The present work investigates the occurrence and significance of aberrant DNA methylation patterns during early stages of atherosclerosis. To this end, we asked whether the genetically atherosclerosis-prone APOEnull mice show any changes in DNA methylation patterns before the appearance of histologically detectable vascular lesion. We exploited a combination of various techniques: DNA fingerprinting, in vitro methyl-accepting assay, 5-methylcytosine quantitation, histone posttranslational modification analysis, Southern blotting, and PCR. Our results show that alterations in DNA methylation profiles, including both hyper-and hypomethylation, were present in aortas and PBMC of 4-week-old mutant mice with no detectable atherosclerotic lesion. Sequencing and expression analysis of 60 leukocytic polymorphisms revealed that epigenetic changes involve transcribed genic sequences, as well as repeated interspersed elements. Furthermore, we showed for the first time that atherogenic lipoproteins promote global DNA hypermethylation in a human monocyte cell line. Taken together, our results unequivocally show that alterations in DNA methylation profiles are early markers of atherosclerosis in a mouse model and may play a causative role in atherogenesis.Atherosclerosis and its complications are a major cause of death and disability in the developed world. The disease is characterized by infiltration of lipid particles in the arterial wall, accompanied by the recruitment of inflammatory and immune cells, migration and proliferation of smooth muscle cells (SMC), 1 and synthesis of extracellular matrix. These processes eventually result in the gradual development of an elevated lipid-rich, fibrocellular lesion (1).In mammals, DNA methyltransferases use S-adenosyl methionine (SAM) as a methyl group donor to methylate the carbon in position 5 of cytosine residues in a CpG dinucleotide (CG) context (2). DNA methylation regulates fundamental biological phenomena such as gene expression, genome stability, mutation rate, genomic imprinting, and X chromosome inactivation (3-6). Both global and gene-specific alterations in DNA methylation are associated with abnormal phenotypes in disease (7,8). For example, cancer cells show global genomic hypomethylation and dense hypermethylation of CpG islands, which are normally unmethylated (9). The identification of cancer type-and stage-specific changes in DNA methylation has justified hopes for novel diagnostic and therapeutic avenues (10).Two general observations suggest that alterations in DNA methylation patterns are involved in atherogenesis (11-13). First, global hypomethylation and dense hypermethylation of certain CpG islands are associated with aging, a major risk factor for atherosclerosis (14). Second, hyperhomocysteinemia and the subsequent decreased production or bioavailability of SAM is associated with an increased risk of cardiovascular disease (15). Accordingly, mice with genetically reduced levels of methylenetetrahydrofolate reductase, a key enzyme in the pathway generating ...

The Nordic countries were screened for the occurrence of cases of autism with a same-sexed twin under age 25 years. Twenty-one pairs (11 monozygotic and 10 dizygotic) of twins and one set of identical triplets were found and extensively examined. The concordance for autism by pair was 91% in the monoygotic and 0% in the dizygotic pairs. The corresponding concordances for cognitive disorder were 91% and 30%, respectively. In most of the pairs discordant for autism, the autistic twin had more perinatal stress. The results lend support for the notion that autism sometimes has a hereditary component and that perinatal stress is involved in some cases.

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Background— Although monocytes in peripheral blood are no longer considered to be a homogeneous population, associations between distinct monocyte subsets and cardiovascular disease have not been highlighted in large epidemiological studies. Methods and Results— The study included 700 randomly selected subjects from the cardiovascular arm of the Malmö Diet and Cancer study. Among these, 123 subjects experienced ischemic cardiovascular events during the follow-up until December 2008. Mononuclear leukocytes frozen at the baseline investigation in 1991 to 1994 were thawed and analyzed with flow cytometry to enumerate monocyte subsets, based on CD14 and CD16 expression. The percentage and number of classical CD14 ++ CD16 − monocytes were increased in the cardiovascular-event group compared with the event-free subjects (median, 69% [interquartile range, 62% to 76%] versus 67% [59% to 72%], P =0.017; 344 [251 to 419] cells/μL versus 297 [212 to 384] cells/μL, P =0.003). The hazard ratio was 1.66 for suffering a cardiovascular event in the highest tertile of the number of CD14 ++ CD16 − monocytes compared with the lowest tertile, even after adjustment for common risk factors (HR, 1.66; 95% CI: 1.02 to 2.72). CD14 ++ CD16 − monocytes did not, however, associate with the extent of atherosclerosis at baseline. In contrast, the percentage of monocytes expressing CD16 was negatively associated to the extent of carotid atherosclerosis measured as intima-media thickness at baseline. The chemokine receptors CCR2, CX3CR1, and CCR5 were not differentially expressed between cases and controls on any of the monocyte subsets, but CCR5 expression on CD14 + CD16 ++ monocytes was negatively associated to carotid intima-media thickness. Conclusions— This study shows that classical CD14 ++ CD16 − monocytes can predict future cardiovascular risk independently of other risk factors in a randomly selected population.

Objective— Regulatory T cells (Tregs) protect against atherosclerosis in experimental models, but their association with cardiovascular disease in humans remains to be elucidated. The aim of the present study was to determine whether circulating Tregs predict the development of acute cardiovascular events in humans. Methods and Results— The study cohort consisted of a random sample of participants (n=700), aged 68 to 73 years, from the Malmö Diet and Cancer Study. Mononuclear leukocytes, stored at −140 ○ C at the baseline investigation in 1991–1994, were thawed and Tregs, defined by the expression of FoxP3 in CD4+ T cells, were analyzed by flow cytometry. There was no detectable loss of cells during storage, and the viability of thawed leukocytes was 95%. A low fraction of both CD4+FoxP3+ and CD4+CD25+FoxP3+ T cells was associated with a higher release of proinflammatory cytokines from activated mononuclear leukocytes, and this association was strongest for CD4+FoxP3+ cells. Eighty-four coronary events and 66 strokes were registered during follow-up until December 31, 2008. In a Cox proportional hazard regression model adjusting for major risk factors, low levels of baseline CD4+FoxP3+ T cells were associated with an increased risk for the development of acute coronary events but not stroke. There were no associations between CD4+CD25+FoxP3+ T cells and development of an acute coronary event or stroke. Conclusion— This study provides prospective evidence for the role of Tregs in the development of myocardial infarction. The findings are in accordance with previous experimental studies and provide clinical support for a protective role of Tregs in atherosclerosis. The lack of association between Tregs and stroke may reflect the more heterogeneous cause of this disease.