title: Renal involvement in lupus is characterized by unique DNA methylation changes in naïve CD4+ T cells.
abstract: Systemic lupus erythematosus is a multi-system disease characterized by wide-spread DNA methylation changes. To identify epigenetic susceptibility loci for lupus nephritis, genome-wide DNA methylation changes in naïve CD4+ T cells were compared between two sets of lupus patients with and without a history of renal involvement. A total of 56 lupus patients (28 with renal involvement and 28 without renal involvement), and 56 age-, sex-, and ethnicity-matched healthy controls were included in our study. 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 the ERK signaling pathway, were among the most hypomethylated. Independent of disease activity, renal involvement is characterized by more robust demethylation in interferon regulated genes differentially methylated in both sets of lupus patients with and without renal involvement (fold change 1.4, P = 0.0014). The type-I interferon master regulator gene IRF7 is only hypomethylated in lupus patients with renal involvement. IRF-7 is an upstream transcription factor that regulates several loci demethylated only with renal involvement such as CD80, HERC5, IFI44, IRF7, ISG15, ISG20, ITGAX, and PARP12 (P = 1.78 × 10(-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 stratifying lupus patients for a history of renal involvement (P = 0.0029). Our data identified novel epigenetic susceptibility loci that are differentially methylated with renal involvement in lupus. These loci will help better understand lupus nephritis, and provide a proof of principle for the potential applicability of specific methylation changes as predictors for specific organ involvement in lupus.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Coit
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Renauer
authors.affiliation: Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Matlock A
authors.initials: MA
authors.lastname: Jeffries
authors.affiliation: Clinical Pharmacology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Joan T
authors.initials: JT
authors.lastname: Merrill
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: W Joseph
authors.initials: WJ
authors.lastname: McCune
authors.affiliation: Division of Rheumatology, Henry Ford Health System, Detroit, MI, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Maksimowicz-McKinnon
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. Electronic address: asawalha@umich.edu.
authors.forename: Amr H
authors.initials: AH
authors.lastname: Sawalha
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D019175:DNA Methylation; D054637:Dual-Specificity Phosphatases / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008181:Lupus Nephritis / Q000235:genetics*; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000235:genetics
chemical_list: D050839:Interferon Regulatory Factor-7; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human; C442320:DUSP5 protein, human; D054637:Dual-Specificity Phosphatases
keywords: Biomarker; EWAS; Epigenetics; Lupus; Methylation; Nephritis