting was assessed by questionnaire between 1997 and 1999 among 3,670 participants from the Whitehall II cohort study (73% male; mean age 56 years). Multivariable-adjusted logistic regression models examined associations of physical activity and leisure time sitting tertiles with odds of incident obesity (BMI ≥ 30 kg/m2) and incident metabolic risk factor clustering (two or more of the following: low HDL-cholesterol, high triacylglycerol, hypertension, hyperglycaemia, insulin resistance) at 5 and 10 year follow-ups.
Physical activity, but not leisure time sitting, was associated with incident obesity. The lowest odds of incident obesity after 5 years were observed for individuals reporting both high physical activity and low leisure time sitting (OR = 0.26; 95% CI 0.11, 0.64), with weaker effects after 10 years. Compared with individuals in the low physical activity/high leisure time sitting group, those with intermediate levels of both physical activity and leisure time sitting had lower odds of incident metabolic risk factor clustering after 5 years (OR 0.53; 95% CI 0.36, 0.78), with similar odds after 10 years.
Both high levels of physical activity and low levels of leisure time sitting may be required to substantially reduce the risk of obesity. Associations with developing metabolic risk factor clustering were less clear.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3323-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Epidemiology; Exercise; Metabolic syndrome; Obesity; Weight regulation
The APOE ε2/3/4 genotype has been associated with low-density lipoprotein cholesterol (LDL-C) and Alzheimer disease. However, evidence for associations with measures of cognitive performance in adults without dementia has been mixed, as it is for physical performance. Associations may also be evident in other genotypes implicated in LDL-C levels. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, genotypic information was obtained for APOE ε2/3/4, rs515135 (APOB), rs2228671 (LDLR) and rs629301 (SORT1) from eight cohorts of adults aged between 44 and 90 + years. We investigated associations with four measures of cognitive (word recall, phonemic fluency, semantic fluency and search speed) and physical capability (grip strength, get up and go/walk speed, timed chair rises and ability to balance) using meta-analyses. Overall, little evidence for associations between any of the genotypes and measures of cognitive capability was observed (e.g. pooled beta for APOE ε4 effect on semantic fluency z score = −0.02; 95 % CI = −0.05 to 0.02; p value = 0.3; n = 18,796). However, there was borderline evidence within studies that negative effects of APOE ε4 on nonverbal ability measures become more apparent with age. Few genotypic associations were observed with physical capability measures. The findings from our large investigation of middle-aged to older adults in the general population suggest that effects of APOE on cognitive capability are at most modest and are domain- and age-specific, while APOE has little influence on physical capability. In addition, other LDL-C-related genotypes have little impact on these traits.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-014-9673-9) contains supplementary material, which is available to authorized users.
Ageing; Apolipoprotein E; Cognition; Single nucleotide polymorphism
Coagulation phenotypes show strong intercorrelations, affect cardiovascular disease risk and are influenced by genetic variants. The objective of this study was to search for novel genetic variants influencing the following coagulation phenotypes: factor VII levels, fibrinogen levels, plasma viscosity and platelet count.
Methods and Results
We genotyped the British Women’s Heart and Health Study (n=3445) and the Whitehall II study (n=5059) using the Illumina HumanCVD BeadArray to investigate genetic associations and pleiotropy. In addition to previously reported associations (SH2B3, F7/F10, PROCR, GCKR, FGA/FGB/FGG, IL5), we identified novel associations at GRK5 (rs10128498, p=1.30×10−6), GCKR (rs1260326, p=1.63×10−6), ZNF259-APOA5 (rs651821, p=7.17×10−6) with plasma viscosity; and at CSF1 (rs333948, p=8.88×10−6) with platelet count. A pleiotropic effect was identified in GCKR which associated with factor VII (p=2.16×10−7) and plasma viscosity (p=1.63×10−6), and, to a lesser extent, ZNF259-APOA5 which associated with factor VII and fibrinogen (p<1.00×10−2) and additionally plasma viscosity (p<1.00×10−5). Triglyceride associated variants were overrepresented in Factor VII and plasma viscosity associations. Adjusting for triglyceride levels resulted in attenuation of associations at the GCKR and ZNF259-APOA5 loci.
In addition to confirming previously reported associations, we identified four SNPs associated with plasma viscosity and platelet count and found evidence of pleiotropic effects with SNPs in GCKR and ZNF259-APOA5. These triglyceride-associated, pleiotropic SNPs suggest a possible causal role for triglycerides in coagulation.
Haemostasis; Thrombosis; HumanCVD; Clotting Factors; Genetic Association
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
The role of sedentary behaviour in metabolically healthy obesity is unknown. We examined cross-sectional differences in television viewing time across metabolic and obesity phenotypes, hypothesizing that healthy obese individuals spend less time viewing television than their unhealthy counterparts.
A nationally representative sample of 4931 older adults in England (mean age 65.1; SD = 8.9 years) was drawn from the 2008/9 wave of the English Longitudinal Study of Ageing. Average weekly television viewing time was derived from two questions about weekday and weekend viewing. Obesity was defined as body mass index ≥ 30 kg/m2, and metabolically healthy as having < 2 metabolic abnormalities (low HDL-cholesterol, high triglycerides, high blood pressure, hyperglycaemia, high inflammation).
After adjusting for covariates including chronic illness, functional limitations and physical activity, mean weekly viewing times were 4.7 (95% confidence interval 2.9, 6.5), 5.8 (2.5, 9.0) and 7.8 (5.7, 9.8) h higher in unhealthy non-obese, healthy obese, and unhealthy obese groups respectively, compared to the healthy non-obese group (p for heterogeneity < 0.001).
A common type of leisure-time sedentary behaviour varies across metabolic and obesity phenotypes. However, healthy obesity is not explained through differences in leisure-time sedentary behaviour.
Sedentary behaviour; Television viewing; Obesity; Metabolic health
Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,578 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5×10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian, and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipids are often associated with cardiovascular and metabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. Our results illustrate the value of genetic data from individuals of diverse ancestries and provide insights into biological mechanisms regulating blood lipids to guide future genetic, biological, and therapeutic research.
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiologic studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P<5×10−8 for each) to examine the role of triglycerides on risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglycerides, and show that the direction and magnitude of both are factors in determining CAD risk. Second, we consider loci with only a strong magnitude of association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol, a polymorphism's strength of effect on triglycerides is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
Both genome-wide association studies and candidate gene studies have reported that the major determinant of plasma levels of the Lipoprotein (a) [Lp(a)] reside within the LPA locus on chromosome 6. We have used data from the Human CVD bead chip to explore the contribution of other candidate genes determining Lp(a) levels.
48,032 single nucleotide polymorphisms (SNPs) from the Illumina Human CVD bead chip were genotyped in 5,059 participants of the Whitehall II study (WHII) of randomly ascertained healthy men and women. SNPs showing association with Lp(a) levels of p< 10−4 outside the LPA locus were selected for replication in a total of an additional 9,463 participants of five European based studies (EAS, EPIC-Norfolk, NPHSII, PROCARDIS, and SAPHIR)
In Whitehall II, apart from the LPA locus (where p values for several SNPs were < 10−30) there was significant association at four loci GALNT2, FABP1, PPARGC1A and TNFRSFF11A. However, a meta-analysis of the six studies did not confirm any of these findings.
Results from this meta analysis of 14,522 participants revealed no candidate genes from the Human CVD bead chip outside the LPA locus to have an effect on Lp(a) levels. Further studies with genome-wide and denser SNP coverage are required to confirm or refute this finding.
Lipoprotein(a); LPA; Illumina Human CVD bead chip; genetic association