Whole genome methylation array analysis reveals new aspects in Balkan endemic nephropathy etiology

Abstract

BackgroundBalkan endemic nephropathy (BEN) represents a chronic progressive interstitial nephritis in striking correlation with uroepithelial tumours of the upper urinary tract. The disease has endemic distribution in the Danube river regions in several Balkan countries.DNA methylation is a primary epigenetic modification that is involved in major processes such as cancer, genomic imprinting, gene silencing, etc. The significance of CpG island methylation status in normal development, cell differentiation and gene expression is widely recognized, although still stays poorly understood.MethodsWe performed whole genome DNA methylation array analysis on DNA pool samples from peripheral blood from 159 affected individuals and 170 healthy individuals. This technique allowed us to determine the methylation status of 27 627 CpG islands throughout the whole genome in healthy controls and BEN patients. Thus we obtained the methylation profile of BEN patients from Bulgarian and Serbian endemic regions.ResultsUsing specifically developed software we compared the methylation profiles of BEN patients and corresponding controls and revealed the differently methylated regions. We then compared the DMRs between all patient-control pairs to determine common changes in the epigenetic profiles.SEC61G, IL17RA, HDAC11 proved to be differently methylated throughout all patient-control pairs. The CpG islands of all 3 genes were hypomethylated compared to controls. This suggests that dysregulation of these genes involved in immunological response could be a common mechanism in BEN pathogenesis in both endemic regions and in both genders.ConclusionOur data propose a new hypothesis that immunologic dysregulation has a place in BEN etiopathogenesis.

Placental growth factor and placental protein 13 in patients with Balkan endemic nephropathy, a worldwide disease

“…10 In BEN patients, the CpG islands of SEC61G, IL17RA, HDAC11 genes were hypomethylated compared to controls. 11 Deregulation of these genes, involved in immunological response, was suggested as a common mechanism in BEN pathogenesis. The acetylation of histone lysine residues was found to be increased at specific sites of H3 and total H4 histones isolated from urothelial cells of patients with BEN.…”

“…10 DNA methylation array analysis on DNA samples from Bulgarian and Serbian endemic regions, and histone acetylation levels in BEN and control patients have revealed marked epigenetic changes, important in the pathogenesis of BEN and a opportunity for selective therapeutic interventions in these patients. 11,12 Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family that also comprises VEGF-A (VEGF), VEGF-B, VEGF-C, and VEGF-D. Unlike VEGF, PlGF has diverse roles in tissue ischemia, malignancy, inflammation, and several other diseases.…”

Erythropoietin inhibits SGK1-dependent Th17 cell induction and Th17 cell–dependent kidney disease

“…ArA is the etiologic agent of human Balkan or Chinese herb nephropathy, a form of interstitial nephritis manifested as renal insufficiency and urinary protein loss (24,25). Interestingly, ArA nephropathy in humans is strongly associated with low serum EPO levels and with abnormalities in the IL-17/IL-17R axis (26). Administration of ArA to B6 mice mimics many aspects of this human disease (27).…”

Global and specific histone acetylation pattern in patients with Balkan endemic nephropathy, a worldwide disease

“…This suggests that dysregulation of these genes involved in immunological response could be a common mechanism in BEN pathogenesis in both endemic regions. 24 Evidence of links between DNA methylation and histone hypoacetylation is accumulating. Several proteins that specifically bind to methylated DNA are associated with complexes that include histone deacetylases (HDACs).…”