Epigenetics of Lipid Phenotypes

Dyslipidemia is a well-established risk factor for cardiovascular disease, the main cause of death worldwide. Blood lipid profiles are patterned by both genetic and environmental factors. In recent years, epigenetics has emerged as a paradigm that unifies these influences. In this review, we have summarized the latest evidence implicating epigenetic mechanisms—DNA methylation, histone modification, and regulation by RNAs—in lipid homeostasis. Key findings have emerged in a number of novel epigenetic loci located in biologically plausible genes (eg, CPT1A, ABCG1, SREBF1, and others), as well as microRNA-33a/b. Evidence from animal and cell culture models suggests a complex interplay between different classes of epigenetic processes in the lipid-related genomic regions. Although epigenetic findings hold the potential to explain the interindividual variability in lipid profiles as well as the underlying mechanisms, they have yet to be translated into effective therapies for dyslipidemia

DNA methylation biomarkers of myocardial infarction and cardiovascular disease

Background: The epigenetic landscape underlying cardiovascular disease (CVD) is not completely understood and the clinical value of the identifed biomarkers is still limited. We aimed to identify diferentially methylated loci associ‑ ated with acute myocardial infarction (AMI) and assess their validity as predictive and causal biomarkers. Results: We designed a case-control, two-stage, epigenome-wide association study on AMI (ndiscovery=391, nvalidation=204). DNA methylation was assessed using the Infnium MethylationEPIC BeadChip. We performed a fxed efects meta-analysis of the two samples. 34 CpGs were associated with AMI. Only 12 of them were available in two independent cohort studies (n~1800 and n~2500) with incident coronary and cardiovascular disease (CHD and CVD, respectively). The Infnium HumanMethylation450 BeadChip was used in those two studies. Four of the 12 CpGs were validated in association with incident CHD: AHRR-mapping cg05575921, PTCD2-mapping cg25769469, intergenic cg21566642 and MPO-mapping cg04988978. We then assessed whether methylation risk scores based on those CpGs improved the predictive capacity of the Framingham risk function, but they did not. Finally, we aimed to study the causality of those associations using a Mendelian randomization approach but only one of the CpGs had a genetic infuence and therefore the results were not conclusive. Conclusions: We have identifed 34 CpGs related to AMI. These loci highlight the relevance of smoking, lipid metab‑ olism, and infammation in the biological mechanisms related to AMI. Four were additionally associated with incident CHD and CVD but did not provide additional predictive informatio

DNA methylation and its relationship with lifestyle, environmental and cardiovascular risk factors

La malaltia cardiovascular, que és primera causa de mortalitat al món, com a fenotip complex depèn tant dels factors ambientals com dels genètics. Les variants genètiques comunes expliquen un 15-20% de l’heretabilitat de la malaltia. La metilació de l’ADN, que regula l’expressió gènica sense alterar la seqüència genètica primària, ha estat proposada com a mecanisme per unificar els efectes de l’estil de vida, els factors ambientals i els genètics. Per estudiar les relacions entre metilació de l’ADN i estil de vida, factors ambientals i factors de risc cardiovascular hem utilitzat estudis d’associació d’epigenoma complet, randomització mendeliana i integració d’òmiques. Hem inclòs dades de 10 estudis diferents, però els resultats han estat basats sobretot en l’estudi REGICOR (REgistre Gironí del COR). Aquesta tesi demostra l’associació entre 63 llocs de metilació (CpGs) i l’exposició al tabaquisme. No troba associació entre contaminació ambiental i metilació de l’ADN. Identifica 94 CpGs associats a obesitat i 14 als nivells lipídics. Observa que els nivells de triglicèrids en sang poden ser modificats i al mateix temps afectar la metilació en els gens CPT1A i SLC7A11, evidenciant la complexitat de l’homeostasis dels lípids. A més, s’ha realitzat el primer estudi que mostra l’associació entre la metilació de l’ADN i la funcionalitat de la HDL. Com a conclusions d’aquesta recerca destaquen la forta associació del tabac a un patró de metilació específic i l’associació entre la metilació de l’ADN i diferents factors de risc cardiovascular amb una relació causal complexa.Coronary artery disease is the first cause of death worldwide, and as a complex disease implies the interplay between genetic and environmental factors. Common genetic variants explain only 15-20% of its heritability. DNA methylation, which regulates the gene expression without altering the DNA sequence, has been proposed as a heritable signature to explain this missing heritability and as a mediator effect of lifestyle and environment on health. To study the relationship between DNA methylation and smoking, air pollution, and cardiovascular risk factors (obesity, lipid profile, and HDL functionality) we used epigenome-wide association studies, Mendelian randomization, and multi-stage omics integration approaches. We included data from ten studies, but the results were mainly based on the REGICOR (REgistre GIroní del COR) cohort. We report the association between smoking and 63 methylation sites (CpGs). We did not find association between air pollution and DNA methylation. We identified 94 CpGs associated with obesity and 14 with lipid profile. We observed that methylation at CPT1A and SLC7A11 can modify or be affected by the triglycerides levels, highlighting the complexity of the lipids homeostasis. Finally, we performed the first study showing an association between DNA methylation and HDL functionality. As conclusions of this research, smoking is strongly associated with a distinctive methylation pattern and there is a relationship between DNA methylation and several cardiovascular risk factors, although its causality is complex

DNA methylation and its relationship with lifestyle, environmental and cardiovascular risk factors

La malaltia cardiovascular, que és primera causa de mortalitat al món, com a fenotip complex depèn tant dels factors ambientals com dels genètics. Les variants genètiques comunes expliquen un 15-20% de l’heretabilitat de la malaltia. La metilació de l’ADN, que regula l’expressió gènica sense alterar la seqüència genètica primària, ha estat proposada com a mecanisme per unificar els efectes de l’estil de vida, els factors ambientals i els genètics. Per estudiar les relacions entre metilació de l’ADN i estil de vida, factors ambientals i factors de risc cardiovascular hem utilitzat estudis d’associació d’epigenoma complet, randomització mendeliana i integració d’òmiques. Hem inclòs dades de 10 estudis diferents, però els resultats han estat basats sobretot en l’estudi REGICOR (REgistre Gironí del COR). Aquesta tesi demostra l’associació entre 63 llocs de metilació (CpGs) i l’exposició al tabaquisme. No troba associació entre contaminació ambiental i metilació de l’ADN. Identifica 94 CpGs associats a obesitat i 14 als nivells lipídics. Observa que els nivells de triglicèrids en sang poden ser modificats i al mateix temps afectar la metilació en els gens CPT1A i SLC7A11, evidenciant la complexitat de l’homeostasis dels lípids. A més, s’ha realitzat el primer estudi que mostra l’associació entre la metilació de l’ADN i la funcionalitat de la HDL. Com a conclusions d’aquesta recerca destaquen la forta associació del tabac a un patró de metilació específic i l’associació entre la metilació de l’ADN i diferents factors de risc cardiovascular amb una relació causal complexa.Coronary artery disease is the first cause of death worldwide, and as a complex disease implies the interplay between genetic and environmental factors. Common genetic variants explain only 15-20% of its heritability. DNA methylation, which regulates the gene expression without altering the DNA sequence, has been proposed as a heritable signature to explain this missing heritability and as a mediator effect of lifestyle and environment on health. To study the relationship between DNA methylation and smoking, air pollution, and cardiovascular risk factors (obesity, lipid profile, and HDL functionality) we used epigenome-wide association studies, Mendelian randomization, and multi-stage omics integration approaches. We included data from ten studies, but the results were mainly based on the REGICOR (REgistre GIroní del COR) cohort. We report the association between smoking and 63 methylation sites (CpGs). We did not find association between air pollution and DNA methylation. We identified 94 CpGs associated with obesity and 14 with lipid profile. We observed that methylation at CPT1A and SLC7A11 can modify or be affected by the triglycerides levels, highlighting the complexity of the lipids homeostasis. Finally, we performed the first study showing an association between DNA methylation and HDL functionality. As conclusions of this research, smoking is strongly associated with a distinctive methylation pattern and there is a relationship between DNA methylation and several cardiovascular risk factors, although its causality is complex

Prevalence and prognosis of high-risk myocardial infarction patient candidates to extended antiplatelet therapy.

INTRODUCTION AND OBJECTIVES: Secondary prevention in myocardial infarction patients is paramount to prevent recurrences. Dual antiplatelet therapy has been shown to reduce the risk of subsequent events up to 1 year and beyond in the PEGASUS-TIMI 54 trial. This study aimed to estimate the annual number of myocardial infarction patients with PEGASUS characteristics in Spain and to analyze short- and long-term outcomes in these patients. METHODS: The number of myocardial infarction patients was estimated assuming a Poisson distribution. Myocardial infarction incidence and mortality rates obtained from population registries (IBERICA and REGICOR) were properly adjusted. The proportion of myocardial infarction patients with PEGASUS characteristics was estimated with a REGICOR cohort of consecutive patients from 2003-2009 (n=1391). This cohort follow-up was used to compare the occurrence of reinfarction and death at 1 year and at the end of the follow-up (4.7 years) in patients with and without PEGASUS characteristics by Cox regression. RESULTS: The estimated annual number of stable myocardial infarction patients aged ≥ 50 years and without bleeding events was 41 311. Of these, 22 493 had at least 1 PEGASUS characteristic (diabetes, previous myocardial infarction, or chronic kidney disease). At 4.7 years of follow-up, having any PEGASUS characteristic or age ≥ 65 years was associated with a higher risk of cardiovascular and all-cause death in adjusted analyses (hazard ratio=3.44 and 2.21, 95% confidence interval, 1.22-9.74 and 1.11-4.42, respectively). CONCLUSIONS: In Spain, more than 50% of the stable myocardial infarction patients aged ≥ 50 years are estimated to have at least 1 PEGASUS characteristic, which substantially increases the long-term risk of cardiovascular and all-cause death.The REGICOR AMI Registry was supported by the Instituto de Salud Carlos III-FEDER (grant numbers RD06/0009, RD12/0042, FIS-90/0672, FIS-93/0568, FIS 94/0539, FIS96/0026-01, FIS99/0655, FIS99/0013-01, FIS 99/9342, PI081327, PI11/01801, CP12/03287 [MG], and IFI14/00007 [SSB]), the Catalan Agency for Management of University and Research Grants (grant numbers 2005SGR00577, 2009SGR1195, 2014SGR240), Fundació La Marató TV3 (grant number ID #081630) and Agència d’Informació, Avaluació i Qualitat en Salut (grant number AATRM 034/33/02). I.R. Dégano was funded by the RECERCAIXA Program, Obra Social ‘‘La Caixa’’ (grant number RE087465)

Adipokines and risk of rheumatoid arthritis : A two-sample multivariable Mendelian randomisation study

Adiponectin, leptin, and resistin are thought to be involved in the pathogenesis of rheumatoid arthritis (RA). However, the causal relationship between these adipokines and the risk for RA is unclear. We performed a range of two-sample Mendelian randomisation (MR) analyses to assess the causal effect of circulating adiponectin, leptin, and resistin on RA risk in European and East Asian individuals. Different sets of adiponectin-, leptin-, and resistin-related genetic variants were used as instruments for genetically determined adipokine levels. As body mass index (BMI) is a risk factor for RA and affects adipokine levels, multivariable MR was used to calculate the causal effect of each adipokine on RA risk taking BMI into account. Several MR analyses revealed no evidence of a causal relationship between circulating adiponectin, leptin, or resistin levels and RA risk in either Europeans or East Asians. Similarly, multivariable MR did not provide evidence of any causal effect of adiponectin, leptin, or resistin on RA risk when taking BMI into account. This MR study shows for the first time that genetically determined levels of adiponectin, leptin, or resistin do not have a direct causal effect on the risk of developing RA after adjustment for BMI

DNA methylation and obesity traits: An epigenome-wide association study. The REGICOR study

Obesity is associated with increased risk of several diseases and has become epidemic. Obesity is highly heritable but the genetic variants identified by genome-wide association studies explain only limited variability. Epigenetics could contribute to explain the missing variability. The study aim was to discover differential methylation patterns related to obesity. We designed an epigenome-wide association study with a discovery phase in a subsample of 641 REGICOR study participants, validated by analysis of 2,515 participants in the Framingham Offspring Study. Blood DNA methylation was assessed using Illumina HumanMethylation450 BeadChip. Next, we meta-analyzed the data using the fixed effects method and performed a functional and pathway analysis using the Ingenuity Pathway Analysis software. We were able to validate 94 CpGs associated with body mass index (BMI) and 49 CpGs associated with waist circumference, located in 95 loci. In addition, we newly discovered 70 CpGs associated with BMI and 33 CpGs related to waist circumference. These CpGs explained 25.94% and 29.22% of the variability of BMI and waist circumference, respectively, in the REGICOR sample. We also evaluated 65 of the 95 validated loci in the GIANT genome-wide association data; 10 of them had Tag SNPs associated with BMI. The top-ranked diseases and functions identified in the functional and pathway analysis were neurologic, psychological, endocrine, and metabolic

An online atlas of human plasma metabolite signatures of gut microbiome composition

Human gut microbiota produce a variety of molecules, some of which enter the bloodstream and impact health. Conversely, dietary or pharmacological compounds may affect the microbiota before entering the circulation. Characterization of these interactions is an important step towards understanding the effects of the gut microbiota on health. In this cross-sectional study, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for a detailed characterization of the gut microbiota and plasma metabolome, respectively, of 8583 participants invited at age 50 to 64 from the population-based Swedish CArdioPulmonary bioImage Study. Here, we find that the gut microbiota explain up to 58% of the variance of individual plasma metabolites and we present 997 associations between alpha diversity and plasma metabolites and 546,819 associations between specific gut metagenomic species and plasma metabolites in an online atlas ( https://gutsyatlas.serve.scilifelab.se/ ). We exemplify the potential of this resource by presenting novel associations between dietary factors and oral medication with the gut microbiome, and microbial species strongly associated with the uremic toxin p-cresol sulfate. This resource can be used as the basis for targeted studies of perturbation of specific metabolites and for identification of candidate plasma biomarkers of gut microbiota composition

Streptococcus Species Abundance in the Gut Is Linked to Subclinical Coronary Atherosclerosis in 8973 Participants From the SCAPIS Cohort

BACKGROUND: Gut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography-based measures of coronary atherosclerosis and to explore relevant clinical correlates. METHODS: We conducted a cross-sectional study of 8973 participants (50 to 65 years of age) without overt atherosclerotic disease from the population-based SCAPIS (Swedish Cardiopulmonary Bioimage Study). Coronary atherosclerosis was measured using coronary artery calcium score and coronary computed tomography angiography. Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of stool, and associations with coronary atherosclerosis were evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva. RESULTS: The mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3%, and 5.4% had at least 1 stenosis with >50% occlusion. Sixty-four species were associated with coronary artery calcium score independent of cardiovascular risk factors, with the strongest associations observed for Streptococcus anginosus and Streptococcus oralis subsp oralis (P<1×10-5). Associations were largely similar across coronary computed tomography angiography-based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations, and 16 with neutrophil counts. Gut microbial species that are commonly found in the oral cavity were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species, including 3 streptococci, correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid β-oxidation, and amino acid degradation were associated with coronary artery calcium score. CONCLUSIONS: This study provides evidence of an association of a gut microbiota composition characterized by increased abundance of Streptococcus spp and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation markers. Further longitudinal and experimental studies are warranted to explore the potential implications of a bacterial component in atherogenesis

Obstructive sleep apnea was associated with the human gut microbiota composition and functional potential in the population-based Swedish CardioPulmonary bioImage Study (SCAPIS)

BACKGROUND: Obstructive sleep apnea (OSA) is a common sleep-breathing disorder linked to increased risk of cardiovascular disease. Intermittent hypoxia and intermittent airway obstruction, hallmarks of OSA, have been shown in animal models to induce substantial changes to the gut microbiota composition and subsequent transplantation of fecal matter to other animals induced changes in blood pressure and glucose metabolism. RESEARCH QUESTION: Does obstructive sleep apnea in adults associate with the composition and metabolic potential of the human gut microbiota? STUDY DESIGN AND METHODS: We used respiratory polygraphy data from up to 3,570 individuals aged 50-64 from the population-based Swedish CardioPulmonary bioImage Study combined with deep shotgun metagenomics of fecal samples to identify cross-sectional associations between three OSA parameters covering apneas and hypopneas, cumulative sleep time in hypoxia and number of oxygen desaturation events with gut microbiota composition. Data collection about potential confounders was based on questionnaires, on-site anthropometric measurements, plasma metabolomics, and linkage with the Swedish Prescribed Drug Register. RESULTS: We found that all three OSA parameters were associated with lower diversity of species in the gut. Further, the OSA-related hypoxia parameters were in multivariable-adjusted analysis associated with the relative abundance of 128 gut bacterial species, including higher abundance of Blautia obeum and Collinsela aerofaciens. The latter species was also independently associated with increased systolic blood pressure. Further, the cumulative time in hypoxia during sleep was associated with the abundance of genes involved in nine gut microbiota metabolic pathways, including propionate production from lactate. Lastly, we observed two heterogeneous sets of plasma metabolites with opposite association with species positively and negatively associated with hypoxia parameters, respectively. INTERPRETATION: OSA-related hypoxia, but not the number of apneas/hypopneas, is associated with specific gut microbiota species and functions. Our findings lay the foundation for future research on the gut microbiota-mediated health effects of OSA