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Vineis P, Chadeau M, Dagnino S, et al., 2020, What's new in the Exposome?, Environment International, Vol: 143, Pages: 1-13, ISSN: 0160-4120
The exposome concept refers to the totality of exposures from a variety of external and internal sources including chemical agents, biological agents, or radiation, from conception onward, over a complete lifetime. It encompasses also “psychosocial components” including the impact of social relations and socio-economic position on health. In this review we provide examples of recent contributions from exposome research, where we believe their application will be of the greatest value for moving forward. So far, environmental epidemiology has mainly focused on hard outcomes, such as mortality, disease exacerbation and hospitalizations. However, there are many subtle outcomes that can be related to environmental exposures, and investigations can be facilitated by an improved understanding of internal biomarkers of exposure and response, through the application of omic technologies. Second, though we have a wealth of studies on environmental pollutants, the assessment of causality is often difficult because of confounding, reverse causation and other uncertainties. Biomarkers and omic technologies may allow better causal attribution, for example using instrumental variables in triangulation, as we discuss here. Even more complex is the understanding of how social relationships (in particular socio-economic differences) influence health and imprint on the fundamental biology of the individual. The identification of molecular changes that are intermediate between social determinants and disease status is a way to fill the gap. Another field in which biomarkers and omics are relevant is the study of mixtures. Epidemiology often deals with complex mixtures (e.g. ambient air pollution, food, smoking) without fully disentangling the compositional complexity of the mixture, or with rudimentary approaches to reflect the overall effect of multiple exposures or components.From the point of view of disease mechanisms, most models hypothesize that several stages need t
Mazidi M, Mikhailidis DP, Banach M, et al., 2020, Impact of serum 25-hydroxyvitamin D 25(OH) on telomere attrition: A Mendelian Randomization study., Clin Nutr, Vol: 39, Pages: 2730-2733
BACKGROUND: Conventional observational studies have suggested that 25-hydroxyvitamin D (25(OH)D) is inversely associated with telomere shortening. We aimed to apply two-sample Mendelian randomization (MR) to assess the causal association between serum 25(OH) D and telomere length (TL). METHODS: MR was implemented by using summary-level data from the largest genome-wide association studies (GWAS) on vitamin D (n = 73 699) and TL (n = 37 684). Inverse variance weighted method (IVW) was used to estimate the causal estimates. Weighted median (WM)-based method, and MR-Egger, leave-one-out were applied as sensitivity analysis. RESULTS: The results of MR demonstrated no effect of 25(OH)D on TL (IVW = β:-0.104, p = 0.219, WM = β:-0.109, p = 0.188; MR Egger = β:-0.127, p = 0.506). None of the 25(OH)D-related single nucleotide polymorphisms (SNPs) were significantly associated with TL. Heterogeneity tests did not detect heterogeneity. Furthermore, MR pleiotropy residual sum and outlier (MR-PRESSO) did not highlight any outliers (p = 0.424). Results of leave-one-out method demonstrated that the links are not driven because of the single SNPs. CONCLUSIONS: Our study does not support any causal effect of 25(OH) D on TL.
Georgakis MK, Gill D, Webb AJS, et al., 2020, Genetically determined blood pressure, antihypertensive drug classes and risk of stroke subtypes, Neurology, Vol: 95, Pages: e353-361, ISSN: 0028-3878
Objective: We employed Mendelian Randomization to explore whether the effects of blood pressure (BP) and BP lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from a GWAS on 757,601 individuals. Applying two-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of WMH.Results: Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not beta blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for CCBs showed particularly strong associations with small vessel stroke and the related radiological phenotype of WMH.Conclusions: This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease.
Elliott P, Muller DC, Schneider-Luftman D, et al., 2020, Estimated 24-hour urinary sodium excretion and incident cardiovascular disease and mortality among 398 628 individuals in UK biobank., Hypertension, Vol: 76, Pages: 1-9, ISSN: 0194-911X
We report on an analysis to explore the association between estimated 24-hour urinary sodium excretion (surrogate for sodium intake) and incident cardiovascular disease (CVD) and mortality. Data were obtained from 398 628 UK Biobank prospective cohort study participants (40-69 years) recruited between 2006 and 2010, with no history of CVD, renal disease, diabetes mellitus or cancer, and cardiovascular events and mortality recorded during follow-up. Hazard ratios between 24-hour sodium excretion were estimated from spot urinary sodium concentrations across incident CVD and its components and all-cause and cause-specific mortality. In restricted cubic splines analyses, there was little evidence for an association between estimated 24-hour sodium excretion and CVD, coronary heart disease, or stroke; hazard ratios for CVD (95% CIs) for the 15th and 85th percentiles (2.5 and 4.2 g/day, respectively) compared with the 50th percentile of estimated sodium excretion (3.2 g/day) were 1.05 (1.01-1.10) and 0.96 (0.92-1.00), respectively. An inverse association was observed with heart failure, but that was no longer apparent in sensitivity analysis. A J-shaped association was observed between estimated sodium excretion and mortality. Our findings do not support a J-shaped association of estimated sodium excretion with CVD, although such an association was apparent for all-cause and cause-specific mortality across a wide range of diseases. Reasons for these differences are unclear; methodological limitations, including the use of estimating equations based on spot urinary data, need to be considered in interpreting our findings.
Mustafa R, Mens M, Pinto RJ, et al., 2020, Metabolomic signatures of microRNAs in cardiovascular traits: A Mendelian randomization analysis, Annual Meeting of the International-Genetic-Epidemiology-Society, Publisher: WILEY, Pages: 506-506, ISSN: 0741-0395
Janki S, Dehghan A, van de Wetering J, et al., 2020, Long-term prognosis after kidney donation: a propensity score matched comparison of living donors and non-donors from two population cohorts, EUROPEAN JOURNAL OF EPIDEMIOLOGY, Vol: 35, Pages: 699-707, ISSN: 0393-2990
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NCD Risk Factor Collaboration NCD-RisC, 2020, Repositioning of the global epicentre of non-optimal cholesterol, Nature, Vol: 582, Pages: 73-77, ISSN: 0028-0836
High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular risk-changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and per
Nano J, Dhana K, Asllanaj E, et al., 2020, Trajectories of BMI Before Diagnosis of Type 2 Diabetes: The Rotterdam Study., Obesity (Silver Spring), Vol: 28, Pages: 1149-1156
OBJECTIVE: People with diabetes show great variability in weight gain and duration of obesity at the time of diagnosis. BMI trajectories and other cardiometabolic risk factors prior to type 2 diabetes were investigated. METHODS: A total of 6,223 participants from the Rotterdam Study cohort were included. BMI patterns before diagnosis of diabetes were identified through latent class trajectories. RESULTS: During a mean follow-up of 13.7 years, 565 participants developed type 2 diabetes. Three distinct trajectories of BMI were identified, including the "progressive overweight" group (n = 481, 85.1%), "progressive weight loss" group (n = 59, 10.4%), and "persistently high BMI" group (n = 25, 4.4%). The majority, the progressive overweight group, was characterized by a steady increase of BMI in the overweight range 10 years before diabetes diagnosis. The progressive weight loss group had fluctuations of glucose and marked beta cell function loss. The persistently high BMI group was characterized by a slight increase in insulin levels and sharp increase of insulin resistance accompanied by a rapid decrease of beta cell function. CONCLUSIONS: Heterogeneity of BMI changes prior to type 2 diabetes was found in a middle-aged and elderly white population. Prevention strategies should be tailored rather than focusing only on high-risk individuals.
Lowry E, Rautio N, Wasenius N, et al., 2020, Early exposure to social disadvantages and later life body mass index beyond genetic predisposition in three generations of Finnish birth cohorts, BMC Public Health, Vol: 20, ISSN: 1471-2458
BACKGROUND: The study aimed to explore the association between early life and life-course exposure to social disadvantage and later life body mass index (BMI) accounting for genetic predisposition and maternal BMI. METHODS: We studied participants of Helsinki Birth Cohort Study born in 1934-1944 (HBCS1934-1944, n = 1277) and Northern Finland Birth Cohorts born in 1966 and 1986 (NFBC1966, n = 5807, NFBC1986, n = 6717). Factor analysis produced scores of social disadvantage based on social and economic elements in early life and adulthood/over the life course, and was categorized as high, intermediate and low. BMI was measured at 62 years in HBCS1934-1944, at 46 years in NFBC1966 and at 16 years in NFBC1986. Multivariable linear regression analysis was used to explore associations between social disadvantages and BMI after adjustments for polygenic risk score for BMI (PRS BMI), maternal BMI and sex. RESULTS: The association between exposure to high early social disadvantage and increased later life BMI persisted after adjustments (β = 0.79, 95% CI, 0.33, 1.25, p < 0.001) in NFBC1966. In NFBC1986 this association was attenuated by PRS BMI (p = 0.181), and in HBCS1934-1944 there was no association between high early social disadvantage and increased later life BMI (β 0.22, 95% CI -0.91,1.35, p = 0.700). In HBCS1934-1944 and NFBC1966, participants who had reduced their exposure to social disadvantage during the life-course had lower later life BMI than those who had increased their exposure (β - 1.34, [- 2.37,-0.31], p = 0.011; β - 0.46, [- 0.89,-0.03], p = 0.038, respectively). CONCLUSIONS: High social disadvantage in early life appears to be associated with higher BMI in later life. Reducing exposure to social disadvantage during the life-course may be a poten
Palaniswamy S, Gill D, De Silva NM, et al., 2020, Could vitamin D reduce obesity-associated inflammation? Observational and Mendelian randomization study, American Journal of Clinical Nutrition, Vol: 111, Pages: 1036-1047, ISSN: 0002-9165
BackgroundObesity is associated with inflammation but the role of vitamin D in this process is not clear.ObjectivesWe aimed to assess the associations between serum 25-hydroxyvitamin D [25(OH)D], BMI, and 16 inflammatory biomarkers, and to assess the role of vitamin D as a potential mediator in the association between higher BMI and inflammation.MethodsNorthern Finland Birth Cohort 1966 (NFBC1966) 31-y data on 3586 individuals were analyzed to examine the observational associations between BMI, 25(OH)D, and 16 inflammatory biomarkers. Multivariable regression analyses and 2-sample regression-based Mendelian randomization (MR) mediation analysis were performed to assess any role of vitamin D in mediating a causal effect of BMI on inflammatory biomarkers [soluble intercellular adhesion molecule 1 (sICAM-1), high sensitivity C-reactive protein (hs-CRP), and α1-acid glycoprotein (AGP)] for which observational associations were detected. For MR, genome-wide association study summary results ranging from 5163 to 806,834 individuals were used for biomarkers, 25(OH)D, and BMI. Findings were triangulated with a literature review of vitamin D supplementation trials.ResultsIn NFBC1966, mean BMI (kg/m2) was 24.8 (95% CI: 24.7, 25.0) and mean 25(OH)D was 50.3 nmol/L (95% CI: 49.8, 50.7 nmol/L). Inflammatory biomarkers correlated as 4 independent clusters: interleukins, adhesion molecules, acute-phase proteins, and chemokines. BMI was positively associated with 9 inflammatory biomarkers and inversely with 25(OH)D (false discovery rate < 0.05). 25(OH)D was inversely associated with sICAM-1, hs-CRP, and AGP, which were positively associated with BMI. The MR analyses showed causal association of BMI on these 3 inflammatory biomarkers. There was no observational or MR evidence that circulating 25(OH)D concentrations mediated the association between BMI and these 3 inflammatory markers. Review of randomized controlled trials (RCTs) supported our findings showing no impact of
Elliott J, Bodinier B, Bond TA, et al., 2020, Predictive accuracy of a polygenic risk score-enhanced prediction model vs a clinical risk score for coronary artery disease, JAMA: Journal of the American Medical Association, Vol: 323, Pages: 636-645, ISSN: 0098-7484
Importance The incremental value of polygenic risk scores in addition to well-established risk prediction models for coronary artery disease (CAD) is uncertain.Objective To examine whether a polygenic risk score for CAD improves risk prediction beyond pooled cohort equations.Design, Setting, and Participants Observational study of UK Biobank participants enrolled from 2006 to 2010. A case-control sample of 15 947 prevalent CAD cases and equal number of age and sex frequency–matched controls was used to optimize the predictive performance of a polygenic risk score for CAD based on summary statistics from published genome-wide association studies. A separate cohort of 352 660 individuals (with follow-up to 2017) was used to evaluate the predictive accuracy of the polygenic risk score, pooled cohort equations, and both combined for incident CAD.Exposures Polygenic risk score for CAD, pooled cohort equations, and both combined.Main Outcomes and Measures CAD (myocardial infarction and its related sequelae). Discrimination, calibration, and reclassification using a risk threshold of 7.5% were assessed.Results In the cohort of 352 660 participants (mean age, 55.9 years; 205 297 women [58.2%]) used to evaluate the predictive accuracy of the examined models, there were 6272 incident CAD events over a median of 8 years of follow-up. CAD discrimination for polygenic risk score, pooled cohort equations, and both combined resulted in C statistics of 0.61 (95% CI, 0.60 to 0.62), 0.76 (95% CI, 0.75 to 0.77), and 0.78 (95% CI, 0.77 to 0.79), respectively. The change in C statistic between the latter 2 models was 0.02 (95% CI, 0.01 to 0.03). Calibration of the models showed overestimation of risk by pooled cohort equations, which was corrected after recalibration. Using a risk threshold of 7.5%, addition of the polygenic risk score to pooled cohort equations resulted in a net reclassification improvement of 4.4% (95% CI, 3.5% to 5.3%) for cases and −0.4% (95% CI, &
Shah S, Henry A, Roselli C, et al., 2020, Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure, NATURE COMMUNICATIONS, Vol: 11
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- Citations: 298
Climaco Pinto R, Dehghan A, Barros AS, et al., 2020, Clinical Research in Cardiovascular Disease using Metabolomics, Systems Medicine: Integrative, Qualitative and Computational Approaches: Volume 1-3, Pages: 468-479, ISBN: 9780128160787
Cardiovascular disease (CVD) comprises a group of complex diseases and remains one of the leading causes of mortality worldwide. Although traditional risk factors such as lifestyle, cholesterol, glucose and hypertension parameters represent the major markers of CVD, there is still a need for more specific markers for CVD risk assessment, patient stratification for treatment, and to study disease mechanisms. Metabolomics and metabolic phenotyping studies are becoming widespread across biomedical research fields. They have proven to be particularly useful in CVD research, namely human case-control studies, pre-clinical animal studies, drug or nutritional intervention studies and in large scale epidemiologic studies. The current chapter aims at describing the current state-of-the-art of metabolomics and metabolic phenotyping applied to CVD research and how the major findings and data can be translated into clinical practice.
Hahn J, Fu Y-P, Brown MR, et al., 2020, Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium., PLoS One, Vol: 15
BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome. METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event. CONCL
Nelson RG, Grams ME, Ballew SH, et al., 2019, Development of Risk Prediction Equations for Incident Chronic Kidney Disease, JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, Vol: 322, Pages: 2104-2114, ISSN: 0098-7484
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- Citations: 95
Suzuki H, Venkataraman AV, Bai W, et al., 2019, Associations of regional brain structural differences with aging, modifiable risk factors for dementia, and cognitive performance, JAMA Network Open, Vol: 2, Pages: 1-19, ISSN: 2574-3805
Importance Identifying brain regions associated with risk factors for dementia could guide mechanistic understanding of risk factors associated with Alzheimer disease (AD).Objectives To characterize volume changes in brain regions associated with aging and modifiable risk factors for dementia (MRFD) and to test whether volume differences in these regions are associated with cognitive performance.Design, Setting, and Participants This cross-sectional study used data from UK Biobank participants who underwent T1-weighted structural brain imaging from August 5, 2014, to October 14, 2016. A voxelwise linear model was applied to test for regional gray matter volume differences associated with aging and MRFD (ie, hypertension, diabetes, obesity, and frequent alcohol use). The potential clinical relevance of these associations was explored by comparing their neuroanatomical distributions with the regional brain atrophy found with AD. Mediation models for risk factors, brain volume differences, and cognitive measures were tested. The primary hypothesis was that common, overlapping regions would be found. Primary analysis was conducted on April 1, 2018.Main Outcomes and Measures Gray matter regions that showed relative atrophy associated with AD, aging, and greater numbers of MRFD.Results Among 8312 participants (mean [SD] age, 62.4 [7.4] years; 3959 [47.1%] men), aging and 4 major MRFD (ie, hypertension, diabetes, obesity, and frequent alcohol use) had independent negative associations with specific gray matter volumes. These regions overlapped neuroanatomically with those showing lower volumes in participants with AD, including the posterior cingulate cortex, the thalamus, the hippocampus, and the orbitofrontal cortex. Associations between these MRFD and spatial memory were mediated by differences in posterior cingulate cortex volume (β = 0.0014; SE = 0.0006; P = .02).Conclusions and Relevance This cross-sectional study
Allaf M, Elghazaly H, Mohamed OG, et al., 2019, Intermittent fasting for the prevention of cardiovascular disease, Cochrane Database of Systematic Reviews, Vol: 2019
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:. To determine the role of intermittent fasting in preventing and reducing the risk of cardiovascular disease (CVD) in people with or without prior documented CVD.
Murphy AM, Smith CE, Murphy LM, et al., 2019, Potential Interplay between Dietary Saturated Fats and Genetic Variants of the NLRP3 Inflammasome to Modulate Insulin Resistance and Diabetes Risk: Insights from a Meta-Analysis of 19 005 Individuals., Mol Nutr Food Res, Vol: 63
SCOPE: Insulin resistance (IR) and inflammation are hallmarks of type 2 diabetes (T2D). The nod-like receptor pyrin domain containing-3 (NLRP3) inflammasome is a metabolic sensor activated by saturated fatty acids (SFA) initiating IL-1β inflammation and IR. Interactions between SFA intake and NLRP3-related genetic variants may alter T2D risk factors. METHODS: Meta-analyses of six Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 19 005) tested interactions between SFA and NLRP3-related single-nucleotide polymorphisms (SNPs) and modulation of fasting insulin, fasting glucose, and homeostasis model assessment of insulin resistance. RESULTS: SFA interacted with rs12143966, wherein each 1% increase in SFA intake increased insulin by 0.0063 IU mL-1 (SE ± 0.002, p = 0.001) per each major (G) allele copy. rs4925663, interacted with SFA (β ± SE = -0.0058 ± 0.002, p = 0.004) to increase insulin by 0.0058 IU mL-1 , per additional copy of the major (C) allele. Both associations are close to the significance threshold (p < 0.0001). rs4925663 causes a missense mutation affecting NLRP3 expression. CONCLUSION: Two NLRP3-related SNPs showed potential interaction with SFA to modulate fasting insulin. Greater dietary SFA intake accentuates T2D risk, which, subject to functional validation, may be further elaborated depending on NLRP3-related genetic variants.
Schmidt AF, Holmes MV, Preiss D, et al., 2019, Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9, BMC Cardiovascular Disorders, Vol: 19, ISSN: 1471-2261
BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
Gill D, Efstathiadou A, Cawood K, et al., 2019, Education protects against coronary heart disease and stroke independently of cognitive function: evidence from Mendelian randomization, International Journal of Epidemiology, Vol: 48, Pages: 1468-1477, ISSN: 0300-5771
Background: There is evidence that education protects against cardiovascular disease. However, it is not known whether such an effect is independent of cognition. Methods: We performed two-sample Mendelian randomization (MR) analyses to investigate the effect of education and cognition respectively, on risk of CHD and ischemic stroke. Additionally, we used multivariable MR to adjust for the effects of cognition and education in the respective analyses to measure the effects of these traits independently of each other.Results: In unadjusted MR, there was evidence that education is causally associated with both CHD and stroke risk (CHD: OR 0.65 per 1-standard deviation [SD, 3.6 years] increase in education; 95% confidence interval [CI] 0.61-0.70, stroke: OR 0.77; 95% CI 0.69-0.86). This effect persisted after adjusting for cognition in multivariable MR (CHD: OR 0.76; 95% CI 0.65-0.89, stroke OR 0.74; 95% CI 0.59-0.92). Cognition had an apparent effect on CHD risk in unadjusted MR (OR per 1-SD increase 0.80; 95% CI 0.74-0.85), however after adjusting for education this was no longer observed (OR 1.03; 95% CI 0.86-1.25). Cognition did not have any notable effect on the risk of developing ischemic stroke, with (OR 0.97; 95% CI 0.87-1.08) or without adjustment for education (OR 1.04; 95% CI 0.79-1.36).Conclusion: This study provides evidence to support that education protects against CHD and ischemic stroke risk independently of cognition, but does not provide evidence to support that cognition protects against CHD and stroke risk independently of education. These findings could have implications for education and health policy.
Tzoulaki I, Castagné R, Boulangé CL, et al., 2019, Serum metabolic signatures of coronary and carotid atherosclerosis and subsequent cardiovascular disease, European Heart Journal, Vol: 40, Pages: 2883-2896, ISSN: 1522-9645
Aims: To characterise serum metabolic signatures associated with atherosclerosis in the coronary or carotid arteries and subsequently their association with incident cardiovascular disease (CVD). Methods and Results: We used untargeted one-dimensional (1D) serum metabolic profiling by proton (1H) nuclear magnetic resonance (NMR) spectroscopy among 3,867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3,569 participants from the Rotterdam and LOLIPOP Studies. Atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-media thickness (IMT). We used multivariable linear regression to evaluate associations between NMR features and atherosclerosis accounting for multiplicity of comparisons. We then examined associations between metabolites associated with atherosclerosis and incident CVD available in MESA and Rotterdam and explored molecular networks through bioinformatics analyses. Overall, 30 NMR measured metabolites were associated with CAC and/or IMT, P =1.3x10-14 to 6.5x10-6 (discovery), P =4.2x10-14 to 4.4x10-2 (replication). These associations were substantially attenuated after adjustment for conventional cardiovascular risk factors. Metabolites associated with atherosclerosis revealed disturbances in lipid and carbohydrate metabolism, branched-chain and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. Analyses of incident CVD events showed inverse associations with creatine, creatinine and phenylalanine, and direct associations with mannose, acetaminophen-glucuronide and lactate as well as apolipoprotein B (P <0.05). Conclusion: Metabolites associated with atherosclerosis were largely consistent between the two vascular beds (coronary and carotid arteries) and predominantly tag pathways that overlap with the known cardiovascular risk factors. We present an integrated systems network that highlights a series of inter-connected pathways underlying atherosclero
Carter A, Gill D, Davies N, et al., 2019, WHAT EXPLAINS THE EFFECT OF EDUCATION ON CARDIOVASCULAR DISEASE? APPLYING MENDELIAN RANDOMISATION TO IDENTIFY THE CONSEQUENCES OF EDUCATION INEQUALITY, Publisher: BMJ PUBLISHING GROUP, Pages: A8-A9, ISSN: 0143-005X
Brahimaj A, Rivadeneira F, Muka T, et al., 2019, Novel metabolic indices and incident type 2 diabetes among women and men: the Rotterdam Study., Diabetologia, Vol: 62, Pages: 1581-1590
AIMS/HYPOTHESIS: Both visceral and truncal fat have been associated with metabolic disturbances. We aimed to investigate the associations of several novel metabolic indices, combining anthropometric and lipid measures, and dual-energy x-ray absorptiometry (DXA) measurements of body fat, with incident type 2 diabetes among women and men from the large population-based Rotterdam Study. METHODS: Cox proportional hazards models were used to investigate associations of visceral adiposity index (VAI), lipid accumulation product (LAP), the product of triacylglycerol and glucose (TyG), their formula components and DXA measures with incident type 2 diabetes. Associations were adjusted for traditional diabetes risk factors. RESULTS: Among 5576 women and 3988 men free of diabetes, 511 women and 388 men developed type 2 diabetes during a median follow-up of 6.5 years. In adjusted models, the three metabolic indices VAI (per 1 SD naturally log-transformed HR; 95% CI) (1.49; 1.36, 1.65 in women; 1.37; 1.22, 1.53 in men), LAP (1.35; 1.16, 1.56 in women; 1.19; 1.01, 1.42 in men) and TyG (1.73; 1.52, 1.98 in women; 1.43; 1.26, 1.62 in men), gynoid fat mass (0.63; 0.45, 0.89) and android to gynoid fat ratio (1.51; 1.16, 1.97) in women were associated with incident type 2 diabetes. BMI (1.45; 1.28, 1.65) was the strongest predictor of type 2 diabetes in men. CONCLUSIONS/INTERPRETATION: Among women, novel combined metabolic indices were stronger risk markers for type 2 diabetes than the traditional anthropometric and laboratory measures and were comparable with DXA measures. Neither combined metabolic indices nor DXA measures were superior to traditional anthropometric and lipid measures in association with type 2 diabetes among men.
Agha G, Mendelson MM, Ward-Caviness CK, et al., 2019, Blood leukocyte DNA methylation predicts risk of future myocardial infarction and coronary heart disease a longitudinal study of 11 461 participants from population-based cohorts, Circulation, Vol: 140, Pages: 645-657, ISSN: 0009-7322
Background:DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.Methods:Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.Results:Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.Conclusion:Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.
Pazoki R, Evangelou E, Mosen-Ansorena D, et al., 2019, GWAS for urinary sodium and potassium excretion highlights pathways shared with cardiovascular traits, Nature Communications, Vol: 10, ISSN: 2041-1723
Urinary sodium and potassium excretion are associated with blood pressure (BP) and cardiovascular disease (CVD). The exact biological link between these traits is yet to be elucidated. Here, we identify 51 loci for sodium and 13 for potassium excretion in a large-scale genome-wide association study (GWAS) on urinary sodium and potassium excretion using data from 446,237 individuals of European descent from the UK Biobank study. We extensively interrogate the results using multiple analyses such as Mendelian randomization, functional assessment, co localization, genetic risk score, and pathway analyses. We identify a shared genetic component between urinary sodium and potassium expression and cardiovascular traits. Ingenuity pathway analysis shows that urinary sodium and potassium excretion loci are over represented in behavioural response to stimuli. Our study highlights pathways that are shared between urinary sodium and potassium excretion and cardiovascular traits.
Gill D, Brewer CF, Monori G, et al., 2019, The effect of genetically determined iron status on risk of venous thromboembolism and carotid atherosclerotic disease: A Mendelian randomization study, Journal of the American Heart Association, Vol: 8, ISSN: 2047-9980
Background: Systemic iron status has been implicated in atherosclerosis and thrombosis. The aim of this work was to investigate the effect of genetically determined iron status on carotid intima-media thickness (cIMT), carotid plaque and venous thromboembolism (VTE) using Mendelian randomization (MR). Methods and Results: Genetic instrumental variables for iron status were selected from a genome-wide meta-analysis of 48,972 subjects. Genetic association estimates for cIMT and carotid plaque were obtained using data from 71,128 and 48,434 participants respectively, whilst estimates for VTE were obtained using data from a study incorporating 7,507 cases and 52,632 controls. Conventional two-sample summary data MR was performed for the main analysis. Higher genetically determined iron status was associated with increased risk of VTE. Odds ratios (ORs) per standard deviation increase in biomarker levels were 1.37 (95% confidence interval 1.14–1.66) for serum iron, 1.25 (1.09–1.43) for transferrin saturation, 1.92 (1.28–2.88) for ferritin, and 0.76 (0.63–0.92) for serum transferrin (with higher transferrin levels representing lower iron status). In contrast, higher iron status was associated with lower risk of carotid plaque. Corresponding ORs were 0.85 (0.73-0.99) for serum iron and 0.89 (0.80–1.00) for transferrin saturation, with concordant trends for serum transferrin and ferritin that did not reach statistical significance. There was no MR evidence of an effect of iron status on cIMT. Conclusions: These findings support previous work to suggest that higher genetically determined iron status is protective against some forms of atherosclerotic disease, but increases risk of thrombosis related to stasis of blood.
Gill D, Georgakis MK, Koskeridis F, et al., 2019, Use of genetic variants related to antihypertensive drugs to inform on efficacy and side effects, Circulation, Vol: 140, Pages: 270-279, ISSN: 0009-7322
Background: Drug effects can be investigated through natural variation in the genes for their protein targets. The current study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are amongst the most commonly used medications worldwide. Methods: Genetic proxies for the effect of antihypertensive drug classes were identified as variants in the genes for the corresponding targets that associated with systolic blood pressure (SBP) at genome-wide significance. Mendelian randomization (MR) estimates for drug effects on coronary heart disease (CHD) and stroke risk were compared to randomized controlled trial (RCT) results. Phenome-wide association study (PheWAS) in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University Biobank (BioVU) and in observational analysis of the UK Biobank.Results: Suitable genetic proxies for angiotensin-converting-enzyme inhibitors (ACEIs), beta-blockers (BBs) and calcium channel blockers (CCBs) were identified. MR estimates for their effect on CHD and stroke risk respectively were comparable to results from RCTs against placebo. PheWAS in the UK Biobank identified an association of the CCB standardized genetic risk score with increased risk of diverticulosis (odds ratio [OR] 1.02 per standard deviation increase, 95%CI 1.01-1.04), with a consistent estimate found in BioVU (OR 1.01, 95%CI 1.00-1.02). Cox regression analysis of drug use in the UK Biobank suggested that this association was specific to non-dihydropyridine CCBs (hazard ratio [HR] 1.49 considering thiazide diuretics as a comparator, 95%CI 1.04-2.14), but not dihydropyridine CCBs (HR 1.04, 95%CI 0.83-1.32). Conclusions: Genetic variants can be used to explore the efficacy and side effects of antihypertensive medications. The identified potential effect of non-dihydropyridine CCBs on diverticulosis risk could have cli
Pazoki R, Evangelou E, Mosen-Ansorena D, et al., 2019, PATHWAYS UNDERLYING URINARY SODIUM AND POTASSIUM EXCRETION AND THE LINK TO BLOOD PRESSURE AND CARDIOVASCULAR DISEASE, Journal of Hypertension, Vol: 37, Pages: e74-e74, ISSN: 0263-6352
Nazarzadeh M, Pinho-Gomes AC, Mohseni H, et al., 2019, BLOOD PRESSURE AND RISK OF VENOUS THROMBOEMBOLISM: A LARGE-SCALE PROSPECTIVE COHORT ANALYSIS AND A MENDELIAN RANDOMISATION STUDY, 29th European Meeting of Hypertension and Cardiovascular Protection of the European-Society-of-Hypertension (ESH), Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: E95-E95, ISSN: 0263-6352
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Gill D, Benyamin B, Moore LSP, et al., 2019, Associations of genetically determined iron status across the phenome: a mendelian randomization study, PLoS Medicine, Vol: 16, ISSN: 1549-1277
BackgroundIron is integral to many physiological processes and variations in its levels, even within the normal range, can have implications for health. The objective of this study was to explore the broad clinical effects of varying iron status.Methods and FindingsGenome-wide association study summary data obtained from 48,972 European individuals (55% female) across 19 cohorts in the Genetics of Iron Status Consortium were used to identify three genetic variants (rs1800562 and rs1799945 in the hemochromatosis gene, and rs855791 in the transmembrane protease serine 6 gene) that associate with increased serum iron, ferritin and transferrin saturation, and decreased transferrin levels, thus serving as instruments for systemic iron status. Phenome-wide association study (PheWAS) of these instruments was performed on 415,482 European individuals (54% female) in the UK Biobank that were aged 40-69 years when recruited from 2006 to 2010, with their genetic data linked to Hospital Episode Statistics from April 1995 to March 2016. Two-sample summary data Mendelian randomization (MR) analysis was performed to investigate the effect of varying iron status on outcomes across the human phenome. MR-PheWAS analysis for the three iron status genetic instruments was performed separately and then pooled by meta-analysis. Correction was made for testing of multiple correlated phenotypes using a 5% false discovery rate threshold. Heterogeneity between MR estimates for different instruments was used to indicate possible bias due to effects of the genetic variants through pathways unrelated to iron status. There were 904 distinct phenotypes included in the MR-PheWAS analyses. After correcting for multiple testing, the three genetic instruments for systemic iron status demonstrated consistent evidence of a causal effect of higher iron status on decreasing risk of traits related to anemia (iron deficiency anemia: odds ratio [OR] scaled to a standard deviation increase in genetically dete
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