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Gene-Specific DNA Methylation Changes Predict Remission in Patients with
ANCA-Associated Vasculitis
#MMPMID27821628
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
J Am Soc Nephrol
2017[Apr]; 28
(4
): 1175-1187
PMID27821628
show ga
ANCA-associated vasculitis is an autoimmune condition characterized by vascular
inflammation and organ damage. Pharmacologically induced remission of this
condition is complicated by relapses. Potential triggers of relapse are
immunologic challenges and environmental insults, both of which associate with
changes in epigenetic silencing modifications. Altered histone modifications
implicated in gene silencing associate with aberrant autoantigen expression. To
establish a link between DNA methylation, a model epigenetic gene silencing
modification, and autoantigen gene expression and disease status in
ANCA-associated vasculitis, we measured gene-specific DNA methylation of the
autoantigen genes myeloperoxidase (MPO) and proteinase 3 (PRTN3) in leukocytes of
patients with ANCA-associated vasculitis observed longitudinally (n=82) and of
healthy controls (n=32). Patients with active disease demonstrated
hypomethylation of MPO and PRTN3 and increased expression of the autoantigens; in
remission, DNA methylation generally increased. Longitudinal analysis revealed
that patients with ANCA-associated vasculitis could be divided into two groups,
on the basis of whether DNA methylation increased or decreased from active
disease to remission. In patients with increased DNA methylation, MPO and PRTN3
expression correlated with DNA methylation. Kaplan-Meier estimate of relapse
revealed patients with increased DNA methylation at the PRTN3 promoter had a
significantly greater probability of a relapse-free period (P<0.001), independent
of ANCA serotype. Patients with decreased DNA methylation at the PRTN3 promoter
had a greater risk of relapse (hazard ratio, 4.55; 95% confidence interval, 2.09
to 9.91). Thus, changes in the DNA methylation status of the PRTN3 promoter may
predict the likelihood of stable remission and explain autoantigen gene
regulation.
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