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Abstract Number: 1623

Differential Methylation Of Interferon-Related Genes Is Associated With Anti-dsDNA Autoantibody Production In Systemic Lupus Erythematosus

Sharon A. Chung1, Joanne Nititham2, Kimberly E. Taylor1, Emon Elboudwarej3, Hong L. Quach3, Lisa F. Barcellos3 and Lindsey A. Criswell2, 1University of California, San Francisco, San Francisco, CA, 2Department of Medicine, University of California, San Francisco, Rosalind Russell Medical Research Center for Arthritis, San Francisco, CA, 3Epidemiology, University of California, Berkeley, Berkeley, CA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: anti-dsDNA, DNA Methylation, epigenetics and systemic lupus erythematosus (SLE)

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Session Information

Title: Systemic Lupus Erythematosus-Human Etiology and Pathogenesis: Genetics and Genomics

Session Type: Abstract Submissions (ACR)

Background/Purpose: DNA methylation studies in systemic lupus erythematosus (SLE) have shown that SLE patients have less methylation in genes regulating the immune response compared to unaffected individuals.  We conducted this study to determine if differences in methylation are associated with specific SLE manifestations, and focused on anti-dsDNA autoantibody production since it indicates more severe disease.

Methods: Genomic DNA from peripheral blood leukocytes was isolated from 326 women with SLE of European descent who never smoked.  Approximately 48% of the SLE cases were anti-dsDNA autoantibody positive.  Using the Illumina HumanMethylation450 Beadchip, the methylation status of 484,740 CpG sites across the genome was characterized in all SLE cases. For analysis, the cases were divided into discovery (n=186) and replication datasets (n=140). Wilcoxon rank sum tests were used to identify sites whose methylation status showed evidence of association with anti-dsDNA autoantibody production. Significantly associated sites in the discovery dataset were examined for association in the replication dataset.  Linear and logistic regression was used to adjust for estimated leukocyte cell proportions, age, disease duration, batch effects, and population substructure (assessed by principal component analysis of previously generated genotype data).

Results: Statistically significant associations between anti-dsDNA autoantibody production and methylation status were identified for 18 sites using the discovery dataset (p<1.0E-07 with Bonferroni correction) and were replicated (p<0.0028, corrected for 18 sites). All associated sites were less methylated in anti-dsDNA positive SLE cases compared to anti-dsDNA negative SLE cases. These 18 sites represent 12 genes, and the most significantly associated sites were in IFIT1, MX1, and RSAD2.  For the top 3 associated sites, the adjusted mean difference in methylation between anti-dsDNA positive and negative SLE cases and the adjusted odds ratio for anti-dsDNA autoantibody production if a subject’s methylation level was below the median are presented in Table 1.  Of note, 7 of 12 associated genes identified are either interferon inducible or involved in the interferon signaling pathway, including the 3 genes shown in Table 1. 

Table 1. The top 3 methylation sites associated with anti-dsDNA autoantibody production.

Site

Gene

Adjusted mean difference in methylation1 (95% CI)

p

Adjusted OR for anti-dsDNA autoantibody2 (95% CI)

p

cg05696877

IFI44L

-15% (-19% to -11%)

9.8E-13

7.2 (4.0-13.1)

5.4E-11

cg21549285

MX1

-18% (-23% to -13%)

1.7E-12

6.5 (3.6-11.9)

4.1E-10

cg10959651

RSAD2

-4.8% (-6.2% to -3.5%)

7.7E-12

7.2 (4.0-12.8)

4.2E-11

1 difference < 0 indicates that methylation levels were lower in the anti-dsDNA positive group

2 OR for anti-dsDNA autoantibody if a subject’s methylation level was below the median

Conclusion: This study suggests that differential methylation is associated with specific SLE manifestations in addition to disease susceptibility.  Among SLE cases, additional hypomethylation of interferon-related and other genes is associated with anti-dsDNA autoantibody production.  Thus, the extent of hypomethylation for critical genes may influence disease severity in SLE. 

 


Disclosure:

S. A. Chung,
None;

J. Nititham,
None;

K. E. Taylor,
None;

E. Elboudwarej,
None;

H. L. Quach,
None;

L. F. Barcellos,
None;

L. A. Criswell,
None.

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