ABSTRACT: The Uppsala Longitudinal Study of Adult Men is a population-based study aimed at identifying risk factors for cardiovascular disease. At the time of biopsy all subjects were ~ 70yr of age We extracted RNA from muscle tissue taken from 129 subjects, when they were aged ~70yr and characterised as disease-free (note the above average longevity in Swedes born circa 1920 compared with US and UK populations). From these samples, 108 yielded RNA of sufficient quality to profile on Affymetrix gene-chips. Only survival data are used in the paper. There are no data from cardiovascular disease subjects; we only profiled the healthy subjects and followed for 20yrs.
Project description:Muscle biopsy samples from healthy male subjects at the baseline belonging to either <29y or >59y age range. These samples were used to design a prototype of multi-tissue molecular diagnostic of healthy physiological age. Resting skeletal muscle sample after an overnight fast. related to GSE18583
Project description:The overall objective of the heritage project is to study the role of the genotype in cardiovascular,metabolic and hormonal responses to aerobic exercise training and the contribution of regular exercise to changes in several cardiovascular disease and diabetes risk factors. The study cohort in this analysis consists of 473 Caucasian subjects (230 male and 243 female) from 99 nuclear families who completed ≥58 of the prescribed 60 exercise-training sessions.The phenotypic expression of each individual’s genotype is assessed under two well-defined environmental conditions, the pre- and post-training conditions. Here we have made the pre-training data available as used in the article Phillips BE, Williams JP, Gustafsson T, Bouchard C, Rankinen T, et al. (2013) Molecular Networks of Human Muscle Adaptation to Exercise and Age. PLoS Genet 9(3): e1003389. doi:10.1371/journal.pgen.1003389 52 U133+2 profiles (17–63 yr) generated from pre-exercise muscle biopsy samples from the HERITAGE Family Study. Heritage_pre dataset.
Project description:Bone marrow-derived progenitor cells are under investigation for cardiovascular repair, but may be altered by disease. We identified 82 differentially expressed genes in CD133+ cells from patients with coronary artery disease (CAD) versus controls, of which 59 were found to be up-regulated and 23 down-regulated. These genes were found to be involved in carbohydrate metabolism, cellular development and signaling, molecular transport and cell differentiation. Following completion of an exercise program, gene expression patterns resembled those of controls in 7 of 10 patients. Blood sampled from 4 healthy subjects (H), and from 10 patients with coronary artery disease at baseline (A) and after 3 months (B) of exercise.
Project description:Obesity is associated with insulin resistance and increased intrahepatic triglyceride (IHTG) content, which are key risk factors for diabetes and cardiovascular disease. However, a subset of obese people does not develop these metabolic complications. We tested the hypothesis that MNO, but not MAO, people are protected from the adverse metabolic effects of weight gain. To this end, global transcriptional profile in adipose tissue before and after weight gain was evaluated by microarray analyses. We collected subcutaneous adipose tissue samples from MNO (n=11) and MAO (n=7) subjects before and after moderate (~6%) weight gain (total 36 samples). We evaluated the effects of weight gain on adipose tissue gene expression in both MNO and MNO subjects.We used the GeneChip Human Gene 1.0 ST array (Affymetrix, Santa Clara, CA, USA).
Project description:Early perturbations in vascular health can be detected by imposing subjects to a high fat (HF) challenge and measure response capacity. Subtle responses can be determined by assessment of whole-genome transcriptional changes. We aimed to magnify differences in health by comparing gene-expression changes in peripheral blood mononuclear cells (PBMCs) towards a high MUFA or SFA challenge between subjects with different cardiovascular disease risk profiles and to identify fatty-acid specific gene-expression pathways. METHODS AND RESULTS: In a cross-over study, 17 lean and 15 obese men (50-70y) received two 95g fat shakes, high in SFAs or MUFAs. PBMC gene-expression profiles were assessed fasted and 4h postprandially. Comparisons were made between groups and shakes. During fasting, 294 genes were significantly different expressed between lean and obese. The challenge increased differences to 607 genes after SFA and 2516 genes after MUFA. In both groups, SFA decreased expression of cholesterol biosynthesis and uptake genes and increased cholesterol efflux genes. MUFA increased inflammatory genes and PPARα targets involved in β-oxidation. CONCLUSION: Based upon gene-expression changes, we conclude that a HF challenge magnifies differences in health, especially after MUFA. Our findings also demonstrate how SFAs and MUFAs exert distinct effects on lipid handling pathways in immune cells. In a double-blind cross-over study, 17 lean and 15 obese men (aged 50-70y) received two high-fat milkshakes containing 95g fat, either high in saturated (SFA) or monounsaturated (MUFA) fatty acids. PBMC gene expression profiles were determined before and 4h after shake consumption.
Project description:The Uppsala Longitudinal Study of Adult Men (ULSAM) study is an ongoing, longitudinal, epidemiologic study started in 1970 and based on men born between 1920 and 1924 in Uppsala, Sweden which were invited to participate at age 50 (N=2,841) [PMID: 9484991]; 81.7% (N=2,322) participated. Individuals were reinvestigated at the ages of 60, 70, 77, 82 and 88 years. Information collected includes a medical questionnaire, blood pressure and anthropometric measurements, glucose tolerance test and 24-hour ambulatory blood pressure. Metbaolomics has been performed on plasma samples from age 70. In the final analysis we included samples from 1,138 individuals.
Project description:Rationale: Physical inactivity is a risk factor for insulin resistance. We examined the effect of nine days of bed rest on basal and insulin stimulated expression of genes potentially involved in insulin action by applying hypothesis-generating microarray in parallel with candidate gene real-time PCR approaches in 20 healthy, young men. Furthermore, we investigated whether bed rest affected DNA methylation in the promoter region of the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) gene. Subjects were re-examined after four weeks of retraining. Findings: Bed rest induced insulin resistance and altered the expression of more than 4,500 genes. These changes were only partly normalized after four weeks of retraining. Pathway analyses revealed significant down-regulation of 34 pathways, predominantly those of genes associated with mitochondrial function including PPARGC1A. Despite induction of insulin resistance, bed rest resulted in a paradoxically increased response to acute insulin in the general expression of genes, particularly those involved in inflammation and endoplasmatic reticulum (ER) stress. Furthermore, bed rest changed gene expressions of several insulin resistance and diabetes candidate genes. We also observed a trend toward increased PPARGC1A DNA methylation after bed rest. Conclusions: Impaired expression of PPARGC1A and other genes involved in mitochondrial function as well as a paradoxically increased response to insulin of genes involved in inflammation and ER stress may contribute to the development of insulin resistance induced by bed rest. Lack of complete normalization of changes after four weeks of exercise retraining underscores the importance of maintaining a minimum of daily physical activity. 50 samples were collected (5 samples from 10 subjects) and included in this study. Ten technical repeats were also performed in this analysis
Project description:To accelerate the development of disease-modifying therapeutics for Huntington’s disease (HD), a dynamic biomarker of disease activity and treatment response is critically needed. Venous cellular whole blood from 8 patients with Huntington's disease (HD) and 6 control subjects were collected in PAXgene tubes (Wiagen, Valencia, CA). RNA was isolated from whole blood using the PAXgene blood RNA kit (Qiagene) with DNase treatment. The biotinylated complementary RNA was fragmented and hybridized to Affymetrix human genome U133A microarrays. The Affymetrix .CEL files were normalized to “all probe sets” in a standardized matter, and scaled to 100 by the MAS5 5.0 algorithm implemented in the Bioconductor package.
Project description:Muscle is a target of growth hormone (GH) action and a major contributor to whole body metabolism. Little is known about how GH regulates metabolic process in muscle or the extent to which muscle contributes to changes in whole body substrate metabolism during GH treatment. To identify GH-responsive genes that regulate substrate metabolism in muscle, we studied six hypopituitary men who underwent whole body metabolic measurement and muscle biopsies before and after two weeks of GH treatment (0.5mg/day). Transcript profiles of four subjects were analysed using Affymetrix GeneChips. Serum insulin-like growth factor I (IGF-I), procollagens I and III were measured by RIA. GH increased serum IGF-I, procollagens I and III, enhanced whole body lipid oxidation, reduced carbohydrate oxidation, and stimulated protein synthesis. It induced gene expression of IGF-I and collagens in muscle. GH reduced expression of several enzymes regulating lipid oxidation and energy production. It reduced calpain 3, increased ribosomal protein L38 expression, and displayed mixed effects on genes encoding myofibrillar proteins. It increased expression of circadian gene CLOCK, and reduced that of PERIOD. In summary, GH exerted concordant effects on muscle expression and blood levels of IGF-I and collagens. It induced changes in genes regulating protein metabolism in parallel with a whole body anabolic effect. The discordance between muscle gene expression profiles and metabolic responses suggests that muscle is unlikely to contribute to GH-induced stimulation of whole body energy and lipid metabolism. GH may regulate circadian function in muscle by modulating circadian gene expression with possible metabolic consequences.
Project description:Individuals of African descent in the United States suffer disproportionately from diseases with a metabolic etiology (obesity, metabolic syndrome, and diabetes), and from the pathological consequences of these disorders (hypertension and cardiovascular disease). Using a combination of genetic/genomic and bioinformatics approaches, we identified a large number of genes that were both differentially expressed between American subjects self-identified to be of either African or European ancestry and that also contained single nucleotide polymorphisms that distinguish distantly related ancestral populations. Several of these genes control the metabolism of simple carbohydrates and are direct targets for the SREBP1, a metabolic transcription factor also differentially expressed between our study populations. These data support the concept of stable patterns of gene transcription unique to a geographic ancestral lineage. The coordinated transcriptional adaptation of carbohydrate metabolism to dietary environmental pressures suggests a genetic and transcriptional mechanism for the disproportionate levels of obesity, diabetes, and cardiovascular disease observed in Americans with African ancestry. Keywords: Ancestry-dependent gene expression, functional genomics, personalized medicine, multi-factoral disease, nutrition, diabetes We utilized a “sample x reference” experimental design strategy in which RNA extracted from human peripheral blood mononuclear cells was hybridized to the microarray slide in the presence of labeled Universal Human Reference RNA (UHRR, Stratagene, LaJolla, CA). A total of 161 subjects were used in this analysis. Briefly, five hundred nanograms of total RNA were used for gene expression profiling following reverse transcription and T-7 polymerase-mediated amplification/labeling with Cyanine-5 CTP. Labeled subject cRNA was co-hybridized to Agilent G4112A Whole Human Genome 44K oligonucleotide arrays with equimolar amounts of Cyanine-3 labeled UHRR. Slides were hybridized, washed, and scanned on an Axon 4000b microarray scanner. The data were processed using GenePix Pro 6 software