Lupus nephritis is characterized by unique DNA methylation changes in naïve CD4+ T cells

Objective. To characterize DNA methylation changes in naïve CD4+ T cells in lupus patients with renal involvement. Methods. Genome-wide DNA methylation changes in naïve CD4+ T cells were identified and compared between two sets of lupus patients with and without a history of renal involvement. A total of 56 lupus patients, and 56 age-, sex-, and ethnicity-matched healthy controls were studied. Results. We identified 191 CG sites and 121 genes that were only differentially methylated in lupus patients with but not without a history of renal involvement. The tyrosine kinase gene TNK2 involved in cell trafficking and tissue invasion, and the phosphatase gene DUSP5 which dephosphorylates and inhibits ERK signaling pathway, are among the most hypomethylated. Renal involvement is characterized by more robust demethylation in interferon-regulated genes in lupus patients. The type-I interferon master regulator IRF7 is only hypomethylated with renal involvement. IRF-7 is an upstream transcription factor that regulates several loci demethylated only with renal involvement such as CD80, HERC5, IFI44, ISG15, ISG20, ITGAX, and PARP12 (p=1.78X10-6). Among the CG sites only hypomethylated with renal involvement, CG10152449 in CHST12 has a sensitivity of 85.7% and a specificity of 64.3% for detecting renal involvement in lupus patients (p=0.0029). Conclusions. We identified novel differentially methylated targets in the presence of renal involvement in lupus. These identified targets will help to better understand lupus nephritis, and provide a proof of principle for the potential applicability of specific methylation changes as predictors for specific organ involvements in lupus