Showing papers by "Meena Kumari published in 2014"
TL;DR: This article identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height, and all common variants together captured 60% of heritability.
Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
1,872 citations
TL;DR: In this article, the causal role of alcohol consumption in cardiovascular disease was investigated using a Mendelian randomisation meta-analysis of 56 epidemiological studies, including 20 259 coronary heart disease cases and 10 164 stroke events.
Abstract: OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.
571 citations
UCL Institute of Child Health1, University of Reading2, University of Tromsø3, German Cancer Research Center4, Boston University5, University of Oulu6, Imperial College London7, University of Groningen8, University of Helsinki9, Sahlgrenska University Hospital10, University College London11, King's College London12, George Washington University13, Wake Forest University14, Gentofte Hospital15, University of Copenhagen16, University of Exeter17, Trinity College, Dublin18, University of Edinburgh19, Ludwig Maximilian University of Munich20, Wellcome Trust Centre for Human Genetics21, University of Oxford22, Oulu University Hospital23, National Institutes of Health24, Finnish Institute of Occupational Health25, Heidelberg University26, University of Southampton27, Turku University Hospital28, University of Turku29, VU University Amsterdam30, Aarhus University Hospital31, University of Bristol32, Uppsala University33, Science for Life Laboratory34, University of Split35, Lund University36, Frederiksberg Hospital37, Harvard University38, University of Tampere39, Medical University of Graz40, Synlab Group41, Vanderbilt University42, GlaxoSmithKline43, University of South Australia44
TL;DR: In this article, the authors used a mendelian randomisation approach to test whether low plasma 25-hydroxyvitamin D (25[OH]D) concentration is causally associated with blood pressure and hypertension risk.
320 citations
TL;DR: In this paper, the authors identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization.
Abstract: 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 loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode 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 new candidate genes for ventricular arrhythmias, LQTS and SCD.
283 citations
TL;DR: 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.
Abstract: 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.
169 citations
Utrecht University1, Queen Mary University of London2, University of Michigan3, McMaster University4, Case Western Reserve University5, University of North Carolina at Chapel Hill6, University of California, San Diego7, University of Pennsylvania8, University of Glasgow9, Stanford University10, Cleveland Clinic11, University of Maryland, Baltimore12, University of Oxford13, University of Wisconsin-Madison14, University of Bristol15, University of Florida16, Erasmus University Rotterdam17, Heidelberg University18, University of Groningen19, Lund University20, University of Leicester21, Glenfield Hospital22, University of Minnesota23, Columbia University24, University College London25, Tulane University26, Harvard University27, University of Cambridge28, University of Washington29, University of Dundee30, Merck & Co.31, Cedars-Sinai Medical Center32, Dalhousie University33, University College Dublin34, VU University Amsterdam35, Fred Hutchinson Cancer Research Center36, Boston University37, Imperial College London38, University of Mississippi39, Johns Hopkins University40, University of Amsterdam41, University of Texas Health Science Center at Houston42, University of London43, University of Pittsburgh44, Hannover Medical School45, University of Ulm46, Medical University of Graz47, Icahn School of Medicine at Mount Sinai48, Royal College of Surgeons in Ireland49, Brigham and Women's Hospital50
TL;DR: The findings extend the understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification and provide support for a putative role in hypertension of several genes.
Abstract: Blood pressure (BP) is a heritable risk factor for cardiovascular disease To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis We replicated findings in an independent set of 68,368 individuals of European ancestry Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2 Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules In summary, we identified previously unknown loci associated with BP Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification
158 citations
Norwegian University of Science and Technology1, University of Queensland2, University of Edinburgh3, University College London4, Erasmus University Rotterdam5, University of Helsinki6, National Institutes of Health7, University of Oulu8, UCL Institute of Child Health9, University of Copenhagen10, VU University Amsterdam11, University of Lausanne12, University of London13, Wellcome Trust Sanger Institute14, University of Bristol15, University of Toronto16, University of Otago17, University of Oxford18, University of Southern Denmark19, Helsinki University Central Hospital20, Oulu University Hospital21
TL;DR: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.
Abstract: 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.
146 citations
TL;DR: The inflammation hypothesis of depression, or more broadly, common mental disorders, proposes that chronic inflammation plays an important role in the pathophysiology of these conditions and direct population-based evidence from long-term inflammation is scarce.
Abstract: The inflammation hypothesis of depression, or more broadly, common mental disorders, proposes that chronic inflammation plays an important role in the pathophysiology of these conditions.1, 2 The hypothesis is supported by experiments of inflammatory stimuli, antidepressant trials and studies on depression-related genes and pathogen host defense,2, 3, 4, 5 but direct population-based evidence from long-term inflammation is scarce. Because of a lack of studies on the effects of chronically elevated inflammation, assessed over several years using repeat measurements, it has remained unclear whether the association between inflammation and common mental disorder is the consequence of acute or chronic inflammation.
98 citations
TL;DR: In this nonclinical population, T2D was associated with a flatter slope in cortisol levels across the day and raised bedtime cortisol values and there was no association between morning cortisol, the cortisol awakening response, and T1D.
Abstract: Context: The hypothalamic pituitary-adrenal axis is thought to play a role in Type 2 Diabetes (T2D). However, the evidence for an association between diurnal cortisol patterns and T2D is equivocal. Objective: The aim was to examine the association of cortisol patterns throughout the day with T2D status in a community-dwelling population. Design: This was a cross-sectional study of T2D status and salivary cortisol from phase 7 (2002–2004) of the Whitehall II study, United Kingdom. Setting: The occupational cohort was originally recruited in 1985–1988. Participants: Three-thousand, five-hundred eight white men and women including 238 participants with T2D aged 50–74 years with complete information on cortisol secretion participated. Outcome Measures: We measured diurnal cortisol (nmol/L) patterns from six saliva samples obtained over the course of a normal day: at waking, +30 min, +2.5, +8, +12 hours, and bedtime. The cortisol awakening response and slope in diurnal secretion were calculated. Results: T2D s...
98 citations
04 Dec 2014
TL;DR: The results indicate a genetic architecture for human height that is characterized by a very large but finite number of causal variants, including mTOR, osteoglycin and binding of hyaluronic acid.
Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate–related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
97 citations
TL;DR: Both short sleep and disturbed sleep are independent risk factors for CVD mortality in women and future studies on sleep may benefit from assessing disturbed sleep in addition to sleep duration in order to capture health-relevant features of inadequate sleep.
Abstract: Background
Both sleep duration and sleep quality are related to future health, but their combined effects on mortality are unsettled. We aimed to examine the individual and joint effects of sleep duration and sleep disturbances on cause-specific mortality in a large prospective cohort study.
TL;DR: Social isolation in childhood is associated with higher levels of C-reactive protein in mid-life, explained in part through complex mechanisms acting across the life course, which may help reduce long-term adult health risk.
University of Bristol1, Norwegian University of Science and Technology2, University of Edinburgh3, University of Queensland4, University of Essex5, University of Helsinki6, National Institutes of Health7, University of Lausanne8, Health Protection Agency9, UCL Institute of Child Health10, Leiden University Medical Center11, Copenhagen University Hospital12, VU University Amsterdam13, University of London14, Wellcome Trust Sanger Institute15, Robertson Centre for Biostatistics16, University of Glasgow17, University of Southern Denmark18, University of Exeter19, University of Otago20, Helsinki University Central Hospital21, St George's, University of London22, University of Copenhagen23, University College London24, University of Dundee25
TL;DR: In this paper, a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers was found to be associated with higher body mass index (BMI) in never smokers and lower BMI in current smokers.
Abstract: 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.
University of Düsseldorf1, University of Helsinki2, National Institutes of Health3, University of Queensland4, University College London5, University of Tampere6, Oulu University Hospital7, University of Ulm8, University of Cambridge9, Helsinki University Central Hospital10, Technische Universität München11, Turku University Hospital12, University of Turku13, Semmelweis University14, University of Tartu15
TL;DR: It is shown that circulating IL-1RA levels are predicted by two independent SNPs at the IL1RN and IL1F10 loci and that genetically raised IL- 1RA may be protective against the development of insulin resistance.
Abstract: The proinflammatory cytokine interleukin (IL)-1β is implicated in the development of insulin resistance and β-cell dysfunction, whereas higher circulating levels of IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor of IL-1β, has been suggested to improve glycemia and β-cell function in patients with type 2 diabetes. To elucidate the protective role of IL-1RA, this study aimed to identify genetic determinants of circulating IL-1RA concentration and to investigate their associations with immunological and metabolic variables related to cardiometabolic risk. In the analysis of seven discovery and four replication cohort studies, two single nucleotide polymorphisms (SNPs) were independently associated with circulating IL-1RA concentration (rs4251961 at the IL1RN locus [n = 13,955, P = 2.76 × 10−21] and rs6759676, closest gene locus IL1F10 [n = 13,994, P = 1.73 × 10−17]). The proportion of the variance in IL-1RA explained by both SNPs combined was 2.0%. IL-1RA–raising alleles of both SNPs were associated with lower circulating C-reactive protein concentration. The IL-1RA–raising allele of rs6759676 was also associated with lower fasting insulin levels and lower HOMA insulin resistance. In conclusion, we show that circulating IL-1RA levels are predicted by two independent SNPs at the IL1RN and IL1F10 loci and that genetically raised IL-1RA may be protective against the development of insulin resistance.
TL;DR: The authors examined the effect of salivary cortisol on cognitive performance and decline in 3229 adults (79% men), mean age 61 years, and found that 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.
TL;DR: In the largest analysis to date, no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD is identified.
TL;DR: The Mendelian randomization analysis did not provide strong evidence of a causal association between alcohol consumption and cognitive ability and the minor allele of rs1229984 was not associated with any cognitive test score.
Abstract: AIMS: To use Mendelian randomization to assess whether alcohol intake was causally associated with cognitive function. DESIGN: Mendelian randomization using a genetic variant related to alcohol intake (ADH1B rs1229984) was used to obtain unbiased estimates of the association between alcohol intake and cognitive performance. SETTING: Europe. PARTICIPANTS: More than 34 000 adults. MEASUREMENTS: Any versus no alcohol intake and units of intake in the previous week was measured by questionnaire. Cognitive function was assessed in terms of immediate and delayed word recall, verbal fluency and processing speed. FINDINGS: Having consumed any versus no alcohol was associated with higher scores by 0.17 standard deviations (SD) [95% confidence interval (CI) = 0.15, 0.20] for immediate recall, 0.17 SD (95% CI = 0.14, 0.19) for delayed recall, 0.17 SD (95% CI = 0.14, 0.19) for verbal fluency and 0.12 SD (95% CI = 0.09, 0.15) for processing speed. The minor allele of rs1229984 was associated with reduced odds of consuming any alcohol (odds ratio = 0.87; 95% CI = 0.80, 0.95; P = 0.001; R(2) = 0.1%; F-statistic = 47). In Mendelian randomization analysis, the minor allele was not associated with any cognitive test score, and instrumental variable analysis suggested no causal association between alcohol consumption and cognition: -0.74 SD (95% CI = -1.88, 0.41) for immediate recall, -1.09 SD (95% CI = -2.38, 0.21) for delayed recall, -0.63 SD (95% CI = -1.78, 0.53) for verbal fluency and -0.16 SD (95% CI = -1.29, 0.97) for processing speed. CONCLUSIONS: The Mendelian randomization analysis did not provide strong evidence of a causal association between alcohol consumption and cognitive ability.
TL;DR: Negative aspects of close relationships, but not positive aspects, were associated with accelerated cognitive aging and the importance of differentiating aspects of social relationships to evaluate their unique associations with cognitive aging is highlighted.
Abstract: 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.
TL;DR: Findings from a 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.
Abstract: The APOE e2/3/4 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 e2/3/4, 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 e4 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 e4 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.
University of Pennsylvania1, University College London2, Novo Nordisk3, University of Leicester4, University of Amsterdam5, University of Cambridge6, Karolinska University Hospital7, Karolinska Institutet8, University Medical Center Utrecht9, Utrecht University10, University Medical Center Groningen11, University of Lübeck12, Fred Hutchinson Cancer Research Center13, Children's Hospital of Philadelphia14
TL;DR: The evidence does not support a causal role for sPLA2-V in CHD and a novel approach for single-nucleotide polymorphism selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead single-molecule polymorphism for PLA2G5 expression, a surrogate for s PLA2- V levels) and CHD events.
Abstract: Background— Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. Although observational studies show a strong association between elevated sPLA2 activity and CHD, no assay to measure sPLA2-V levels exists, and the only evidence linking the sPLA2-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA2-V in coronary heart disease (CHD) pathogenesis.
Methods and Results— Using data from the Advanced Study of Aortic Pathology, we identified the single-nucleotide polymorphism in PLA2G5 showing the strongest association with PLA2G5 mRNA expression levels as a proxy for sPLA2-V levels. We tested the association of this SNP with sPLA2 activity and CHD events in 4 prospective and 14 case–control studies with 27 230 events and 70 500 controls. rs525380C>A showed the strongest association with PLA2G5 mRNA expression ( P =5.1×10−6). There was no association of rs525380C>A with plasma sPLA2 activity (difference in geometric mean of sPLA2 activity per rs525380 A-allele 0.4% (95% confidence intervals [−0.9%, 1.6%]; P =0.56). In meta-analyses, the odds ratio for CHD per A-allele was 1.02 (95% confidence intervals [0.99, 1.04]; P =0.20).
Conclusions— This novel approach for single-nucleotide polymorphism selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead single-nucleotide polymorphism for PLA2G5 expression, a surrogate for sPLA2-V levels) and CHD events. The evidence does not support a causal role for sPLA2-V in CHD.
TL;DR: This study provides the first evidence in humans that the CRHR1 gene interacts with exposure to a negative social environment to predict loneliness in older adults.
Abstract: Objective Both adverse social environments and genetic factors contribute to loneliness in old age. Mixed findings between older adults' social relations with their children and their levels of loneliness suggested that a gene × social environment interaction may be operating. We examine whether the effects of infrequent contact with children and low levels of perceived social support from children on loneliness in older adults are moderated by two candidate single nucleotide polymorphisms (i.e., rs1876831 and rs242938) in the corticotrophin releasing hormone receptor 1 (CRHR1) gene. Design This was a longitudinal observational study. Setting and Participants: A population-based sub-sample of 1,374 community-dwelling older adults aged 65 years and older was examined from both the 2003–2004 and 2006–2007 English Longitudinal Study of Aging assessments. Measurements Our main outcome measure is loneliness, which was assessed by four items extracted from the ULCA loneliness scale. Results Compared with older adults carrying the CT/TT genotypes, individuals homozygous for the C allele of rs1876831 reported higher levels of loneliness in the context of infrequent social contact with children and lower levels of perceived social support from children. No gene × social environment interactions were found for loneliness between rs242938 and an adverse social environment related to children. Conclusions This study provides the first evidence in humans that the CRHR1 gene interacts with exposure to a negative social environment to predict loneliness in older adults.
TL;DR: Evidence is provided for a more nuanced understanding of the role of negative emotions in long-term physical health and the risk of physiological dysregulation in civil service workers from the Whitehall II cohort.
28 Aug 2014
TL;DR: The integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
Abstract: 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 loci associated with QT interval that collectively explain ∼8–10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval–associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode 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 new candidate genes for ventricular arrhythmias, LQTS and SCD.
TL;DR: Data do not support a role for the promoter single-nucleotide polymorphism rs2227744G>A F2R polymorphism in the development of COPD but suggest a protective role for this polymorphism from frequent exacerbations.
Abstract: Proteinase-activated receptor-1 (PAR-1) plays a key role in mediating the interplay between coagulation and inflammation in response to injury. The aim of this study was to investigate the role of the promoter single-nucleotide polymorphism (SNP) rs2227744G>A in modulating PAR-1/F2R gene expression in the context of chronic obstructive pulmonary disease (COPD) and COPD exacerbations. The function of the rs2227744G>A SNP was investigated by using reporter gene assays. The frequency of the polymorphism in the UK population was assessed by genotyping 8,579 healthy individuals from the Whitehall II and English Longitudinal Study of Ageing cohorts. The rs2227744G>A SNP was genotyped in a carefully phenotyped cohort of 203 COPD cases and matched controls. The results were further replicated in two different COPD cohorts. The minor allele of the rs2227744G>A polymorphism was found to increase F2R expression by 2.6-fold (P A SNP was not significantly associated with COPD, or with lung function, in all cohorts. The minor allele of the SNP was found to be associated with protection from frequent exacerbations (P = 0.04) in the cohort of COPD patients for which exacerbation frequency was available. Considering exacerbations as a continuous variable, the presence of the minor allele was associated with a significantly lower COPD exacerbation rate (3.03 vs. 1.98 exacerbations/year, Mann-Whitney U-test P = 0.04). Taken together, these data do not support a role for the rs2227744G>A F2R polymorphism in the development of COPD but suggest a protective role for this polymorphism from frequent exacerbations. Studies in separate cohorts to replicate these findings are warranted.
TL;DR: In this article, a series of two-photon active 4-dimethylaminocinnamoyl coumarins were synthesized and large TP absorption cross-sections were measured for all the coumarin in dilute solutions.
Abstract: A series of two-photon (TP) active 4-dimethylaminocinnamoyl coumarins were synthesized. These compounds exhibit red shift in absorption and considerable Stokes shift in emission spectra in comparison to the parent coumarin. Large TP absorption cross-sections were measured for all the coumarins in dilute solutions. A correlation between the chemical structure and TP characteristics was established. TP confocal microscopy revealed that these coumarin derivatives can be internalized by cancer cells rendering them a potential candidate as a label in TP confocal imaging.
TL;DR: Risk exposure related to SEP accumulates across life and contributes to raised levels of D-dimer in middle age in women only, and the association of haemostatic markers and social differences in health may be mediated by inflammatory and other markers.
Abstract: The aim is to examine the association of lifecourse socioeconomic position (SEP) on circulating levels of D-dimer. Data from the 1958 British birth cohort were used, social class was determined at three stages of respondents' life: at birth, at 23 and at 42 years. A cumulative indicator score of SEP (CIS) was calculated ranging from 0 (always in the highest social class) to 9 (always in the lowest social class). In men and women, associations were observed between CIS and D-dimer (P<0.05). Thus, the respondents in more disadvantaged social classes had elevated levels of D-dimer compared to respondents in less disadvantaged social class. In multivariate analyses, the association of disadvantaged social position with D-dimer was largely explained by fibrinogen, C-reactive protein and von Willebrand Factor in women, and additionally by smoking, alcohol consumption and physical activity in men. Socioeconomic circumstances across the lifecourse at various stages also contribute independently to raised levels of D-dimer in middle age in women only. Risk exposure related to SEP accumulates across life and contributes to raised levels of D-dimer. The association of haemostatic markers and social differences in health may be mediated by inflammatory and other markers.
01 Jan 2014
01 Jan 2014
01 Jan 2014
TL;DR: It is suggested that variability in hypothalamic-pituitary-adrenal function is not a strong contributor to cognitive aging and changes in cortisol measures between 2002/2004 and 2007/ 2009 or chronically elevated levels were not associated with cognitive performance in 2007/2009.
Abstract: 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 (b ¼ 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.
01 Jan 2014