scholarly journals Epigenetic Regulation of F2RL3 Associates with Myocardial Infarction and Platelet Function

2022 ◽  
Author(s):  
Laura Jayne Corbin ◽  
Stephen J White ◽  
Amy Taylor ◽  
Christopher Michael Williams ◽  
Kurt Taylor ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Dna Methylation ◽  
Platelet Reactivity ◽  
Atherosclerotic Cardiovascular Disease ◽  
Dna Hypomethylation ◽  
Exon 2 ◽  
Increased Risk

Background: DNA hypomethylation at the F2RL3 locus has been associated with both smoking and atherosclerotic cardiovascular disease; whether these smoking-related associations form a pathway to disease is unknown. F2RL3 encodes protease-activated receptor 4, a potent thrombin receptor expressed on platelets. Given the role of thrombin in platelet activation and the role of thrombus formation in myocardial infarction, alterations to this biological pathway could be important for ischemic cardiovascular disease. Methods: We conducted multiple independent experiments to assess whether DNA hypomethylation at F2RL3 in response to smoking is associated with risk of myocardial infarction via changes to platelet reactivity. Using cohort data (N=3,205), we explored the relationship between smoking, DNA hypomethylation at F2RL3 and myocardial infarction. We compared platelet reactivity in individuals with low versus high DNA methylation at F2RL3 (N=41). We used an in vitro model to explore the biological response of F2RL3 to cigarette smoke extract (CSE). Finally, a series of reporter constructs were used to investigate how differential methylation could impact F2RL3 gene expression. Results: Observationally, DNA methylation at F2RL3 mediated an estimated 34% of the smoking effect on increased risk of myocardial infarction. An association between methylation group (low/high) and platelet reactivity was observed in response to PAR4 stimulation. In cells, CSE exposure was associated with a 4.9 to 9.3% reduction in DNA methylation at F2RL3 and a corresponding 1.7 (95% CI: 1.2, 2.4, p=0.04) fold increase in F2RL3 mRNA. Results from reporter assays suggest the exon 2 region of F2RL3 may help control gene expression. Conclusions: Smoking-induced epigenetic DNA hypomethylation at F2RL3 appears to increase PAR4 expression with potential downstream consequences for platelet reactivity. Combined evidence here not only identifies F2RL3 DNA methylation as a possible contributory pathway from smoking to cardiovascular disease risk, but from any feature potentially influencing F2RL3 regulation in a similar manner.

scholarly journals Epigenetic regulation of PAR4-related platelet activation: mechanistic links between environmental exposure and cardiovascular disease

2018 ◽  
Author(s):  
Laura J. Corbin ◽  
Amy E. Taylor ◽  
Stephen J. White ◽  
Christopher M. Williams ◽  
Kurt Taylor ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Dna Methylation ◽  
Platelet Activation ◽  
Cardiovascular Health ◽  
Platelet Reactivity ◽  
Dna Hypomethylation ◽  
Enhancer Activity ◽  
Exon 2 ◽  
Short Term Exposure

AbstractProtease-activated receptor 4 (PAR4) is a potent thrombin receptor. Epigenetic control of theF2RL3locus (which encodes for PAR4) via DNA methylation is associated with both smoking and cardiovascular disease. We examined the association between DNA hypomethylation atF2RL3and risk of cardiovascular disease, focusing on acute myocardial infarction (AMI) (n=853 cases / 2,352 controls). We usedin vitrocell models to dissect the role of DNA methylation in regulating expression ofF2RL3.We investigated the interplay betweenF2RL3DNA methylation and platelet function in human (n=41). Lastly, we used Mendelian randomization to unify observational and functional work by assessing evidence for causal relationships using data from UK Biobank (n=407,141) and CARDIoGRAMplusC4D (n=184,305). Observationally, one standard deviation (SD) decrease in DNA methylation atF2RL3was associated with a 25% increase in the odds of AMI.In vitro, short-term exposure of cells to cigarette smoke reducedF2RL3DNA methylation and increased gene expression. Transcriptional assays flagged a role for a CEBP recognition sequence in modulating the enhancer activity ofF2RL3exon 2. Lower DNA methylation atF2RL3was associated with increased platelet reactivity in human. The estimated casual odds ratio of ischaemic heart disease was 1.03 (95% CI: 1.00, 1.07) per 1 SD decrease inF2RL3DNA. In conclusion, we show that DNA methylation-dependent platelet activation is part of a complex system of features contributing to cardiovascular health. Tailoring therapeutic intervention to new knowledge ofF2RL3/PAR4 function should be explored to ameliorate the detrimental effects of this risk factor on cardiovascular health.One sentence summaryDNA methylation-dependent platelet activation is a likely causal contributor to cardiovascular health.

scholarly journals Early Pregnancy Exposure to Ambient Air Pollution among Late-Onset Preeclamptic Cases Is Associated with Placental DNA Hypomethylation of Specific Genes and Slower Placental Maturation

Toxics ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 338
Author(s):  
Karin Engström ◽  
Yumjirmaa Mandakh ◽  
Lana Garmire ◽  
Zahra Masoumi ◽  
Christina Isaxon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Air Pollution ◽  
Early Pregnancy ◽  
Late Onset ◽  
Dispersion Model ◽  
Ambient Air ◽  
Ambient Air Pollution ◽  
Dna Hypomethylation ◽  
Increased Risk

Exposure to ambient air pollution during pregnancy has been associated with an increased risk of preeclampsia (PE). Some suggested mechanisms behind this association are changes in placental DNA methylation and gene expression. The objective of this study was to identify how early pregnancy exposure to ambient nitrogen oxides (NOx) among PE cases and normotensive controls influence DNA methylation (EPIC array) and gene expression (RNA-seq). The study included placentas from 111 women (29 PE cases/82 controls) in Scania, Sweden. First-trimester NOx exposure was assessed at the participants’ residence using a dispersion model and categorized via median split into high or low NOx. Placental gestational epigenetic age was derived from the DNA methylation data. We identified six differentially methylated positions (DMPs, q < 0.05) comparing controls with low NOx vs. cases with high NOx and 14 DMPs comparing cases and controls with high NOx. Placentas with female fetuses showed more DMPs (N = 309) than male-derived placentas (N = 1). Placentas from PE cases with high NOx demonstrated gestational age deceleration compared to controls with low NOx (p = 0.034). No differentially expressed genes (DEGs, q < 0.05) were found. In conclusion, early pregnancy exposure to NOx affected placental DNA methylation in PE, resulting in placental immaturity and showing sexual dimorphism.

Chronic Inflammatory Diseases and Atherosclerotic Cardiovascular Disease: Innocent Bystanders or Partners in Crime?

2018 ◽  
Vol 24 (3) ◽  
pp. 281-290 ◽  
Author(s):  
Peter Riis Hansen
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Inflammatory Diseases ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cvd Risk Factors ◽  
Cvd Risk ◽  
Chronic Inflammatory Diseases ◽  
Increased Risk ◽  
Shared Risk

Inflammation plays a significant role in atherosclerosis and cardiovascular disease (CVD). Patients with chronic inflammatory diseases are at increased risk of CVD, but it is debated whether this association is causal or dependent on shared risk factors, other exposures, genes, and/or inflammatory pathways. The current review summarizes epidemiological, clinical, and experimental data supporting the role of shared inflammatory mechanisms between atherosclerotic CVD and rheumatoid arthritis, psoriasis, inflammatory bowel disease, and periodontitis, respectively, and provides insights to future prospects in this area of research. Awareness of the role of inflammation in CVD in patients with chronic inflammatory diseases and the potential for anti-inflammatory therapy, e.g., with tumor necrosis factor-α inhibitors, to also reduce atherosclerotic CVD has evolved into guideline- based recommendations. These include regular CVD risk assessment, aggressive treatment of traditional CVD risk factors, and recognition of reduced CVD as an added benefit of strict inflammatory disease control. At present, chronic inflammatory diseases would appear to qualify as partners in crime and not merely innocent bystanders to CVD. However, definite incremental contributions of inflammation versus effects of the complex interplay with other CVD risk factors may never be fully elucidated and for the foreseeable future, inflammation is posed to maintain its current position as both a marker and a maker of CVD, with clinical utility both for identification of patient at risk of CVD and as target for therapy to reduce CVD.

Mean platelet volume mediated the relationships between heavy metals exposure and atherosclerotic cardiovascular disease risk: A community-based study

2019 ◽  
Vol 27 (8) ◽  
pp. 830-839
Author(s):  
Chunmei Zhu ◽  
Bin Wang ◽  
Lili Xiao ◽  
Yanjun Guo ◽  
Yun Zhou ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Cardiovascular Disease ◽  
Mean Platelet Volume ◽  
Atherosclerotic Cardiovascular Disease ◽  
Platelet Volume ◽  
Mediation Analyses ◽  
Increased Risk ◽  
Ascvd Risk ◽  
Metals Exposure

Background Heavy metals were related to increased risk of atherosclerotic cardiovascular disease (ASCVD). However, potential mechanisms under such associations remain unclear. We aimed to investigate the mediating role of mean platelet volume in the associations between heavy metals exposure and 10-year ASCVD risk. Method Urinary heavy metals and mean platelet volume were measured in 3081 adults from the Wuhan-Zhuhai cohort in China. The associations between urinary heavy metals, mean platelet volume and 10-year ASCVD risk were separately analyzed through generalized linear models and logistic regression models. Mediation analyses were conducted to assess the role of mean platelet volume in the associations between urinary heavy metals and 10-year ASCVD risk. Results After adjusting for potential confounders, 10-year ASCVD risk was positively associated with urinary iron (odds ratio (OR) = 1.142, 95% confidence interval (1.038–1.256)), copper (OR = 1.384 (1.197–1.601)), zinc (OR = 1.520 (1.296–1.783)), cadmium (OR = 1.153 (0.990, 1.342)) and antimony (OR = 1.452 (1.237–1.704)), and negatively related with urinary barium (OR = 0.905 (0.831–0.985)). Also, we found significant dose–response relationships between urinary iron, zinc, antimony and mean platelet volume, as well as between mean platelet volume and 10-year ASCVD risk (all pfor trends < 0.05). Furthermore, mediation analyses indicated that mean platelet volume mediated 17.55%, 6.15% and 7.38% of the associations between urinary iron, zinc, antimony and 10-year ASCVD risk, respectively (all pvalue < 0.05). Conclusions Elevated concentrations of urinary iron, copper, zinc, cadmium and antimony were associated with increased risk of 10-year ASCVD. Mean platelet volume partially mediated the associations of urinary iron, zinc and antimony with 10-year ASCVD risk.

scholarly journals Divergence among rice cultivars reveals roles for transposition and epimutation in ongoing evolution of genomic imprinting

2021 ◽  
Vol 118 (29) ◽  
pp. e2104445118
Author(s):  
Jessica A. Rodrigues ◽  
Ping-Hung Hsieh ◽  
Deling Ruan ◽  
Toshiro Nishimura ◽  
Manoj K. Sharma ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Genomic Imprinting ◽  
Small Rnas ◽  
Imprinted Genes ◽  
Dna Hypomethylation ◽  
Transcription Start ◽  
Specific Expression ◽  
Parent Of Origin

Parent-of-origin–dependent gene expression in mammals and flowering plants results from differing chromatin imprints (genomic imprinting) between maternally and paternally inherited alleles. Imprinted gene expression in the endosperm of seeds is associated with localized hypomethylation of maternally but not paternally inherited DNA, with certain small RNAs also displaying parent-of-origin–specific expression. To understand the evolution of imprinting mechanisms in Oryza sativa (rice), we analyzed imprinting divergence among four cultivars that span both japonica and indica subspecies: Nipponbare, Kitaake, 93-11, and IR64. Most imprinted genes are imprinted across cultivars and enriched for functions in chromatin and transcriptional regulation, development, and signaling. However, 4 to 11% of imprinted genes display divergent imprinting. Analyses of DNA methylation and small RNAs revealed that endosperm-specific 24-nt small RNA–producing loci show weak RNA-directed DNA methylation, frequently overlap genes, and are imprinted four times more often than genes. However, imprinting divergence most often correlated with local DNA methylation epimutations (9 of 17 assessable loci), which were largely stable within subspecies. Small insertion/deletion events and transposable element insertions accompanied 4 of the 9 locally epimutated loci and associated with imprinting divergence at another 4 of the remaining 8 loci. Correlating epigenetic and genetic variation occurred at key regulatory regions—the promoter and transcription start site of maternally biased genes, and the promoter and gene body of paternally biased genes. Our results reinforce models for the role of maternal-specific DNA hypomethylation in imprinting of both maternally and paternally biased genes, and highlight the role of transposition and epimutation in rice imprinting evolution.

scholarly journals Dietary and Blood Lipids in Cardiovascular Disease

2020 ◽  
pp. 11-21
Author(s):  
Sheikh Salahuddin Ahmed
Keyword(s):  
Cardiovascular Disease ◽  
Blood Lipids ◽  
Cardiovascular Health ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atherosclerotic Cardiovascular Disease ◽  
Structural Protein ◽  
Lipoprotein Particles ◽  
Increased Risk

Blood lipids are essential for life; at the same time, elevated or reduced levels of some of the components of lipid are related to risk of atherosclerotic cardiovascular disease (ASCVD). This article provides a review on dietary and blood lipids with their impact on cardiovascular health. The role of apolipoprotein B (ApoB), Lipoprotein(a) ((Lp(a)) and other lipoprotein particles in the development of ASCVD has been reviewed. There are new evidences that ApoB the structural protein of most of the lipoprotein particles (carrier of blood lipids), in addition to low density lipoprotein-cholesterol (LDL-C), plays a central role in the pathogenesis of atherosclerosis with increased risk for ASCVD. Elevated levels of Lp(a) concentrations are associated with an increased risk of ASCVD, but it appears to be a weaker risk factor than ApoB or LDL-C.

Estimation of the increased risk associated with recurrent events or polyvascular atherosclerotic cardiovascular disease in the United Kingdom

2020 ◽  
pp. 204748731989921 ◽  
Author(s):  
Mark D Danese ◽  
Peter Pemberton-Ross ◽  
David Catterick ◽  
Guillermo Villa
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
United Kingdom ◽  
Ischemic Stroke ◽  
Event History ◽  
Atherosclerotic Cardiovascular Disease ◽  
Risk Equation ◽  
Increased Risk ◽  
Event Histories

Aims The aims of this study were to re-estimate the international REduction of Atherothrombosis for Continued Health (REACH) risk equation using United Kingdom data and to distinguish different relative hazards for specific atherosclerotic cardiovascular disease event histories. Methods and results Patients in the UK Clinical Research Practice Datalink (CPRD) were included as of 1 January 2005 if they were 40 years or older, had 2 or more years of prior data, received one or more moderate or high-intensity statin in the previous year, and had a history of myocardial infarction, ischemic stroke, or other atherosclerotic cardiovascular disease. Patients were followed until a composite endpoint of myocardial infarction, ischemic stroke or cardiovascular death, loss to follow-up, or end of observation. We re-estimated the REACH risk equation hazard ratios (HRs) using CPRD data (re-estimated REACH model). Our event history model replaced the REACH vascular bed variables with more specific event histories. There were 60,838 patients with 5.25 years of mean follow-up. In the validation model, HRs were in the same direction, and generally greater than REACH. In the event history model, HRs compared to other atherosclerotic cardiovascular disease alone included: recurrent myocardial infarction (HR 1.19, 95% confidence interval (CI) 1.05–1.34), recurrent ischemic stroke (HR 1.36, 95% CI 1.03–1.80), myocardial infarction and other atherosclerotic cardiovascular disease (HR 1.31, 95% CI 1.23–1.38), ischemic stroke and other atherosclerotic cardiovascular disease (HR 1.40, 95% CI 1.23–1.60), myocardial infarction and ischemic stroke (HR 1.94, 95% CI 1.23–3.04), and myocardial infarction, ischemic stroke and other atherosclerotic cardiovascular disease (HR 1.93, 95% CI 1.47–2.54). Conclusion A detailed cardiovascular event history may be useful for estimating the relative risk of future cardiovascular events.

Abstract 13196: The Utility of Silent Myocardial Infarction on Electrocardiogram as an ASCVD Risk Enhancer for Primary Prevention: The Multi-Ethnic Study of Atherosclerosis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Matthew J Singleton ◽  
Charles German ◽  
Elsayed Z Soliman ◽  
Gregory Burke ◽  
Joseph Yeboah
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Cox Proportional Hazards Model ◽  
P Value ◽  
Atherosclerotic Cardiovascular Disease ◽  
Intermediate Risk ◽  
Net Reclassification Improvement ◽  
Increased Risk ◽  
Ascvd Risk ◽  
Silent Myocardial Infarction

Introduction: The 2018 AHA/ACC cholesterol guidelines introduced a new list of markers called “risk enhancers” that, if present, confer an increased risk of atherosclerotic cardiovascular disease (ASCVD). Notably absent is silent myocardial infarction (SMI) on electrocardiogram (ECG), even though SMI has been shown to be associated with future ASCVD. Hypothesis: Adding SMI to the pooled cohort equation (PCE) will improve risk discrimination and classification in those with intermediate ASCVD risk (5 - 20% 10-year risk). Methods: SMI was defined as a major Q-wave abnormality or minor Q/QS waves in the setting of major ST-T abnormalities in the absence of history of clinical cardiovascular disease. Incident ASCVD events included myocardial infarction, coronary heart disease death, and fatal and non-fatal stroke. Results: Among 2,278 intermediate-risk MESA participants, 48 (2.1%) had SMI at baseline. Over 32,150 person-years (median 15.8), incident ASCVD events occurred in 297/2,230 (13%) of those without SMI and 13/48 (27%) of those with SMI. In a Cox proportional hazards model that was adjusted for calculated 10-year ASCVD risk based on the PCE, SMI was associated with increased risk of ASCVD (HR 2.22, 95% CI 1.27 - 3.87, p = 0.005). Adding SMI to the PCE did not improve discrimination, with areas under the receiver operating characteristic curves for models without and with SMI of 0.5812 and 0.5874, respectively (p-value for difference 0.22; Figure 1a). The net reclassification improvement for adding SMI as a risk enhancer to reclassify participants from intermediate-risk to high-risk was 0.0242 (95% CI 0.0011 - 0.0472, p = 0.04; Figure 1b). Conclusions: Our findings suggest that the prevalence of SMI is 2.1% among those without known clinical cardiovascular disease considered intermediate-risk by the pooled cohort equation. In our analysis, SMI only modestly improved classification of risk, suggesting that it may not be very useful as an ASCVD risk enhancer.

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