332 results found
Wielscher M, Mandaviya PR, Kuehnel B, et al., 2022, DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases., Nat Commun, Vol: 13
We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.
Dehghan A, Said S, Karhunen V, et al., 2022, Genetic analysis of over half a million people characterises C-reactive protein loci, Nature Communications, ISSN: 2041-1723
Portilla-Fernandez E, Klarin D, Hwang S-J, et al., 2022, Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study., Human Molecular Genetics, ISSN: 0964-6906
Progressive dilation of the infrarenal aortic diameter is a consequence of the ageing process and is considered the main determinant of Abdominal Aortic Aneurysm (AAA). We aimed to investigate the genetic and clinical determinants of abdominal aortic diameter (AAD). We conducted a meta-analysis of genome-wide association studies in ten cohorts (n = 13 542) imputed to the 1000 Genome Project reference panel including 12 815 subjects in the discovery phase and 727 subjects (PBIO) as replication. Maximum anterior-posterior diameter of the infrarenal aorta was used as AAD. We also included exome array data (n = 14 480) from seven epidemiologic studies. Single-variant and gene-based associations were done using SeqMeta package. A Mendelian randomization analysis was applied to investigate the causal effect of a number of clinical risk factors on AAD. In GWAS on AAD, rs74448815 in the intronic region of LDLRAD4 reached genome-wide significance (beta = -0.02, SE = 0.004, p-value = 2.10 × 10-8). The association replicated in the PBIO1 cohort (p-value = 8.19 × 10-4). In exome-array single-variant analysis (p-value threshold = 9 × 10-7), the lowest p-value was found for rs239259 located in SLC22A20 (beta = 0.007, p-value =1.2 × 10-5). In the gene-based analysis (p-value threshold = 1.85 × 10-6), PCSK5 showed an association with AAD (p-value = 8.03 × 10-7). Furthermore, in Mendelian randomization analyses, we found evidence for genetic association of pulse pressure (beta = -0.003, p-value = 0.02), triglycerides (beta = -0.16, p-value = 0.008) and height (beta = 0.03, p-value<0.0001), known risk factors for AAA, consistent with a
Brahimaj A, Ahmadizar F, Vernooij MW, et al., 2022, Epicardial fat volume and the risk of cardiometabolic diseases among women and men from the general population, EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY, Vol: 28, Pages: E14-E16, ISSN: 2047-4873
Mazidi M, Dehghan A, Mikhailidis D, et al., 2021, The Association between Coffee and Caffeine Consumption and Renal Function: Insight from Individual-Level Data, Mendelian Randomization, and Meta-Analysis, Archives of Medical Science, ISSN: 1734-1922
<jats:sec><jats:title>Introduction</jats:title><jats:p>By applying on two-sample Mendelian randomization and systematic review and meta-analysis we investigated the association between caffeine and coffee intake with prevalent CKD and markers of renal function.</jats:p></jats:sec><jats:sec><jats:title>Material and methods</jats:title><jats:p>For the individual data analysis we analysed the NHANES data on renal function markers and caffeine intake. MR was implemented by using summary-level data from the largest ever GWAS conducted on coffee intake (N=91,462) and kidney function.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Finally, we included the data of 18,436 participants, 6.9% had prevalent CKD (based on eGFR). Caffeine intake for general population was 131.1±1.1 mg. The percentage of participants with CKD, by caffeine quartile was 16.6% in the first (lowest) quartile, 13.9% in the second, 12.2% in the third and 11.0% in the top quartile (p<0.001). After adjustment, for increasing quartiles for caffeine consumption, mean urine albumin, albumin-creatinine ratio and estimated glomerular filtration rate (GFR) did not change significantly (p>0.234). In fully adjusted logistic regression models, there was no significant difference in chances of CKD prevalence (p-trend=0.745). In the same line, results of MR showed no impact of coffee intake on CKD (IVW=β: -0.0191, SE: 0.069, p=0.781), on eGFR (overall= IVW= β: -0.0005, SE: 0.005, p=0.926) both in diabetic (IVW= β: -0.006, SE: 0.009, p=0.478), and non-diabetic patients (IVW= β: -6.772, SE: 0.006, p=0.991). Results from the meta-analysis indicted that coffee consumption was not significantly associated with CKD (OR: 0.85, 95%CI 0.71-1.02, p=0.090, n=6 studies, I2=0.32).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title&g
Al-Jafar R, Elliott P, Tsilidis KK, et al., 2021, London Ramadan Fasting Study (LORANS): Rationale, design, and methods
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Hundreds of millions of Muslims fast during the month of Ramadan. The London Ramadan Fasting Study (LORANS) aims to assess the lifestyle changes during this month and investigate the effect of Ramadan fasting on health.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>LORANS is an observational study of participants that follow religious fasting in Ramadan. We advertised, recruited, and visited participants in five mosques in London, United Kingdom. In total, 146 individuals were recruited before Ramadan in May 2019 of which 85 participated in the follow up visit after Ramadan. The study protocol was approved by the ethics committee affiliated to Imperial College London. A written informed consent was signed by all the participants. Every participant completed a questionnaire, a physical examination, and gave blood samples at each visit. Moreover, they completed a 3-day food diary before Ramadan and once again during Ramadan to record dietary changes during the month of fasting.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The mean age of participants was 45.6± 15.9 years. 47.1% of the participants were females, 25.5% were obese, 4.7% were smokers, 14% were diabetic, 24% were hypertensive, and 5.2% had cardiovascular diseases. Data collection covered demographics, lifestyle, food intake, blood pressure, anthropometric measurements, body composition, and metabolic biomarker profiling.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>By engaging with mosques, proper introduction of the study aims and convenient recruitment in the mosque, we were able to recruit a balanced population regarding age and sex and collected valuable data on Ramadan fasting using high-quality
Portilla-Fernandez E, Hwang S-J, Wilson R, et al., 2021, Meta-analysis of epigenome-wide association studies of carotid intima-media thickness, EUROPEAN JOURNAL OF EPIDEMIOLOGY, Vol: 36, Pages: 1143-1155, ISSN: 0393-2990
Garcia-Segura ME, Durainayagam BR, Liggi S, et al., 2021, Pathway-based integration of multi-omics data reveals lipidomics alterations validated in an Alzheimer’s Disease mouse model and risk loci carriers
<jats:title>Abstract</jats:title><jats:p>Alzheimer’s Disease (AD) is a highly prevalent neurodegenerative disorder. Despite increasing evidence of important metabolic dysregulation in AD, the underlying metabolic changes that may impact amyloid plaque formation are not understood, particularly for late onset AD. This study analyzed genome-wide association studies (GWAS), transcriptomics and proteomics data obtained from several data repositories to obtain differentially expressed (DE) multi-omics elements in mouse models of AD. We characterized the metabolic modulation in these datasets using gene ontology, and transcription factor, pathway and cell-type enrichment analysis. A predicted lipid signature was extracted from genome-scale metabolic networks (GSMN) and subsequently validated in a lipidomic dataset derived from cortical tissue of ABCA7-null mice, a mouse model of one of the genes associated with late onset AD. Moreover, a metabolome-wide association study (MWAS) was performed to further characterize the association between dysregulated lipid metabolism in human blood serum and AD.</jats:p><jats:p>We found 203 DE transcripts, 164 DE proteins and 58 DE GWAS-derived mouse orthologs associated with significantly enriched metabolic biological processes. Lipid and bioenergetics metabolic pathways were significantly over-represented across the AD multi-omics datasets. Microglia and astrocytes were significantly enriched in the lipid-predominant AD-metabolic transcriptome. We also extracted a predicted lipid signature that was validated and robustly modelled class separation in the ABCA7 mice cortical lipidome, with 11 of these lipid species exhibiting statistically significant modulations. MWAS revealed 298 AD single nucleotide polymorphisms (SNP)-metabolite associations, of which 70% corresponded to lipid classes.</jats:p><jats:p>These results support the importance of lipid metabolism dysregulation in AD and highl
Karabegović I, Dehghan A, Elliott P, et al., 2021, Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption, Nature Communications, Vol: 12, ISSN: 2041-1723
Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10−7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10−6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.
Pazoki R, Elliott J, Evangelou E, et al., 2021, Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes, Nature Communications, Vol: 12, ISSN: 2041-1723
Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.
Ahluwalia TS, Prins BP, Abdollahi M, et al., 2021, Genome-wide association study of circulating interleukin 6 levels identifies novel loci., Hum Mol Genet, Vol: 30, Pages: 393-409
Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
Gill D, Cameron AC, Burgess S, et al., 2021, Urate, blood pressure and cardiovascular disease: evidence from Mendelian randomization and meta-analysis of clinical trials, Hypertension, Vol: 77, Pages: 383-392, ISSN: 0194-911X
Serum urate has been implicated in hypertension and cardiovascular disease, but it is not known whether it is exerting a causal effect. To investigate this, we performed Mendelian randomization analysis using data from UK Biobank, Million Veterans Program and genome-wide association study consortia, and meta-analysis of randomized controlled trials. The main Mendelian randomization analyses showed that every 1-SD increase in genetically predicted serum urate was associated with an increased risk of coronary heart disease (odds ratio, 1.19 [95% CI, 1.10–1.30]; P=4×10−5), peripheral artery disease (1.12 [95% CI, 1.03–1.21]; P=9×10−3), and stroke (1.11 [95% CI, 1.05–1.18]; P=2×10−4). In Mendelian randomization mediation analyses, elevated blood pressure was estimated to mediate approximately one-third of the effect of urate on cardiovascular disease risk. Systematic review and meta-analysis of randomized controlled trials showed a favorable effect of urate-lowering treatment on systolic blood pressure (mean difference, −2.55 mm Hg [95% CI, −4.06 to −1.05]; P=1×10−3) and major adverse cardiovascular events in those with previous cardiovascular disease (odds ratio, 0.40 [95% CI, 0.22–0.73]; P=3×10−3) but no significant effect on major adverse cardiovascular events in all individuals (odds ratio, 0.67 [95% CI, 0.44–1.03]; P=0.07). In summary, these Mendelian randomization and clinical trial data support an effect of higher serum urate on increasing blood pressure, which may mediate a consequent effect on cardiovascular disease risk. High-quality trials are necessary to provide definitive evidence on the specific clinical contexts where urate lowering may be of cardiovascular benefit.
Maners J, Gill D, Pankratz N, et al., 2020, A Mendelian randomization of γ′ and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke, Blood, Vol: 136, Pages: 3062-3069, ISSN: 0006-4971
Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ′) fibrinogen is an isoform of fibrinogen that has anticoagulant properties. We applied 2-sample Mendelian randomization (MR) to estimate the causal effect of total circulating fibrinogen and its isoform, γ′ fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from genome-wide association studies. Genetic instruments for γ′ fibrinogen and total fibrinogen were selected, and the inverse-variance weighted MR approach was used to estimate causal effects in the main analysis, complemented by sensitivity analyses that are more robust to the inclusion of pleiotropic variants, including MR-Egger, weighted median MR, and weighted mode MR. The main inverse-variance weighted MR estimates based on a combination of 16 genetic instruments for γ′ fibrinogen and 75 genetic instruments for total fibrinogen indicated a protective effect of higher γ′ fibrinogen and higher total fibrinogen on VTE risk. There was also a protective effect of higher γ′ fibrinogen levels on cardioembolic and large artery stroke risk. Effect estimates were consistent across sensitivity analyses. Our results provide evidence to support effects of genetically determined γ′ fibrinogen on VTE and ischemic stroke risk. Further research is needed to explore mechanisms underlying these effects and their clinical applications.
Kolbeinsson A, Filippi S, Panagakis I, et al., 2020, Accelerated MRI-predicted brain ageing and its associations with cardiometabolic and brain disorders, Scientific Reports, Vol: 10, ISSN: 2045-2322
Brain structure in later life reflects both influences of intrinsic aging and those of lifestyle, environment and disease. We developed a deep neural network model trained on brain MRI scans of healthy people to predict “healthy” brain age. Brain regions most informative for the prediction included the cerebellum, hippocampus, amygdala and insular cortex. We then applied this model to data from an independent group of people not stratified for health. A phenome-wide association analysis of over 1,410 traits in the UK Biobank with differences between the predicted and chronological ages for the second group identified significant associations with over 40 traits including diseases (e.g., type I and type II diabetes), disease risk factors (e.g., increased diastolic blood pressure and body mass index), and poorer cognitive function. These observations highlight relationships between brain and systemic health and have implications for understanding contributions of the latter to late life dementia risk.
van Herpt TTW, Ligthart S, Leening MJG, et al., 2020, Lifetime risk to progress from pre-diabetes to type 2 diabetes among women and men: comparison between American Diabetes Association and World Health Organization diagnostic criteria., BMJ Open Diabetes Res Care, Vol: 8
INTRODUCTION: Pre-diabetes, a status conferring high risk of overt diabetes, is defined differently by the American Diabetes Association (ADA) and the WHO. We investigated the impact of applying definitions of pre-diabetes on lifetime risk of diabetes in women and men from the general population. RESEARCH DESIGN AND METHODS: We used data from 8844 women without diabetes and men aged ≥45 years from the prospective population-based Rotterdam Study in the Netherlands. In both gender groups, we calculated pre-diabetes prevalence according to ADA and WHO criteria and estimated the 10-year and lifetime risk to progress to overt diabetes with adjustment for competing risk of death. RESULTS: Out of 8844 individuals, pre-diabetes was identified in 3492 individuals (prevalence 40%, 95% CI 38% to 41%) according to ADA and 1382 individuals (prevalence 16%, 95% CI 15% to 16%) according to WHO criteria. In both women and men and each age category, ADA prevalence estimates doubled WHO-defined pre-diabetes. For women and men aged 45 years having ADA-defined pre-diabetes, the 10-year risk of diabetes was 14.2% (95% CI 6.0% to 22.5%) and 9.2% (95% CI 3.4% to 15.0%) compared with 23.2% (95% CI 6.8% to 39.6%) and 24.6% (95% CI 8.4% to 40.8%) in women and men with WHO-defined pre-diabetes. At age 45 years, the remaining lifetime risk to progress to overt diabetes was 57.5% (95% CI 51.8% to 63.2%) vs 80.2% (95% CI 74.1% to 86.3%) in women and 46.1% (95% CI 40.8% to 51.4%) vs 68.4% (95% CI 58.3% to 78.5%) in men with pre-diabetes according to ADA and WHO definitions, respectively. CONCLUSION: Prevalence of pre-diabetes differed considerably in both women and men when applying ADA and WHO pre-diabetes definitions. Women with pre-diabetes had higher lifetime risk to progress to diabetes. The lifetime risk of diabetes was lower in women and men with ADA-defined pre-diabetes as compared with WHO. Improvement of pre-diabetes definition considering appropriate sex-specific and
Nazarzadeh M, Pinho-Gomes A-C, Bidel Z, et al., 2020, Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study, European Heart Journal, Vol: 41, Pages: 3913-3920, ISSN: 0195-668X
AIMS: Aortic valve stenosis is commonly considered a degenerative disorder with no recommended preventive intervention, with only valve replacement surgery or catheter intervention as treatment options. We sought to assess the causal association between exposure to lipid levels and risk of aortic stenosis. METHODS AND RESULTS: Causality of association was assessed using two-sample Mendelian randomization framework through different statistical methods. We retrieved summary estimations of 157 genetic variants that have been shown to be associated with plasma lipid levels in the Global Lipids Genetics Consortium that included 188 577 participants, mostly European ancestry, and genetic association with aortic stenosis as the main outcome from a total of 432 173 participants in the UK Biobank. Secondary negative control outcomes included aortic regurgitation and mitral regurgitation. The odds ratio for developing aortic stenosis per unit increase in lipid parameter was 1.52 [95% confidence interval (CI) 1.22-1.90; per 0.98 mmol/L] for low density lipoprotein (LDL)-cholesterol, 1.03 (95% CI 0.80-1.31; per 0.41 mmol/L) for high density lipoprotein (HDL)-cholesterol, and 1.38 (95% CI 0.92-2.07; per 1 mmol/L) for triglycerides. There was no evidence of a causal association between any of the lipid parameters and aortic or mitral regurgitation. CONCLUSION: Lifelong exposure to high LDL-cholesterol increases the risk of symptomatic aortic stenosis, suggesting that LDL-lowering treatment may be effective in its prevention.
Huang J, Zuber V, Matthews P, et al., 2020, Sleep, major depressive disorder and Alzheimer’s disease: a Mendelian randomisation study, Neurology, Vol: 95, ISSN: 0028-3878
ObjectiveTo explore the causal relationships between sleep, major depressive disorder (MDD), and Alzheimer’s disease (AD).MethodsWe conducted bi-directional two-sample Mendelian randomisation analyses. Genetic associations were obtained from the largest genome-wide association studies currently available in UK Biobank (N=446,118), the Psychiatric Genomics Consortium (N=18,759), and the International Genomics of Alzheimer’s Project (N=63,926). We used the inverse variance weighted Mendelian randomisation method to estimate causal effects, and weighted median and MR-Egger for sensitivity analyses to test for pleiotropic effects. ResultsWe found that higher risk of AD was significantly associated with being a “morning person” (odds ratio (OR)=1.01, P=0.001), shorter sleep duration (self-reported: β=-0.006, P=1.9×10-4; accelerometer-based: β=-0.015, P=6.9×10-5), less likely to report long sleep (β=-0.003, P=7.3×10-7), earlier timing of the least active 5 hours (β=-0.024, P=1.7×10-13), and a smaller number of sleep episodes (β=-0.025, P=5.7×10-14) after adjusting for multiple comparisons. We also found that higher risk of AD was associated with lower risk of insomnia (OR=0.99, P=7×10-13). However, we did not find evidence either that these abnormal sleep patterns were causally related to AD or for a significant causal relationship between MDD and risk of AD. ConclusionWe found that AD may causally influence sleep patterns. However, we did not find evidence supporting a causal role of disturbed sleep patterns for AD or evidence for a causal relationship between MDD and AD.
Bai W, Suzuki H, Huang J, et al., 2020, A population-based phenome-wide association study of cardiac and aortic structure and function, Nature Medicine, Vol: 26, Pages: 1654-1662, ISSN: 1078-8956
Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed cardiovascular magnetic resonance images from a population-based study, the UK Biobank, using an automated machine-learning-based analysis pipeline. We report a comprehensive range of structural and functional phenotypes for the heart and aorta across 26,893 participants, and explore how these phenotypes vary according to sex, age and major cardiovascular risk factors. We extended this analysis with a phenome-wide association study, in which we tested for correlations of a wide range of non-imaging phenotypes of the participants with imaging phenotypes. We further explored the associations of imaging phenotypes with early-life factors, mental health and cognitive function using both observational analysis and Mendelian randomization. Our study illustrates how population-based cardiac and aortic imaging phenotypes can be used to better define cardiovascular disease risks as well as heart–brain health interactions, highlighting new opportunities for studying disease mechanisms and developing image-based biomarkers.
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
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
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
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, ISSN: 2041-1723
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
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