Genetic, Genomic and Epigenomic Studies of Balkan Endemic Nephropathy (Ben)

Open access


BEN is a primary, chronic tubulointerstitial nephritis characterized with chronic anemia, absence of edema, xantoderma, normal blood pressure and normal findings on the fundus oculi. The disease is distributed in restricted areas in Bulgaria, Romania, Croatia, Bosnia, Former Yugoslavia. Despite numerous studies on genetic and environmental factors and their possible involvement in BEN, its etiopathogenesis still remains elusive.

Our recent study aim to elucidate the possible epigenetic component in BEN development. Whole genome DNA array methylation analysis was applied to compare the methylation profiles of male and female BEN patients from endemic regions in Bulgaria and Serbia and healthy controls.

All three most prominent candidate genes with aberrations in the epigenetic profile discovered with this study are involved in the inflammatory/immune processes and oncogenesis. These data are in concordance with the reported pathological alterations in BEN. This research supports the role of epigenetic changes in BEN pathology.

Exome sequencing of 22.000 genes with Illumina Nextera Exome Enrichment Kit revealed three mutant genes (CELA1, HSPG2, and KCNK5) in BEN patients which encode proteins involved in basement membrane/extracellular matrix and vascular tone, tightly connected to process of angiogenesis. We suggest that an abnormal process of angiogenesis plays a key role in the molecular pathogenesis of BEN.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Stefanovic V Cukuranovic Rade Miljkovic Sladjana Marinkovica Dragoslav Toncheva Draga. Fifty years of Balkan endemic nephropathy: Challenges of study using epidemiological methods. Renal Failure. 2009; 31(5): 409-418.

  • 2. Toncheva D Dimitrov Tz. Genetic predisposition to Balkan endemic nephropathy. Nephron 1996 72 564-569.

  • 3. Stefanovic V Toncheva D Atanasova S Polenakovic M. Etiology of Balkan Endemic Nephropathy and associated urothelial cancer. Am J Nephrol. 2006; 26(1): 1-11.

  • 4. Zaharieva B Stock C Ambros P Dimitrov Tz Toncheva D.: First report on cytogenetic changes in an uroepithelial tumor of a patient with Balkan Endemic Nephropathy. BJMG. 1999; 2(3): 35-37.

  • 5. Toncheva D.I Atanassova S Gergov Tz.D Todorovska E.G Roeva I.G Georgiev Tch. et al. Genetic changes in uroepithelial tumors of patients with Balkan Endemic Nephropathy. Journal of Nephrology. 2002; 15(4): 387-393.

  • 6. Toncheva D Dimitrov Tz Stojanova St. Etiology of Balkan endemic nephropathy: A multifactorial disease? Eur J of Epidemiology. 1998; 14: 389-394.

  • 7. Galabov A Kamarinchev B Toncheva D Stoitsova S Dimitrov Tz. Are viruses causative agents of the Balkan Endemic Nephropathy. Proceedings Tenth Congress of the Bulgarian Microbiologists with International Participation. Plovdiv October 9-12 2002.

  • 8. Toncheva D Dimitrov Tz Tzoneva M. Cytogenetic study in Balkan endemic nephropathy. Nephron. 1988; 48: 18-21.

  • 9. Toncheva D.I Gergov T.D Tzoneva M.T Bouchakliev Z.P. Spontaneous and induced chromosome aberrations in Balkan endemic nephropathy. Kidney International. 1991; 40 (SUPPL. 34): S-97-101.

  • 10. Atanassova S Dimitrova A Dimitrov Tz Kaneva R Kremenski I Toncheva D. Comparative study of CYP2D6 gene polymorphism in healthy Bulgarian population and patients with Balkan endemic nephropathy. BJMG. 2000; 3(3): 27-30.

  • 11. Atanasova SY Ahsen N von Toncheva DI Dimitrov TG Oellerich M Armstrong VW. Genetic polymorphisms of cytochrome P450 among patients with Balkan endemic nephropathy (BEN). Clin Biochem. 2005; 38(3): 223-228.

  • 12. Atanasova S Ahsen N von Tz. Dimitrov M. Oellerich D. Toncheva: First study of NAT1 and NAT2 polymorphisms in Bulgarian patients with Balkan endemic nephropathy (BEN) and healthy controls. Biotechnol. & Biotechnol. Eq. 2004; 18(1): 95-103.

  • 13. Atanasova S Ahsen N von Dimitrov Tz Armstrong V Oellerich M Toncheva D. Real time polymerase chain reaction for genotyping of the transforming grow factor β1 polymorphism Thr263Ile in patients with Balkan endemic nephropathy and in a healthy Bulgarian population. BJMG. 2002; 5 (3&4): 37-40.

  • 14. Toncheva D Ahsen N. von Atanasova S Dimitrov Tz Armstrong V Oellerich M. Identification of NQO1 and GSTs genotype frequencies in Bulgarian patients with Balkan endemic nephropathy. J Nephrol. 2004; 17: 384-389.

  • 15. Atanasova S Ahsen N. von Dimitrov Tz Armstrong V Oellerich M Toncheva D. MDR1 haplotypes modify BEN disease risk: A study in Bulgarian patients with Balkan endemic nephropathy compared to healthy controls. Nephron Exp Nephrol. 2004; 96(1)e7 - e13 DOI: 10.1159/000075571

  • 16. Mantle P Modalca Mirela Nicholls Andrew Tatu Calin Tatu Diana and Toncheva Draga. Comparative 1H NMR metabolomic urinalysis of people diagnosed with Balkan endemic nephropathy and healthy subjects in Romania and Bulgaria: a pilot study. Toxins. 2011; 3: 815-833.

  • 17. Toncheva D Galabov A Laich A Atanassova S Kamarinchev B Dimitrov Tz Fuchs D. Urinary neopterin concentration in patients with Balkan endemic nephropathy. Kidney Int. 2003; 64: 1817-1821.

  • 18. Toncheva D Mihailova-Hristova M Vazharova R Staneva R Karachanak S Dimitrov P et. al. NGS nominated CELA1 HSPG2 and KCNK5 as candida te-genes for predisposition to Balkan Endemic Nephropathy. BioMed Res Int. 2014; 1-7 doi: 10.1155/2014/920723

  • 19. Shen L et al. Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters. PLoS Genet. 2007; 3(10): p. 2023-36.

  • 20. Weinhold B. Epigenetics: the science of change. Environ Health Perspect. 2006; 114(3): p. A160-7.

  • 21. Bjornsson H.T et al. Intra-individual change over time in DNA methylation with familial clustering. JAMA 2008; 299(24): p. 2877-83.

  • 22. Wolfe K.H. and W.-H. Li Molecular evolution meets the genomics revolution. Nat Genet.

  • 23. Esteller M and Herman J.G. Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. The Journal of Pathology. 2002; 196(1): p. 1-7.

  • 24. Kulis M. and Esteller M. 2 - DNA Methylation and Cancer in Advances in Genetics H. Zdenko and U. Toshikazu Editors. 2010 Academic Press. p. 27-56.

  • 25. Das P.M. and Singal R. DNA methylation and cancer. J Clin Oncol. 2004; 22(22): p. 4632-42.

  • 26. Richardson B. DNA methylation and autoimmune disease. Clinical Immunology. 2003; 109(1): p. 72-79.

  • 27. Stefanovic Vladisav Jelakovic Bojan Cukuranovic Rade Bukvic Dana Nikolic Jovan Lukic Ljiljana et al. Diagnostic criteria for Balkan endemic nephropathy: proposal by an international panel. Renal Failure. 2007; 29(7): p. 867-80.

  • 28. Staneva Rada Blaga G Rukova B Hadjidekova Savina Nesheva Desislava Antonova Olga et al. Whole genome methylation array analysis reveals new aspects in Balkan Endemic Nephropathy etiology. BMC Nephrol. 2013; 14: 225.

Journal information
Impact Factor

CiteScore 2017: 0.45

SCImago Journal Rank (SJR) 2018: 0.177

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 293 170 5
PDF Downloads 150 92 1