Article: Physical activity is associated with decreased global DNA methylation in Swedish older individuals.Scandinavian journal of clinical and laboratory investigation 11/2012; · 1.38 Impact Factor
Anna Witasp, Louise Nordfors, Juan Jesus Carrero, Karin Luttropp, Bengt Lindholm, Martin Schalling, Peter Stenvinkel[show abstract] [hide abstract]
ABSTRACT: The tools of modern molecular biology are evolving rapidly, resulting in vastly more efficient approaches to illuminating human genetic variations and their effects on common multifactorial disorders such as chronic kidney disease (CKD). Indeed, candidate gene association studies and genome-wide association studies (GWASs) have generated novel genetic variants in previously unrecognized biological pathways, highlighting disease mechanisms with a potential role in CKD etiology, morbidity and mortality. Nephrologists now need to find ways to make use of these advancements and meet the increasingly stringent requirements for valid study design, data handling and interpretation of genetic studies. Adding to our prior article in this journal, which introduced the basics of genotype-phenotype association studies in CKD, this second article focuses on how to ascertain robust and reproducible findings by applying adequate methodological and statistical approaches to genotype-phenotype studies in CKD populations. Moreover, this review will briefly discuss genotype-based risk prediction, pharmacotherapy, drug target identification and individualized treatment solutions, specifically highlighting potentially important findings in CKD patients. This increased knowledge will hopefully facilitate the exciting transition from conventional clinical medicine to gene-based medicine. However, before this can be accomplished, unsolved issues regarding the complex human genetic architecture as well technical and clinically oriented obstacles will have to be overcome. Additionally, new policies and standardized risk evaluations for genetic testing in the clinical setting will have to be established to guarantee that CKD patients are provided with high-quality genotype-guided counseling that will help to improve their poor outcomes.Journal of nephrology 10/2012; · 1.65 Impact Factor
Louise Nordfors, Karin Luttropp, Juan Jesus Carrero, Anna Witasp, Peter Stenvinkel, Bengt Lindholm, Martin Schalling[show abstract] [hide abstract]
ABSTRACT: In spite of extensive research resulting in major advances in renal care including technological improvements of dialysis, the poor outcome of chronic kidney disease patients has only marginally been improved since the 1980s. It has thus become clear that new strategies are needed to move forward. There are now great expectations that increased knowledge about genetic characteristics combined with other biological markers will identify pathophysiological pathways involved in the initiation and progression of renal damage and that this in turn will help define tools for early disease intervention and personalized treatment strategies. Already, new methodologies have made it possible to study the heritable component of many kidney diseases, and it is probable that DNA-based diagnostics will be performed on a regular basis for many conditions in the near future. This article discusses basic genetic concepts and highlights some of the novel approaches available for genome-wide genetic analyses. We hope that it may serve as an introduction to the research field of what we call "nephrogenetics." A second article in this series will focus on the interpretation and evaluation of genetic association studies and how to make use of this information to improve patient care and outcomes.Journal of nephrology 03/2012; 25(2):141-9. · 1.65 Impact Factor
Sawako Kato, Bengt Lindholm, Peter Stenvinkel, Tomas J Ekström, Karin Luttropp, Yukio Yuzawa, Yoshinari Yasuda, Yoshinari Tsuruta, Shoichi Maruyama[show abstract] [hide abstract]
ABSTRACT: Inflammation is an established mortality risk factor in chronic kidney disease (CKD) patients. Although a previous report showed that uremic Caucasian patients with inflammation had signs of global DNA hypermethylation, it is still unknown whether DNA hypermethylation is linked to inflammatory markers including a marker of bacterial infections in Japanese CKD patients. In 44 consecutive incident dialysis patients (26 males, mean age 59 ± 12 years) without clinical signs of infection, global DNA methylation was evaluated in peripheral blood DNA using the HpaII/MspI ratio by the luminometric methylation assay method. A lower ratio of HpaII/MspI indicates global DNA hypermethylation. Procalcitonin (PCT), a marker of inflammation due to bacterial infections, was measured using an immunochromatographic assay. The patients were divided into hyper- and hypomethylation groups based on the median value of the HpaII/MspI ratio 0.31 (range 0.29-0.37). Whereas patients in the hypermethylation group had higher ferritin levels [133.0 (51.5-247.3) vs. 59.5 (40.0-119.0) ng/ml; p = 0.046], there were no significant differences in age, gender, diabetes, smoking, anemia or serum albumin levels. However, the HpaII/MspI ratio showed significant negative correlations with PCT (ρ = -0.32, p = 0.035) and ferritin (ρ = -0.33, p = 0.027) in Spearman's rank test. In a multiple linear regression analysis, PCT and ferritin were associated with a lower HpaII/MspI ratio (R(2) = 0.24, p = 0.013). In this study, global DNA hypermethylation was associated with ferritin and, most likely, PCT, suggesting that inflammation induced by subclinical bacterial infection promoted DNA methylation.Nephron extra. 01/2012; 2(1):159-68.
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ABSTRACT: Epigenetic alterations regulate the utilization of the genome by permitting or inhibiting access of transcription factors and associated complexes. Although there are several different types of epigenetic alterations, such as acetylation and methylation of histone tails, the one which has been the most extensively studied is DNA-methylation, wherein the cytosine residue in a CpG dinucleotide is methylated. Luminometric Methylation Assay (LUMA) enables researchers to study global methylation by using methylation-sensitive restriction enzymes followed by Pyrosequencing(®) which quantitates the number of cuts in the genome relative to an internal standard. The relative measurement of global methylation levels is simple and enables up to 96 samples to be analyzed at the same time.Methods in molecular biology (Clifton, N.J.) 01/2011; 791:135-44.