Preferential Association of Complement Receptor 2 Variants with Anti-dsDNA Autoantibodies in Systemic Lupus Erythematosus

Brendan M. Giles¹, Jian Zhao², Kara M. Lough¹, Patrick M. Gaffney on behalf of LLAS2³, Marta E. Alarcon-Riquelme on behalf of BIOLUPUS⁴, Elizabeth E. Brown on behalf of PROFILE⁵, Lindsey A. Criswell⁶, Gary S. Gilkeson⁷, Chaim O. Jacob⁸, Judith A. James⁹, Joan T. Merrill¹⁰, Kathy L. Moser¹¹, Timothy B. Niewold¹², R. Hal Scofield¹³, Timothy J. Vyse¹⁴, John B. Harley¹⁵, Kenneth M. Kaufman¹⁶, Jennifer A. Kelly¹¹, Carl D. Langefeld¹⁷, Jeffrey C. Edberg¹⁸, Robert P. Kimberly¹⁹, Daniela Ulgiati²⁰, Betty P. Tsao²¹ and Susan A. Boackle²², ¹University of Colorado School of Medicine, Aurora, CO, ²Division of Rheumatology, Department of Medicine, David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA, ³Arthritis and Immunology Prog, Oklahoma Medical Research Foundation, Oklahoma City, OK, ⁴Arthritis & Clinical Immunology, Oklahoma Medical Research Foundation, Center for Genomics and Oncological Research Pfizer-University of Granada-Junta de Andalucia, Oklahoma City, OK, ⁵University of Alabama at Birmingham, Birmingham, AL, ⁶Department of Medicine, University of California, San Francisco, Rosalind Russell Medical Research Center for Arthritis, San Francisco, CA, ⁷Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, SC, ⁸Division of Rheumatology, University of Southern California Keck School of Medicine, Los Angeles, CA, ⁹Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City, OK, ¹⁰Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹¹Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹²Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, ¹³Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹⁴Division of Genetics and Molecular Medicine and Division of Immunology, Infection and Inflammatory Disease, King's College London, London, United Kingdom, ¹⁵Division of Rheumatology and The Center for Autoimmune Genomics & Etiology, University of Cincinnati, Cincinnati Children's Hospital Medical Center; US Department of Veterans Affairs Medical Center, Cincinnati, OH, ¹⁶Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹⁷Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, ¹⁸Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, ¹⁹Clinical Immun & Rheumatology, University of Alabama at Birmingham, Birmingham, AL, ²⁰University of Western Australia, Perth, Western Australia, Australia, ²¹Medicine/Rheumatology, UCLA School of Medicine, Los Angeles, CA, ²²Medicine/Rheumatology, University of Colorado School of Medicine, Aurora, CO

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Systemic lupus erythematosus (SLE)

Session Information

Title: Systemic Lupus Erythematosus - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Complement receptor 2 (CR2/CD21) is primarily expressed on B cells and follicular dendritic cells (FDC) and is required for normal humoral immune responses. We have previously identified CR2 variants associated with systemic lupus erythematosus (SLE) susceptibility. To understand how CR2 might contribute to disease development, we explored the association of CR2 polymorphisms with specific clinical manifestations of SLE.

Methods: We genotyped 49 CR2 single-nucleotide polymorphisms (SNPs) and assessed them for association with 14 clinical manifestations of SLE in 7,427 European-Americans (EA) cases and controls. We imputed genotypes for untyped SNPs, identified functional implications of associated SNPs, and evaluated haplotype-associated RNA and protein expression profiles in primary B cells from healthy control subjects.

Results: We detected a strong association between CR2 SNPs and anti-dsDNA autoantibodies in EA SLE subjects, and identified two SNP haplotypes independently associated with the absence (H1: 7.0% vs. 10.4%, P=1.2×10^-5) and presence (H2: 5.8% vs. 3.8%, P=7.0×10^-4) of anti-dsDNA autoantibodies. The H1 haplotype contained imputed SNPs extending into the proximal complement receptor 1 (CR1/CD35) gene. Three phenotypes were found in healthy control subjects with the H1 haplotype compared to the H2 haplotype: 1) decreased mRNA levels for the CR2 long isoform (p=0.0293), which is expressed primarily on FDC, 2) increased expression of CR1 (p=0.0353), and 3) positive correlation of surface CR2 with ligand binding capacity (H1: p=0.0311; H2: p=0.2967).

Conclusion: These data indicate that CR2 haplotypes are preferentially associated with anti-dsDNA autoantibodies and may modify both B cell and FDC responses. The association of imputed CR1 SNPs and altered B cell CR1 expression suggest that an extended haplotype encompassing both genes is responsible. Anti-dsDNA antibodies fluctuate with lupus disease activity, are associated with more severe disease, and are among the last autoantibodies to appear prior to the onset of clinical symptoms. Therefore, understanding the mechanisms by which they are regulated has important therapeutic implications.

*These authors contributed equally to this work

Disclosure:

B. M. Giles,
None;

J. Zhao,
None;

K. M. Lough,
None;

P. M. Gaffney on behalf of LLAS2,
None;

M. E. Alarcon-Riquelme on behalf of BIOLUPUS,
None;

E. E. Brown on behalf of PROFILE,
None;

L. A. Criswell,
None;

G. S. Gilkeson,
None;

C. O. Jacob,
None;

J. A. James,
None;

J. T. Merrill,
None;

K. L. Moser,
None;

T. B. Niewold,
None;

R. H. Scofield,
None;

T. J. Vyse,
None;

J. B. Harley,
None;

K. M. Kaufman,
None;

J. A. Kelly,
None;

C. D. Langefeld,
None;

J. C. Edberg,
None;

R. P. Kimberly,
None;

D. Ulgiati,
None;

B. P. Tsao,
None;

S. A. Boackle,
None.

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