Dynamics of Methylation of CpG Sites Associated With Systemic Lupus Erythematosus Subtypes in a Longitudinal Cohort

OBJECTIVE: Findings from cross‐sectional studies have revealed associations between DNA methylation and systemic lupus erythematosus (SLE) outcomes. This study was undertaken to investigate the dynamics of DNA methylation by examining participants from an SLE longitudinal cohort using samples collected at 2 time points. METHODS: A total of 101 participants from the California Lupus Epidemiology Study were included in our analysis. DNA was extracted from blood samples collected at the time of enrolment in the cohort and samples collected after 2 years and was analyzed using Illumina EPIC BeadChip kit. Paired t‐tests were used to identify genome‐wide changes which included 256 CpG sites previously found to be associated with SLE subtypes. Linear mixed models were developed to understand the relationship between DNA methylation and disease activity, medication use, and sample cell‐type proportions, adjusted for age, sex, and genetic principal components. RESULTS: The majority of CpGs that were previously determined to be associated with SLE subtypes remained stable over 2 years (185 CpGs [72.3%]; t‐test false discovery rate >0.05). Compared to background genome‐wide methylation, there was an enrichment of SLE subtype–associated CpGs that changed over time (27.7% versus 0.34%). Changes in cell‐type proportions were associated with changes at 67 CpGs (P < 2.70 × 10(−5)), and 15 CpGs had at least 1 significant association with immunosuppressant use. CONCLUSION: In this longitudinal SLE cohort, we identified a subset of SLE subtype–associated CpGs that remained stable over time and may be useful as biomarkers of disease subtypes. Another subset of SLE subtype–associated CpGs changed at a higher proportion compared to the genome‐wide methylome. Additional studies are needed to understand the etiology and impact of these changes on methylation of SLE‐associated CpGs.