| 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. |
- 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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| 3. |
- Luttropp, Karin
(författare)
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Ageing and inflammation with focus on end-stage renal diseases : genetic and epigenetic factors
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The presence of ageing-associated disorders at a relatively young age in patients suffering from chronic kidney disease (CKD) has led to the hypothesis that CKD is characterized by accelerated ageing, resulting in a marked discrepancy between chronological and biological age. Factors that accelerate biological ageing, such as inflammation, oxidative stress, and toxins, impact the processes of cellular senescence and/or apoptosis, thereby shortening the life span of cells, and consequently, of the organism as a whole. Numerous studies have linked increased cellular senescence and apoptosis to disorders commonly associated with ageing, such as cardiovascular disease (CVD), osteoporosis, and cognitive dysfunction – all of which are common in the uremic phenotype. In Study I, we demonstrate that increased arterial gene expression of cyclin-dependent kinase inhibitor 2A (CDKN2A), a known inducer of cellular senescence, is associated with the presence of CVD and vascular calcification (VC) in CKD patients. Furthermore, there is a positive correlation between CDKN2A expression and the expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2), both of which are involved in osteogenesis. We also show a tentative relationship between a higher degree of VC and increasing p16INK4a expression, a cognate protein of CDKN2A. In Study II, we use telomere length as a biomarker of biological age, showing that CKD patients have shorter telomeres than non-CKD controls. In addition, our results indicate a possible association between longitudinal telomere length, folate, and immunosuppressive treatment in patients undergoing renal transplantation (RTx). This suggests that anti- metabolite therapy may have an impact on biological ageing in RTx patients. In Study III, we show that the global methylation status in dialysis and RTx patients at baseline and after 12 months of renal replacement therapy (RRT) differs at several sites in the genome from that of age- and gender-matched healthy controls. Furthermore, differences in methylation between patients and controls can be found at CpG sites located in genes with known functional relevance to CKD, cellular ageing, CVD and/or metabolic disease. Continuing our investigations of factors affecting epigenetic status, Study IV investigates the association between the degree of self-reported physical activity and global DNA methylation in Swedish seniors. In this study, we demonstrate that individuals who reported higher physical activity had less global DNA methylation than those who were less physically active. Study V describes the application of a multifactorial mathematical model for predicting the presence of inflammation in a dataset generated from 225 incident dialysis patients. Eight of the ten features with the highest predictive factor were single nucleotide polymorphisms (SNPs), suggesting a large genetic influence on inflammation in CKD patients. In Study VI, the interplay between inflammatory status, genotype, and mortality is demonstrated in two cohorts of incident dialysis patients. The mortality was reduced in inflamed individuals carrying a 32 base-pair deletion in the C-C motif chemokine receptor 5 (CCR5) gene compared to individuals who were inflamed but lacked the deletion.
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