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Hypomethylation of CYP 2E1 and DUSP 22 Promoters Associated With Disease Activity and Erosive Disease Among Rheumatoid Arthritis Patients
Author(s) -
Mok Amanda,
Rhead Brooke,
Holingue Calliope,
Shao Xiaorong,
Quach Hong L.,
Quach Diana,
Sinclair Elizabeth,
Graf Jonathan,
Imboden John,
Link Thomas,
Harrison Ruby,
Chernitskiy Vladimir,
Barcellos Lisa F.,
Criswell Lindsey A.
Publication year - 2018
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40408
Subject(s) - dna methylation , medicine , immunology , rheumatoid arthritis , methylation , cpg site , cd14 , disease , oncology , biology , immune system , gene , genetics , gene expression
Objective Epigenetic modifications have previously been associated with rheumatoid arthritis ( RA ). In this study, we aimed to determine whether differential DNA methylation in peripheral blood cell subpopulations is associated with any of 4 clinical outcomes among RA patients. Methods Peripheral blood samples were obtained from 63 patients in the University of California, San Francisco RA cohort (all satisfied the American College of Rheumatology classification criteria; 57 were seropositive for rheumatoid factor and/or anti‐cyclic citrullinated protein). Fluorescence‐activated cell sorting was used to separate the cells into 4 immune cell subpopulations ( CD 14+ monocytes, CD 19+ B cells, CD 4+ naive T cells, and CD 4+ memory T cells) per individual, and 229 epigenome‐wide DNA methylation profiles were generated using Illumina HumanMethylation450 BeadChips. Differentially methylated positions and regions associated with the Clinical Disease Activity Index score, erosive disease, RA Articular Damage score, Sharp score, medication at time of blood draw, smoking status, and disease duration were identified using robust regression models and empirical Bayes variance estimators. Results Differential methylation of CpG sites associated with clinical outcomes was observed in all 4 cell types. Hypomethylated regions in the CYP 2E1 and DUSP 22 gene promoters were associated with active and erosive disease, respectively. Pathway analyses suggested that the biologic mechanisms underlying each clinical outcome are cell type–specific. Evidence of independent effects on DNA methylation from smoking, medication use, and disease duration were also identified. Conclusion Methylation signatures specific to RA clinical outcomes may have utility as biomarkers or predictors of exposure, disease progression, and disease severity.