Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD

Prenatal Particulate Air Pollution and DNA Methylation in Newborns: An Epigenome-Wide Meta-Analysis

BACKGROUND: Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes. OBJECTIVES: We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter [Formula: see text] ([Formula: see text]) or [Formula: see text] ([Formula: see text]) and DNA methylation in newborns and children. METHODS: We meta-analyzed associations between exposure to [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression. RESULTS: Six CpGs were significantly associ

Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium.

Development Psychopathology in context: famil

Astrocytic and neuronal oxidative metabolism are coupled to the rate of glutamate-glutamine cycle in the tree shrew visual cortex.

Astrocytes play an important role in glutamatergic neurotransmission, namely by clearing synaptic glutamate and converting it into glutamine that is transferred back to neurons. The rate of this glutamate-glutamine cycle (V &lt;sub&gt;NT&lt;/sub&gt; ) has been proposed to couple to that of glucose utilization and of neuronal tricarboxylic acid (TCA) cycle. In this study, we tested the hypothesis that glutamatergic neurotransmission is also coupled to the TCA cycle rate in astrocytes. For that we investigated energy metabolism by means of magnetic resonance spectroscopy (MRS) in the primary visual cortex of tree shrews (Tupaia belangeri) under light isoflurane anesthesia at rest and during continuous visual stimulation. After identifying the activated cortical volume by blood oxygenation level-dependent functional magnetic resonance imaging, &lt;sup&gt;1&lt;/sup&gt; H MRS was performed to measure stimulation-induced variations in metabolite concentrations. Relative to baseline, stimulation of cortical activity for 20 min caused a reduction of glucose concentration by -0.34 ± 0.09 µmol/g (p &lt; 0.001), as well as a -9% ± 1% decrease of the ratio of phosphocreatine-to-creatine (p &lt; 0.05). Then &lt;sup&gt;13&lt;/sup&gt; C MRS during [1,6- &lt;sup&gt;13&lt;/sup&gt; C]glucose infusion was employed to measure fluxes of energy metabolism. Stimulation of glutamatergic activity, as indicated by a 20% increase of V &lt;sub&gt;NT&lt;/sub&gt; , resulted in increased TCA cycle rates in neurons by 12% ( VTCAn, p &lt; 0.001) and in astrocytes by 24% ( VTCAg, p = 0.007). We further observed linear relationships between V &lt;sub&gt;NT&lt;/sub&gt; and both VTCAn and VTCAg. Altogether, these results suggest that in the tree shrew primary visual cortex glutamatergic neurotransmission is linked to overall glucose oxidation and to mitochondrial metabolism in both neurons and astrocytes

Fine particle exposure changes DNA methylation within days and weeks: Discovering novel systemic pathways using a genome-wide approach.

BACKGROUND: Many epidemiological studies have shown that particulate matter (PM) concentrations are associated with an increase of respiratory and cardiovascular diseases, as well as lung cancer. DNA methylation has been identified as a possible link but so far it has only been analyzed in candidate sites.&nbsp; RESULTS: We collected whole blood samples from three independent studies, KORA F3 (2004-05) and F4 (2006-08) from Germany and NAS (1999-2007) from US, and measured genome-wide DNA methylation proportions with the Illumina 450k BeadChip. PM concentration was measured daily at fixed monitoring stations and three different trailing averages were considered and regressed against DNA methylation: 2-day, 7-day and 28-day. Random-effect meta-analysis was performed to pool the study-specific results and revealed 13 CpG (cytosine-guanine dinucleotide) sites as associated with PM concentration (one for 2-day average, two for 7-day and ten for 28-day) at a genome-wide Bonferroni significance level (p&lt;=7.5E-8). Five of these sites showed homogeneous associations across the three studies, both sites from the 7-day average results and 3 for the 28-day average. 10 out of 13 expressed increased methylation and there was no overlap of significant sites between the models for the three different trailing averages.&nbsp; CONCLUSION: The PM-related CpG sites found in our study suggest novel plausible systemic pathways between ambient particulate matter exposure and adverse health effect through DNA methylation variations

A genome-wide analysis of DNA methylation and fine particulate matter air pollution in three study populations: KORA F3, KORA F4, and the Normative Aging Study.

BACKGROUND: Epidemiological studies have reported associations between particulate matter (PM) concentrations and cancer, respiratory, and cardiovascular diseases. DNA methylation has been identified as a possible link but so far it has only been analyzed in candidate sites. OBJECTIVES: To study the association between DNA methylation and short- and mid-term air pollution exposure using genome-wide data, and identify potential biological pathways for additional investigation. METHODS: We collected whole blood samples from three independent studies, KORA F3 (2004-05) and F4 (2006-08) from Germany and Normative Aging Study (1999-2007) from the US, and measured genome-wide DNA methylation proportions with the Illumina 450k BeadChip. PM concentration was measured daily at fixed monitoring stations and three different trailing averages were considered and regressed against DNA methylation: 2-day, 7-day and 28-day. Meta-analysis was performed to pool the study-specific results. RESULTS: Random-effect meta-analysis revealed 12 CpG (cytosine-guanine dinucleotide) sites as associated with PM concentration (one for 2-day average, one for 7-day and ten for 28-day) at a genome-wide Bonferroni significance level (p&lt;=7.5E-8); 9 out of these 12 sites expressed increased methylation. Through estimation of I-squared statistics for homogeneity assessment across the studies, four of these sites (annotated in NSMAF, C1orf212, MSGN1, NXN) showed p&gt;0.05 and I(2)&lt;0.5: the site from the 7-day average results and 3 for the 28-day average. Applying False Discovery Rate, p-value&lt;0.05 was observed in 8 and 1819 additional CpGs at 7- and 28-day average PM2.5 exposure respectively. CONCLUSION: The PM-related CpG sites found in our study suggest novel plausible systemic pathways linking ambient particulate matter exposure to adverse health effect through variations in DNA methylation

Long-term exposure to air pollution is associated with biological aging.

Long-term exposure to air pollution is associated with age-related diseases. We explored the association between accelerated biological aging and air pollution, a potential mechanism linking air pollution and health. We estimated long-term exposure to PM10, PM2.5, PM2.5 absorbance/black carbon (BC), and NOx via land-use regression models in individuals from the KORA F4 cohort. Accelerated biological aging was assessed using telomere length (TeloAA) and three epigenetic measures: DNA methylation age acceleration (DNAmAA), extrinsic epigenetic age acceleration (correlated with immune cell counts, EEAA), and intrinsic epigenetic age acceleration (independent of immune cell counts, IEAA). We also investigated sex-specific associations between air pollution and biological aging, given the published association between sex and aging measures. In KORA an interquartile range (0.97 &micro;g/m3) increase in PM2.5 was associated with a 0.33 y increase in EEAA (CI = 0.01, 0.64; P = 0.04). BC and NOx (indicators or traffic exposure) were associated with DNAmAA and IEAA in women, while TeloAA was inversely associated with BC in men. We replicated this inverse BC-TeloAA association in the Normative Aging Study, a male cohort based in the USA. A multiple phenotype analysis in KORA F4 combining all aging measures showed that BC and PM10 were broadly associated with biological aging in men. Thus, we conclude that long-term exposure to air pollution is associated with biological aging measures, potentially in a sex-specific manner. However, many of the associations were relatively weak and further replication of overall and sex-specific associations is warranted

Exceptional AGN long-timescale X-ray variability: The case of PHL 1092

PHL 1092 is a z ∼ 0.4 high-luminosity counterpart of the class of Narrow–Line Seyfert 1 galaxies. In 2008, PHL 1092 was found to be in a remarkably low X-ray flux state during an XMM–Newton observation. Its 2 keV flux density had dropped by a factor of ∼ 260 with respect to a previous observation performed 4.5 yr earlier. The UV flux remained almost constant, resulting in a significant steepening of the optical-to-X-ray slope αox from − 1.57 to − 2.51, making PHL 1092 one of the most extreme X-ray weak quasars with no observed broad absorption lines (BALs) in the UV. We have monitored the source since 2008 with three further XMM–Newton observations, producing a simultaneous UV and X-ray database spanning almost 10 yr in total in the activity of the source. We present here results from our monitoring campaign

Presence of peroxisomal membrane proteins in liver and fibroblasts from patients with the Zellweger syndrome and related disorders: Evidence for the existence of peroxisomal ghosts

The presence and intracellular localization of peroxisomal integral membrane proteins (PMP) were investigated in liver and cultured skin fibroblasts from control subjects and patients with the Zellweger syndrome and related disorders in which peroxisomes are virtually absent. Immunoblotting experiments showed that 22, 36 and 69 kDa PMPs were present and were confined to the membranous fraction both in the control liver and in the livers from the Zellweger patients. The 22 and 36 kDa PMPs were present in significantly lower amounts in the patients' livers than in the control liver. A reduced amount of the 69 kDa PMP was found in liver from one Zellweger but not in liver from another. The subcellular localization in fibroblasts of catalase and the 69 kDa PMP was studied by indirect immunofluorescence. A characteristic punctate fluorescence was seen in control cells incubated with either anti-(catalase) or with anti-(69 kDa PMP). Incubation of mutant cells with anti-(catalase) resulted in a diffuse fluorescence, whereas with anti-(69 kDa PMP) fluorescent particles were visualized which, in some cell lines, were larger and fewer in number than in control cells. Cryosections of control and mutant cells were examined by electron microscopy using immunogold labeling. Control cells contained small structures consisting of a single membrane enclosing a homogeneous matrix; the membranes reacted with anti-(69 kDa PMP) and the matrix with anti-(catalase). The mutant cell lines contained spherical or ellipsoidal structures whose membranes reacted with anti-(69 kDa PMP); no labeling was observed with anti-(catalase). We conclude that peroxisomal ghosts, the membranes of which contain the 69 kDa PMP, are present in peroxisome-deficient cell lines from all complementation groups studied so far