Gene-Specific DNA Methylation Changes Predict Remission in Patients with ANCA-Associated Vasculitis.
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 ofMPOandPRTN3and 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,MPOandPRTN3expression correlated with DNA methylation. Kaplan-Meier estimate of relapse revealed patients with increased DNA methylation at thePRTN3promoter had a significantly greater probability of a relapse-free period (P<0.001), independent of ANCA serotype. Patients with decreased DNA methylation at thePRTN3promoter 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 thePRTN3promoter may predict the likelihood of stable remission and explain autoantigen gene regulation.
Kidney Center, Department of Medicine, Division of Nephrology and Hypertension.|Department of Pathology and Laboratory Medicine, and.
Britta E
BE
Jones
Kidney Center, Department of Medicine, Division of Nephrology and Hypertension.
Jiajin
J
Yang
Kidney Center, Department of Medicine, Division of Nephrology and Hypertension.
Akhil
A
Muthigi
Kidney Center, Department of Medicine, Division of Nephrology and Hypertension.
Susan L
SL
Hogan
Kidney Center, Department of Medicine, Division of Nephrology and Hypertension.
Yichun
Y
Hu
Kidney Center, Department of Medicine, Division of Nephrology and Hypertension.|Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Joshua
J
Starmer
Kidney Center, Department of Medicine, Division of Nephrology and Hypertension.
Candace D
CD
Henderson
Kidney Center, Department of Medicine, Division of Nephrology and Hypertension.
Caroline J
CJ
Poulton
Kidney Center, Department of Medicine, Division of Nephrology and Hypertension.
Elizabeth J
EJ
Brant
Kidney Center, Department of Medicine, Division of Nephrology and Hypertension.
William F
WF
Pendergraft
Kidney Center, Department of Medicine, Division of Nephrology and Hypertension.|Department of Pathology and Laboratory Medicine, and.
J Charles
JC
Jennette
Kidney Center, Department of Medicine, Division of Nephrology and Hypertension.
Ronald J
RJ
Falk
Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, dciavatt@med.unc.edu.|Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Dominic J
DJ
Ciavatta
D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000235:genetics*; D001324:Autoantigens / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D053146:Myeloblastin / Q000235:genetics*; D009195:Peroxidase / Q000235:genetics*; D011379:Prognosis; D012074:Remission Induction
D001324:Autoantigens; D009195:Peroxidase; D053146:Myeloblastin
ANCA; DNA methylation; epigenetics; gene expression; vasculitis