ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2703

An Intronic CR2 Polymorphism Associated With Systemic Lupus Erythematosus Alters CTCF Binding and CR1 Expression

Jian Zhao1, Brendan M. Giles2, Rhonda L. Taylor3, Gabriel A. Yette2, Kara M. Lough2, Lawrence J. Abraham3, Hui Wu4, Patrick M. Gaffney5, Jennifer A. Kelly6, Kenneth M. Kaufman7,8, John B. Harley9,10, Carl D. Langefeld11, Elizabeth E. Brown12, Jeffrey C. Edberg13, Robert P. Kimberly14, Daniela Ulgiati3, Betty P. Tsao1 and Susan A. Boackle15, 1Division of Rheumatology, Department of Medicine, David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA, 2University of Colorado School of Medicine, Aurora, CO, 3University of Western Australia, Perth, Western Australia, Australia, 4Rheumatology, David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA, 5Oklahoma Medical Research Foundation, Oklahoma City, OK, 6Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 7U.S. Department of Veterans Affairs Medical Center, Cincinnati, OH, 81Center for Autoimmune Genomics and Etiology and Rheumatology Division, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, 9Division of Rheumatology and The Center for Autoimmune Genomics & Etiology, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 10US Department of Veterans Affairs Medical Center, Cincinnati, OH, 11Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 12University of Alabama at Birmingham, Birmingham, AL, 13Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 14Clinical Immun & Rheumatology, University of Alabama at Birmingham, Birmingham, AL, 15Medicine/Rheumatology, University of Colorado School of Medicine, Aurora, CO

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: Systemic Lupus Erythematosus - Human Etiology and Pathogenesis II

Session Type: Abstract Submissions (ACR)

Background/Purpose: Systemic lupus erythematosus (SLE) is characterized by the production of antibodies to nuclear antigens, which form immune complexes that deposit in tissues and cause damage. Complement receptor 2 (CR2/CD21) is primarily expressed on B cells and follicular dendritic cells (FDC), and is required for normal humoral immune responses. Complement receptor 1 (CR1/CD35) is associated with CR2 on the B cell surface, and its cofactor activity is required for the conversion of iC3b to C3dg, the specific ligand for CR2. We previously identified CR2 variants associated with decreased risk of SLE. To identify the causal variant(s) for the association, we conducted trans-ancestral fine-mapping of CR2and the surrounding genomic region.

Methods: Genotyped and imputed genetic variants located in a 57.6kb region spanning 5’ of CR2 to intron 1 of CR1 were assessed for association with SLE in 15,750 unrelated case-control subjects from four ancestral groups using a logistic regression model adjusted for gender and global ancestry. Allele-specific functional effects of associated variants were determined using electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP)-PCR, quantitative real-time PCR, and quantitative flow cytometry.

Results: The strongest association signal was detected at rs1876453, located in intron 1 of CR2 (Pmeta=4.2×10-4, OR 0.85), specifically when subjects with lupus were stratified based on the presence of dsDNA autoantibodies (case-control Pmeta=7.6×10-7, OR 0.71; case-only Pmeta=1.9×10-4, OR 0.75). Using EMSA, we demonstrated that the minor allele at rs1876453 altered the formation of several DNA-protein complexes, including one containing the highly conserved 11 zinc-finger protein CCCTC-binding factor (CTCF), which has pleiotropic effects on genomic organization, gene regulation, and alternative splicing. The allele-specific effects of rs1876453 on CTCF binding were confirmed by ChIP-PCR, with three-fold higher enrichment of the region surrounding this variant in the presence of the major allele (p = 0.0178). Although allele-specific effects of rs1876453 on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on the B cells of subjects harboring the minor allele (p = 0.0248 and p = 0.0006, respectively).

Conclusion: These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active, and severe lupus, understanding its mechanisms will have important therapeutic implications.

Disclosure:

J. Zhao,
None;

B. M. Giles,
None;

R. L. Taylor,
None;

G. A. Yette,
None;

K. M. Lough,
None;

L. J. Abraham,
None;

H. Wu,
None;

P. M. Gaffney,
None;

J. A. Kelly,
None;

K. M. Kaufman,
None;

J. B. Harley,
None;

C. D. Langefeld,
None;

E. E. Brown,
None;

J. C. Edberg,
None;

R. P. Kimberly,
None;

D. Ulgiati,
None;

B. P. Tsao,
None;

S. A. Boackle,
None.

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