OBJECTIVE -Telomeres are DNA sequences necessary for DNA replication, which shorten at cell division at a rate related to levels of oxidative stress. Once shortened to a critical length, cells are triggered into replicative senescence. Type 2 diabetes is associated with oxidative DNA damage, and we hypothesized that telomere shortening would characterize type 2 diabetes.RESEARCH DESIGN AND METHODS -We studied 21 male type 2 diabetic subjects (mean age 61.2 years, mean HbA 1c 7.9%) selected to limit confounding effects on telomere length and 29 matched control subjects. Telomere length was measured in peripheral venous monocyte and T-cells (naïve and memory) by fluorescent in situ hybridization and oxidative DNA damage by flow cytometry of oxidized DNA bases. Peripheral insulin resistance (homeostasis model assessment) and high-sensitivity C-reactive protein (hsCRP) were measured.RESULTS -Mean monocyte telomere length in the diabetic group was highly significantly lower than in control subjects (4.0 [1.1] vs. 5.5 [1.1]; P Ͻ 0.0001), without significant differences in lymphocyte telomere length. There was a trend toward increased oxidative DNA damage in all diabetes cell types examined and a significant inverse relationship between oxidative DNA damage and telomere length (r ϭ Ϫ0.55; P ϭ 0.018) in the diabetic group. Telomere length was unrelated to plasma CRP concentration or insulin resistance.CONCLUSIONS -Monocyte telomere shortening in type 2 diabetes could be due to increased oxidative DNA damage to monocyte precursors during cell division. This data suggests that monocytes adhering to vascular endothelium and entering the vessel wall in type 2 diabetes are from a population with shorter telomeres and at increased risk of replicative senescence within vascular plaque. Diabetes Care 29:283-289, 2006T elomeres are tandem repeats of the DNA sequence TTAGGG extending over 6 -15 kb at the end of eukaryotic chromosomes and are necessary for both successful DNA replication and chromosomal integrity (1-3). Telomeres in somatic human cells shorten by 30 -200 bp each cell division, and once shortened to a critical length, cells are triggered into replicative senescence, an irreversible cell cycle block in G0/G1 (1-5) where cells function differently (1,2,5,6) and are more likely to undergo apoptosis if exposed to increased oxidative insult (7). Rates of telomere shortening, and therefore telomere length, are highly dependent on oxidatively induced strand breaks in telomeric DNA and on cellular oxidant balance (1)(2)(3)5,6,8,9), and we and others have shown that lymphocyte DNA from subjects with type 2 diabetes is characterized by increased susceptibility to oxidative damage (10 -12). Telomeric DNA is particularly prone to oxidative damage at the GGG sequence (13,14), and it is probable that oxidatively induced single-and double-strand DNA breaks in people with type 2 diabetes (10 -12) would translate into accelerated telomere shortening and a progression to replicative senescence (1-3). Many of the dysf u n c t i o n s...
Early life experiences, including those in utero, have been linked to increased risk for adult-onset chronic disease. The underlying assumption is that there is a critical period of developmental plasticity in utero when selection of the fetal phenotype that is best adapted to the intrauterine environment occurs. The current study is the first to test the idea that extreme maternal psychosocial stressors, as observed in the Democratic Republic of Congo, may modify locus-specific epigenetic marks in the newborn resulting in altered health outcomes. Here we show a significant correlation between culturally relevant measures of maternal prenatal stress, newborn birth weight and newborn methylation in the promoter of the glucocorticoid receptor NR3C1. Increased methylation may constrain plasticity in subsequent gene expression and restrict the range of stress adaptation responses possible in affected individuals, thus increasing their risk for adult-onset diseases.
Vitamin D is now known to be of physiological importance outside of bone health and calcium homeostasis, and there is mounting evidence that it plays a beneficial role in the prevention and/or treatment of a wide range of diseases. In this brief review the known effects of vitamin D on immune function are described in relation to respiratory health. Vitamin D appears capable of inhibiting pulmonary inflammatory responses while enhancing innate defence mechanisms against respiratory pathogens. Population-based studies showing an association between circulating vitamin D levels and lung function provide strong justification for randomized controlled clinical trials of vitamin D supplementation in patients with respiratory diseases to assess both efficacy and optimal dosage.
Recent population-based 1-4 and clinical studies 5 have identified a range of factors associated with human gut microbiome variation. Murine quantitative trait loci 6 , human twin studies 7 and microbiome genome-wide association studies (mGWAS) 1,3,8-12 have provided evidence for genetic contributions to microbiome composition. Despite this, there is still poor overlap in genetic association across human studies. Using appropriate taxon-specific models along with support from independent cohorts, we show association between human host genotype and gut microbiome variation. We also suggest that interpretation of applied analyses using genetic associations is complicated by the likely overlap between genetic contributions and heritable components of host environment. Using fecal derived 16S rRNA gene sequences and host genotype data from the Flemish Gut Flora Project (FGFP, n=2223) and two German cohorts (FoCus, n=950, PopGen n=717), we identify genetic associations involving multiple microbial traits (MTs). Two of these associations achieved a study-level p-value threshold of 1.57x10−10; an association between Ruminococcus and rs150018970 near RAPGEF1 on chromosome 9, and between Coprococcus and rs561177583 within LINC01787 on chromosome 1. Exploratory analysis was undertaken using 11 other genomewide associations with strong evidence for association (p-value < 2.5x10 −08) and a previously reported signal of association between rs4988235 (MCM6/LCT) and Bifidobacterium. Across these 14 SNPs there was evidence of signal overlap with other GWAS including those for age at menarche and cardiometabolic traits. Mendelian randomization (MR) analysis was able to estimate associations between MTs and disease (including Bifidobacterium and body composition), however in the absence of clear microbiome driven effects, caution is needed in interpretation. Overall, this work marks a growing catalog of genetic associations which will provide insight into the contribution of host genotype to gut microbiome. Despite this, the uncertain origin of association signals will likely complicate future work looking to dissect function or use associations for causal inference analysis. Main Human host-microbiome mGWAS are still in their infancy and feature a paucity of overlap for even the most compelling signals across studies 13. This is an observation influenced by environmental variables dominating microbial trait variation 1 and the complications of variation in sample collection, storage conditions, DNA extraction method, PCR primers, and amplicon versus shotgun sequencing 14. While recent advances are Postdoctoral Fellowship (1221620N). SVS is supported by Marie Curie Actions FP7 People
Germ line mutations in the breast cancer susceptibility gene BRCA2 predispose to early-onset breast cancer, but the function of the nuclear protein encoded by the gene is ill defined. Using the yeast two-hybrid system with fragments of human BRCA2, we identified an interaction with the human DSS1 (deleted in split hand/split foot) gene. Yeast and mammalian two-hybrid assays showed that DSS1 can associate with BRCA2 in the region of amino acids 2472 to 2957 in the C terminus of the protein. Using coimmunoprecipitation of epitope-tagged BRCA2 and DSS1 cDNA constructs transiently expressed in COS cells, we were able to demonstrate an association. Furthermore, endogenous BRCA2 could be coimmunoprecipitated with endogenous DSS1 in MCF7 cells, demonstrating an in vivo association. Apparent orthologues of the mammalian DSS1 gene were identified in the genome of the yeasts Schizosaccharomyces pombe and Saccharomyces cerevisiae. Yeast strains in which these DSS1-like genes were deleted showed a temperature-sensitive growth phenotype, which was analyzed by flow cytometry. This provides evidence for a link between the BRCA2 tumor suppressor gene and a gene required for completion of the cell cycle.
Exposure to stress early in life permanently shapes activity of the hypothalamic-pituitary-adrenocortical (HPA) axis and the brain. Prenatally, glucocorticoids pass through the placenta to the fetus with postnatal impacts on brain development, birth weight, and HPA axis functioning. Little is known about the biological mechanisms by which prenatal stress affects postnatal functioning. This study addresses this gap by examining the effect of chronic stress and traumatic war-related stress on epigenetic changes in four key genes regulating the HPA axis in neonatal cord blood, placenta, and maternal blood: CRH, CRHBP, NR3C1, and FKBP5. Participants were 24 mother-newborn dyads in the conflict-ridden region of the eastern Democratic Republic of Congo. Birth weight data were collected at delivery and maternal interviews were conducted to assess culturally relevant chronic and war-related stressors. Chronic stress and war trauma had widespread effects on HPA axis gene methylation, with significant effects observed at transcription factor binding sites in all target genes tested. Some changes in methylation were unique to chronic or war stress, whereas others were observed across both stressor types. Moreover, stress exposures impacted maternal and fetal tissues differently, supporting theoretical models that stress impacts vary according to life phase. Methylation in several NR3C1 and CRH CpG sites, all located at transcription factor binding sites, was associated with birth weight. These findings suggest that prenatal stress exposure impacts development via epigenetic changes in HPA axis genes.
The melanocortin 1 receptor (MC1R) regulates pigmentation in humans and other vertebrates. Variants of MC1R with reduced function are associated with pale skin color and red hair in humans of primarily European origin. We amplified and sequenced a fragment of the MC1R gene (mc1r) from two Neanderthal remains. Both specimens have a mutation that was not found in approximately 3700 modern humans analyzed. Functional analyses show that this variant reduces MC1R activity to a level that alters hair and/or skin pigmentation in humans. The impaired activity of this variant suggests that Neanderthals varied in pigmentation levels, potentially on the scale observed in modern humans. Our data suggest that inactive MC1R variants evolved independently in both modern humans and Neanderthals.
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