Epigenetic modifications in ANCA-associated vasculitis (AAV)

Written by Neveen A Soliman on Wednesday, 05 April 2017. Posted in OLA Blog

Epigenetic modifications in ANCA-associated vasculitis (AAV)

AAV is a relapsing and remitting autoimmune disease characterized by vascular inflammation and organ damage.

-       Generally characterized by circulating ANCA, reactive to proteinase 3 (PR3) or myeloperoxidase (MPO).

-        Thought to be triggered by certain environmental exposures, such as silica dust, infections, or drug exposure.

-       Different clinical disease phenotypes are recognized.

-       Pharmacologically induced remission of this condition is complicated by relapses.

-       Recently, different genetic susceptibility loci have been identified according to ANCA serotype, with polymorphisms in HLAPRTN3, and SERPINA1 encoding MHC molecules, PR3, and its natural inhibitor α-1-antitrypsin, respectively, being associated with PR3-ANCA disease.

Methylation of DNA cytosine bases

-       Is an essential and well-studied epigenetic modification that may regulate and coordinate gene expression.

-       Methylated gene promoter or enhancer regions are thought to block accessibility to transcriptional activators and prevent gene transcription.

The potential link between environmental triggers, DNA methylation changes, and resultant variation in gene expression that may translate into particular phenotypes has made this topic attractive to many researchers.

 

In a recently published study in JASN by Jones et al:

http://jasn.asnjournals.org/content/28/4/1175.long

 First, they examined methylation and gene expression in patients with AAV and healthy controls:

  1. In both MPO and PRTN3 genes, DNA methylation was reduced in active disease compared with healthy controls and rebounded in disease remission.

Value: could further studies into methylation and gene expression unravel the mechanism(s) underlying ANCA formation leading to novel targeted therapeutics?

 

Second, they investigated whether DNA methylation patterns can be used to predict disease relapse:

  1. Patients with increased DNA methylation at the PRTN3 locus during remission were less likely to relapse, regardless of their autoantigen serotype. 

Value: could this be useful in the quest for biomarkers or prognostic indicators in the disease course that might later guide cessation or intensification of therapy?

 

Also future studies investigating potential key players in mediating autoimmune disease in response to environmental cues may further elucidate the role of epigenetic modifications in immune-mediated kidney diseases.

 

Jones BE, Yang J, Muthigi A, Hogan SL, Hu Y, Starmer J, Henderson CD, Poulton CJ, Brant EJ, Pendergraft WF 3rd, Jennette JC, Falk RJ, Ciavatta DJ: Gene-specific DNA methylation changes predict remission in patients with ANCA-associated vasculitis. J Am Soc Nephrol 28: 1175–1187, 2017

 

Neveen A Soliman ElShakhs

Professor Neveen A Soliman ElShakhs MD, PhD

OLA Director

Dr. Neveen A Soliman ElShakhs is a Professor of Pediatrics and Pediatric Nephrology, Kasr Al Ainy...
Posted: 2 weeks 5 days ago by nsoliman #21415
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Recent in brief: breakthrough findings in challenging diseases with potential clinical implications!
Posted: 2 weeks 5 days ago by elnahas #21416
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Thank you very much Prof Neveen for this very interesting Blog.

Whilst we focused for decades on genetic variations underlying phenotypic changes and behavioural patterns, there is little doubt that the epigenetic contribution to disease is equally relevant and may explain the two hit hypothesis whereby a genetically determined disease such as PKD only expresses itself in some but not all affected individuals...as the second hit may be modulated by epigenetic factors, some acquired, for the full expression of the disease ?!

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