Repetitive element hypermethylation in multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) is a complex disorder of the central nervous system whose cause is currently unknown. Evidence is increasing that DNA methylation alterations could be involved in inflammatory and neurodegenerative diseases and could contribute to MS pathogenesis. Repetitive elements Alu, LINE-1 and SAT-α, are widely known as estimators of global DNA methylation. We investigated Alu, LINE-1 and SAT-α methylation levels to evaluate their difference in a case-control setup and their role as a marker of disability. RESULTS: We obtained blood samples from 51 MS patients and 137 healthy volunteers matched by gender, age and smoking. Methylation was assessed using bisulfite-PCR-pyrosequencing. For all participants, medical history, physical and neurological examinations and screening laboratory tests were collected. All repetitive elements were hypermethylated in MS patients compared to healthy controls. A lower Expanded Disability Status Scale (EDSS) score was associated with a lower levels of LINE-1 methylation for 'EDSS = 1.0' and '1.5 ≤ EDSS ≤ 2.5' compared to an EDSS higher than 3, while Alu was associated with a higher level of methylation in these groups: 'EDSS = 1.0' and '1.5 ≤ EDSS ≤ 2.5'. CONCLUSIONS: MS patients exhibit an hypermethylation in repetitive elements compared to healthy controls. Alu and LINE-1 were associated with degree of EDSS score. Forthcoming studies focusing on epigenetics and the multifactorial pathogenetic mechanism of MS could elucidate these links further.

Extracellular histones mediate the effects of metal-rich air particles on blood coagulation.

BACKGROUND: Epidemiological studies have shown associations of particulate matter (PM) exposure with hypercoagulability and thrombosis. Extracellular circulating histones have recently been identified as novel mediators of inflammatory and procoagulant responses. The potential roles of extracellular histones in PM-related hypercoagulability have yet not been investigated. OBJECTIVES: In 63 steel workers, we evaluated the effects of exposure to PM and PM metal components on two extracellular histone modifications (H3K4me3 and H3K9ac); and the association of H3K4me3 and H3K9ac with coagulation markers. METHODS: Extracellular H3K4me3 and H3K9ac were determined in plasma through enzyme-linked immunosorbent assays. Coagulation markers included endogenous thrombin potentials (ETPs), tissue-type plasminogen activator antigen (t-PA) and D-dimer. Exposure to PM with aerodynamic diameters <1 µm (PM1) or <10 µm (PM10) and PM10 metal components were estimated for each participant. RESULTS: The coagulation marker ETP, measured in the presence of soluble thrombomodulin (ETP TM+), showed significant positive associations with PM1 (ß=107.84, p=0.03), PM10 (ß=83.06, p=0.02), and zinc (ß=75.14, p=0.03); and a marginal association with iron (ß=122.58, p=0.07). Additional PM effects were observed on t-PA, D-dimer, and ETP TM+. PM1 exposure was associated with increased plasma H3K4me3 and H3K9ac (ß=0.20, p=0.02; ß=0.16, p=0.05, respectively). H3K4me3, but not H3K9ac, was associated with zinc (ß=0.13, p=0.03) and iron (ß=0.32, p=0.01) contained in PM. ETP TM+ was increased in association with higher plasma H3K4me3 (ß=0.50, p=0.05) and H3K9ac (ß=0.54, p=0.05). CONCLUSIONS: This observational study suggests potential roles of extracellular histones in PM-induced hypercoagulability. Experimental studies are warranted to further characterize these findings.

[Epigenetic effects as mediators of procoagulant action of thin dust with high metal content. Study on occupational epidemiology]. / Effetti epigenetici come mediatori dell'azione pro-coagulante delle polveri sottili ad alto contenuto metallico. Uno studio di epidemiologia occupazionale.

Blood hypo-methylation mediates the effects of metal-rich airborne particles on blood coagulation: An occupational epidemiological study. Particulate matter (PM) exposure is associated with increased coagulation and thrombosis, but the biological mechanism has not yet been clarified. DNA methylation represents a potential mechanism because it can be modified by environmental factors. Foundry workers are exposed to PM components and showed increased cardiovascular risk. In a group of 63 steel workers we found that PM and zinc airborne levels were negatively associated with leukocyte DNA methylation in genes NOS3 and ET-1 (b = -1.1; p = 0.002 and b = -1.5; p = 0.003, for zinc exposure respectively in multivariate regression models; b = -0.9 with p = 0.01 for PM10 exposure and NOS3) and in turn, DNA hypo-methylation resulted associated with increased Endogenous Thrombin Potential (for NOS3 b = -45.0, p = 0.001; and for ET-1 b = -16.4, p = 0.03). Our study based on healthy subject exposed in occupational setting, suggests that gene specific hypomethylation contributes to environmentally-induced hypercoagulability.

Urinary chromium is associated with changes in leukocyte miRNA expression in obese subjects.

BACKGROUND/OBJECTIVES: Epidemiological studies suggest a link between chromium (Cr) status and cardiovascular disease. Increased urinary excretion of Cr was reported in subjects with diabetes compared with non-diabetic controls and those with non-diabetic insulin resistance. Epigenetic alterations have been linked to the presence of Cr, and microRNA (miRNA) expression has been implicated in the pathogenesis of metabolic diseases and cardiovascular diseases (CVDs). We investigated the association between Cr excretion and miRNA expression in leukocytes from obese subjects. We also examined the relationship between altered miRNA expression and selected clinical parameters to further investigate mechanisms linking Cr to metabolic diseases and CVDs. SUBJECTS/METHODS: We analyzed urinary Cr in 90 Italian subjects using inductively coupled plasma-mass spectrometry. Peripheral blood miRNA levels were screened with TaqMan Low-Density Array Human MicroRNA A. Cr level-associated expression of miRNAs was detected with multivariate regression analyses, and the top 10 candidate miRNAs were selected for validation. We also used multivariate regression analyses to assess possible associations between validated miRNAs and glycated hemoglobin (A1c) and blood pressure (BP). The validated miRNAs were further investigated by functional analysis with Ingenuity Pathway Analysis software. RESULTS: Urinary Cr levels (mean: 0.35 µg/l; s.d.=0.24) ranged from 0.05 to 1.27 µg/l. In the screening phase, 43 miRNAs were negatively associated with Cr. Of the top 10 miRNAs selected for validation, nine (miR-451, miR-301, miR-15b, miR-21, miR-26a, miR-362-3p, miR-182, miR-183 and miR-486-3p) were downregulated in association with Cr (P-false discovery rate (FDR)<0.10). miR-451 expression was associated with A1c (ß=-0.06; P=0.0416), whereas miR-486-3p expression was associated both with diastolic (ß=2.1; P=0.004) and systolic BP (ß=3.3; P=0.003). CONCLUSIONS: These results indicate that miR-451 and miR-486-3p are involved in the link between Cr levels and metabolic diseases and CVDs.