ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: L8

Differential DNA Methylation Associated with Lupus Nephritis

Renuka Nayak1, Sharon A. Chung2, Joanne Nitiham3 and Lindsey A. Criswell3, 1Rheumatology, University of California - San Francisco, San Francisco, CA, 2School of Medicine, University of California, San Francisco, Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, San Francisco, CA, 3Medicine, University of California, San Francisco, Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, San Francisco, CA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: , , ,

Session Information

Title: ACR Late-breaking Abstract Poster Presentations

Session Type: Late-Breaking Abstracts

Background/Purpose: Genetic and epigenetic factors contribute to the progression of systemic lupus erythematosus (SLE).  We now have technologies that allow us to identify these factors and their influence on SLE manifestations.  While recent studies have found genetic polymorphisms that are associated with lupus nephritis, few studies have examined epigenetic marks associated with this morbid SLE complication.  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 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 identified 8 methylation sites that were significantly differentially methylated among patients  with LN compared to those without LN (p<1.5 x 10-6). These 8 sites were present in 5 unique genes (PRR4, HIF3A, KLF13, GRIK1, and SMC4), 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)

Conclusion: These results demonstrate that DNA methylation levels are associated with lupus nephritis.  Further characterization of these differentially methylated sites/regions will be useful in understanding the pathogenesis of lupus nephritis and stratifying patients to determine their risk of lupus nephritis.

Disclosure:

R. Nayak,
None;

S. A. Chung,
None;

J. Nitiham,
None;

L. A. Criswell,
None.

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