Genomic studies of Systemic Lupus Erythematosus

National Human Genome Research Institute

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Abstract

During the current reporting period, we examined longitudinal data on 101 SLE pairs from the CLUES study. The 101 participants self-reported race or ethnicity as the following: 29 White, 13 Black, 34 Asian, 22 Hispanic, and 3 unspecified. Previous cross-sectional studies have shown associations between DNA methylation with SLE risk and clinical outcomes. To study the changes of DNA methylation across two time points for the 101 SLE patients, we profiled DNA from whole blood using the Illumina Methylation EPIC BeadChip which consists of 850,000 CpGs genomewide. After quality control measures, 720,683 CpG sites remained for analysis. We applied ComBat to adjust for plate to mitigate batch effects. We then adjusted the methylation values with residuals for estimated cell proportion heterogeneity using the reference-based Houseman algorithm. We then performed paired t-tests of the two time points which were on average 2 years apart. For the next analysis phase, we kept 309 CpG sites that had a false discovery rate (FDR) p-value < 0.05 and an absolute mean methylation beta value difference of more than 0.03 between the two time points. We then used mixed models adjusting for age, sex and genetic principal components on the remaining sites to understand the relationship between DNA methylation and disease activity, medication use and sample cell proportions. The most significant results of the pathway analysis of the top 309 CpG sites identified the human immune response to tuberculosis and the RIG-1-like receptor pathway. Additional pathways that had an FDR p-value <0.05 included immune pathways such as antigen processing, virus response and type II IFN signaling. The majority of previously described CpGs associated with SLE remained stable. In a previous study, CLUES cohort patients were clustered into three subtypes according to American College of Rheumatology SLE classification criteria. According to subtype, 256 CpGs were shown to be differentially methylated. Of those 256 sites in the previous study, 185 CpGs (72.3%) remained stable over time in this longitudinal study. Across the genome-wide methylome, only 2,423 (0.34%) CpG sites of the changed significantly in the t-tests using an FDR p-value < 0.05. In this well-characterized cohort, the majority of methylation signatures in whole blood associated with SLE clinical outcomes remained stable over the 2-year time period. A manuscript describing these results is being prepared for submission.