Background/Purpose: Genetic and epigenetic factors contribute to the progression of systemic lupus erythematosus (SLE).  We have the ability to identify these factors and their influence on SLE manifestations.  Few studies have examined epigenetic marks associated with lupus nephritis.  In contrast to genetic polymorphisms which are heritable and fixed, epigenetic modifications are heritable but also modifiable by environmental factors.  Therefore epigenetic modifications can provide new insights into the development and progression of SLE nephritis.  The focus of this study is to determine whether differentially methylated DNA sites are associated with lupus nephritis.

Methods: We previously enrolled 326 consecutive Caucasian non-smokers with SLE, 80 (25%) of whom met the ACR classification criterion for lupus nephritis (LN) or had evidence of LN on renal biopsy.  We used the Illumina Infinium HumanMethylation450 BeadChip to examine ~480,000 epigenetic marks (i.e. methylation marks) on the genomic DNA of each patient. This high-throughput array profiles CpG sites in ~23,000 genes and assesses methylation for sites in promoters, 5’ and 3’ regions, gene bodies, CpG islands, CpG island shores, and outside of CpG islands.

Results: Using multivariate analysis controlling for age, disease duration and other variables, we previously identified 7 methylation sites that were significantly differentially methylated among patients  with LN compared to those without LN (p<1 x 10^-6). These 7 sites were present in 4 unique genes (PRR4, HIF3A, KLF13, and SYNGR1), with HIF3A having three methylation sites that were significantly associated with LN.  None of these genes have been previously associated with lupus nephritis. However, HIF3A has been implicated in renal cell carcinoma and KLF13 has been previously associated with lupus.   We also examined candidate genes that are known to play roles in the development of SLE or LN and found differential methylation of sites in HIVEP3 (p=0.006) and in FRMD4A (p=9.05x 10^-5).  Here, we extended our  analysis to include additional significant methylation marks (top 6,000) and found  functional enrichment for:  “response to interferon gamma,” “regulation of Th2 differentiation” and “positive regulation of kidney development.”  We compared our results to those of a smaller study examining differential methylation in naive CD4+ T cells in LN patients and were able to replicate a significant number of their differentially methylated genes in our study (p<0.001).

Conclusion: These results demonstrate that DNA methylation levels are reproducibly associated with lupus nephritis.  Additionally, pathogenesis of LN may involve epigenetic modification of the interferon gamma pathway, Th2 differentiation and genes involved in renal development.  These findings  may be useful in stratifying patients to determine their risk of lupus nephritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/differential-dna-methylation-associated-with-lupus-nephritis-shows-enrichment-in-genes-involved-in-regulation-of-th2-differentiation-and-renal-development/