| 1. |
- Chambers, John C., et al.
(författare)
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Genetic loci influencing kidney function and chronic kidney disease
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 373-375
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Tidskriftsartikel (refereegranskat)abstract
- Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.
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| 2. |
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| 3. |
- Lind, Lars, et al.
(författare)
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Global DNA hypermethylation is associated with high serum levels of persistent organic pollutants in an elderly population
- 2013
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 59, s. 456-461
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Tidskriftsartikel (refereegranskat)abstract
- Dioxin exposure has experimentally been associated with changes in DNA methylation, an epigenetic change that is associated with disease. The present study aims to investigate if serum levels of dioxin and other persistent environmental pollutants are related to global DNA methylation in a human sample. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (all aged 70), global DNA methylation was measured by the Luminometric Methylation Assay in 524 subjects. Twenty-three different POPs, including 16 PCBs, five pesticides, one dioxin (OCDD) and one brominated flame retardant (BDE47) were analysed by HRGC/HRMS. Ten single nucleotide polymorphisms (SNPs) in the Aryl hydrocarbon (Ah)-receptor were analysed by mini-sequencing. High levels of toxic equivalency (TEQ) for PCBs and dioxin were associated with DNA hypermethylation (p = 0.030). This was mainly attributed to coplanar non-ortho PCBs. While no significant associations were found between DNA methylation and SNPs in the Ah-receptor, an interaction was found between the SNP rs2237297 and TEQ so that TEQ was associated with hypermethylation (p = 0.009) only in subjects with one G-allele (n = 103). Also high levels of the PCB126 congener, the OCDD, and the pesticide metabolite p,p'-DDE were related to DNA hypermethylation (p = 0.01, 0.03 and 0.003, respectively). In conclusion, in a sample of elderly subjects, high TEQ including PCBs and the dioxin OCDD and high serum levels of PCB126, OCDD, and p,p'-DDE were related to global DNA hypermethylation in a cross-sectional analysis. (C) 2013 Elsevier Ltd. All rights reserved.
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| 5. |
- Nordfors, Louise
(författare)
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Molecular mechanisms of weight regulation in obesity and chronic renal failure with special reference to leptin and uncoupling protein 2
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity, which increases the risk of developing serious medical disorders, such as cardiovascular disease and diabetes, is threatening to become a global epidemic, meaning escalating healthcare costs for society and reduced quality of life for the individual. Thus, there is a large unmet need for improved preventive strategies and effective treatments. This emphasizes the necessity of understanding the molecular mechanisms controlling energy regulation as well as identifying the genes that are important in the development of obesity. The identification of the LEP gene and its product leptin, as well as two novel uncoupling proteins, UCP2 and UCP3, has further elucidated the complex network of mechanisms underlying body weight regulation in animal models and in man. Several hundred Swedish obese and lean subjects were screened for mutations in the LEP gene using solid-phase sequencing and single strand conformation polymorphism analysis (SSCP), without finding any sequence variations. However, an 80% increase in LEP mRNA levels in obese compared to non-obese subjects was demonstrated in subcutaneous adipose tissue using in situ hybridization (paper 1). LEP expression was 75% higher in obese women than in obese men, indicating a sex dimorphism in the LEP gene regulation. The role of leptin expression and secretion in the regulation of circulating leptin levels was investigated in obese and non-obese women (paper 11). Both LEP expression and leptin secretion rates were twice as high in obese women, resulting in a five-fold elevation of plasma leptin in the obese subjects. Fat cell volume accounted for 70-80% of secretion rate variations, while leptin mRNA levels accounted for about 40% of the variations in secretion rates and plasma leptin. Hyperleptinemia may be one of the factors inducing anorexia and weight loss in chronic renal failure (CRF). In paper III, the glomerular filtration rate (GFR) was shown to correlate with serum leptin and the hyperleptinemia, caused by decreased plasma clearance, resulted in downregulation of LEP gene expression. Inflammation stimulated LEP gene expression in patients with CRF, suggesting that the hyperleptinemia induced feedback inhibition of LEP gene expression is overcome by inflammatory cytokines. Following PD treatment, strong positive correlations were seen between changes in LEP expression and changes in both body fat mass and serum leptin. In paper IV, the importance of aberrations in the regulation of UCP2 and UCP3 for obesity was investigated. In skeletal muscle of obese males, we detected a 28 % decrease in UCP2 mRNA levels, compared to controls. In paper V, we investigated if the insertion/deletion polymorphism in the UCP2 gene could influence changes in body composition during PD. Following 12 months of PD, a significant increase in body weight and body fat mass was seen in patients who were homozygous for the deletion, while a significant reduction in lean body mass was seen in the heterozygotes. In 790 Swedish subjects, we found a significant association between the UCP2 polymorphism and BMI. SNP-genotyping of more than 1000 Swedish subjects revealed a significant association between a locus on chromosome 10 and BMI in males, using pyrosequencing for single nucleotide polymorphism (SNP) analysis (paper VI).
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| 6. |
- Witasp, Anna, et al.
(författare)
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Expression of inflammatory and insulin signaling genes in adipose tissue in response to elective surgery
- 2010
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 95:7, s. 3460-3469
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Tidskriftsartikel (refereegranskat)abstract
- Context: The mechanisms behind postoperative insulin resistance and impaired glucose utilization are not fully understood. Objective: In this study, we aimed to specifically evaluate the transcription profile of genes in the insulin and adipokine signaling pathways in sc and omental adipose tissue after surgical injury. Design: Relative expression of 21 target genes was analyzed in both sc and omental adipose tissue sampled at the beginning and at the end of operation. Setting: The study was conducted at a university-affiliated hospital. Patients: Twelve nondiabetic patients [seven females; age, 65 (range, 46-72) yr; body mass index, 24.8 (16.5-29.8) kg/m(2)] undergoing major abdominal surgery were included. Main Outcome Measurements: The changes in mRNA levels were analyzed. Results: After surgery, both sc and omental adipose tissue mRNA levels of genes involved in the IL6 and nicotinamide phosphoribosyltransferase pathways were increased, whereas mRNA levels of insulin receptor substrate 1 and adiponectin were reduced (P < 0.05). TNF pathway genes were differently regulated between sc and omental adipose tissue, and glucose transporter 4 mRNA levels were decreased only in omental adipose tissue. Conclusions: The transcriptional output of pivotal inflammatory and insulin signaling pathway genes is altered after surgery, and this pattern differs between different fat depots. This could be of importance for the metabolic aberrations associated to postsurgical complications, such as insulin resistance and hyperglycemia. (J Clin Endocrinol Metab 95: 3460-3469, 2010)
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| 7. |
- Witasp, Anna, et al.
(författare)
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Increased expression of inflammatory pathway genes in skeletal muscle during surgery
- 2009
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Ingår i: Clinical Nutrition. - : Elsevier BV. - 0261-5614 .- 1532-1983. ; 28:3, s. 291-298
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Postoperative insulin resistance, resulting in hyperglycemia, is strongly associated to morbidity and mortality in surgical patients but the underlying mechanisms are unclear. As increasing data suggests a link between inflammation and insulin resistance, we aimed to evaluate if the expression of inflammatory and insulin signaling genes is regulated in skeletal muscle during surgery. METHODS: Eight patients (4 females, 63 [46-69] years, body mass index 25.5 [16.5-29.8]kg/m(2)) undergoing major abdominal surgery were included. Biopsies from m. rectus abdominis were obtained at the beginning and at the end of the operation. mRNA levels of 45 genes were analyzed. RESULTS: The time elapsed between the two biopsies was 224 (198-310) min. An increased (p<0.05) expression was noted for genes encoding both inflammatory mediators, such as interleukin 6, tumor necrosis factor, and nuclear factor of kappa light polypeptide gene enhancer in B cells, and metabolic regulators, such as peroxisome proliferator-activated receptor delta, while the analysis did not detect significant expression changes of the insulin signaling pathway genes. CONCLUSIONS: The observed gene expression changes in skeletal muscle during surgery occurred mainly in inflammatory pathways, suggesting a possible role for inflammation in the development of postoperative insulin resistance.
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