Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


Risk Alleles of SLE Associated IL10 SNPs Conferred Differential Binding to Transcription Factors.

Sakurai1,  Daisuke, Zhao1,  Jian, Deng1,  Yun, Kaufman2,  Kenneth, Kelly3,  Jennifer A., Kimberly,  Robert P., on behalf of PROFILE investigators,  

David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA
University of Chicago, Chicago, IL
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
Oklahoma Medical Research Foundation and Oklahoma University Health Sciences Center, Oklahoma City, OK
Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC
Medical University of SC, Charleston, SC
Wake Forest University Health Sciences, Winston-Salem, NC
National Defense Medical Center, Taipei
Seoul National University College of Medicine, Seoul, South Korea
7Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital and The Ohio State University, Columbus, OH
UCLA David Geffen School of Medicine, Los Angeles, CA
Oklahoma Medical Research Foundation, Oklahoma CIty, OK
University of California Los Angeles, Los Angeles, CA
Oklahoma Medical Research Foundation, Oklahoma City, OK
Cincinnati Children's Hospital Medical Center and the US Department of Veterans Affairs Medical Center, Cincinnati, OH
Hanyang University Hospital for Rheumatic Diseases, Clinical Research Center for Rheumatoid Arthritis (CRCRA), Seoul, South Korea
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
Divisions of Genetics and Molecular Medicine and Immunology, King's College London, London, United Kingdom

Background/Purpose:

Interleukin-10 (IL-10) is produced at high levels by B cells and monocytes of SLE patients and promotes B cell hyperactivity and autoantibody production in these individuals. In a trans-ancestral study, we assessed 16,003 case-control samples to fine map of the IL10 locus and to evaluate SLE-associated SNPs for potential functions.

Methods:

Eight tag SNPs selected from HapMap CEU dataset to cover the IL10 locus and 347 ancestry informative markers (AIMs) were genotyped on a customized Illumina array. Samples used in association tests included European Americans (EA), African Americans and Gullahs (AA&Gullah), Asians (AS) and Hispanic and Native Americans (Hisp&NA). AIMs were used to estimate global ancestry for each subject and eliminate genetic outliers. We performed Chi-square test to compare the allelic difference between cases and controls, likelihood ratio test to distinguish independent signals from associated SNPs. K562 nuclear extracts were used in electrophoresis mobility shift assay (EMSA) to assess whether SLE-associated IL10 SNPs might function in IL-10 regulation.

Results:

In EA, six SNPs that defined a 6-kb haplotype block were significantly associated with SLE, exhibiting the strongest signal at rs3024505 (P=2.25×10-8, OR=1.29, 18.2% in 3980 cases vs. 14.7% in 3546 controls). Association signals of the other 5 SNPs were eliminated after conditioning on rs3024505, suggesting rs3024505 alone could explain the association of IL10 with SLE in EA. In non-European ancestries, the SLE-associated allele of rs3024505 present at lower allele frequencies consistently exhibited higher frequencies in cases than controls (AA&Gullah: 4.5% in 1680 cases vs. 3.9% in 1935 controls, AS: 3.1% in 1272 cases vs. 2.7% in 1270 controls, Hisp&NA: 9.0% in 1580 cases vs. 8.3% in 812 controls) but was not significantly associated with SLE. rs3024505 located at 1kb down-stream of 3'UTR was in complete linkage disequilibrium (LD) with rs3122605 (10kb up-stream of 5'UTR), rs3024493 (intron 3) and rs3024495 (intron 4). EMSA results in Figure 1 revealed no binding activity to nuclear extracts using DNA fragments containing rs3024505 or rs3024493, but preferential binding activity in the risk allele of rs3122605 and rs3024495 compared to its respective non-risk allele. These results were consistent with bioinformatic predictions that the risk allele of rs3122605 and rs3024495 conferred differential binding to lymphoid transcription factors MZF1 and CP2/ZID, respectively.

Conclusion:

Our trans-ancestral mapping localized the association of IL10 with SLE to rs3024505 in European ancestry, which was in complete LD with rs3122605 and rs3024495 located in the 5' upstream region and intron 4, respectively. Preferential binding to transcription factors by the risk allele of rs3122605 and rs3024495 might regulate expression of IL10 transcripts, predisposing to SLE.

To cite this abstract, please use the following information:
Sakurai, Daisuke, Zhao, Jian, Deng, Yun, Kaufman, Kenneth, Kelly, Jennifer A., Kimberly, Robert P., et al; Risk Alleles of SLE Associated IL10 SNPs Conferred Differential Binding to Transcription Factors. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2477
DOI:

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