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.
Genome-Wide Association Scan of Antigenic Epitopes of Lupus Specific Autoantibodies in European Americans.
Lin1, Chee Paul, Adrianto1, Indra, Hale1, Jessica J., Kelly1, Jennifer A., Glenn1, Stuart B., Anderson1, Jourdan, Kaufman2, Kenneth M.
Oklahoma Medical Research Foundation, Oklahoma City, OK
Oklahoma Medical Research Foundation, Cincinnati, OK
Cincinnati Children's Hospital Medical Center, Cincinnati, OH
King's College London, Guy's Hospital, London, United Kingdom
University of Alabama at Birmingham, Birmingham, AL
Wake Forest University Health Sciences, Winston-Salem, NC
David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA
Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California San Francisco, San Francisco, CA
Keck School of Medicine University of Southern California, Los Angeles, CA
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by multi-organ-system involvement and the production of autoantibodies that can lead to tissue inflammation, destruction of cells and even end-organ damage. Susceptibility to SLE is likely to arise from a complex network of gene-environment interactions. Several studies support these contributions of environmental exposure to the development of disease. A temporal sequence of specific immune targets of select autoantibodies is observed in patients prior to disease classification and in phases of early pathogenesis. Curiously these autoantibodies are closely related to the antibodies that emerge in some lupus patients in response to viral infection, specifically Epstein-Barr Virus (EBV). In this study, we conduct a genome-wide association study (GWAS) of the three initial humoral antigenic epitopes of Sm B' (PPPGMRPP), Sm D1 (a Gly-Arg repeat) and 60kD Ro (amino acids 169180) to evaluate the genetic influence on the production of these early autoimmune antigenic structures in SLE cases.
A sample of 703 independent SLE patients of European descent was recruited from multiple institutions and their genotypes were obtained from several large-scale genetic studies. Sera of these patients were tested for antibodies directed against early humoral epitopes of Sm B' (PPPGMRPP), Sm D1 (GRGRGRGR) and 60kD Ro (TKYKQRNWSHK) constructed on poly-lysine backbones. We used enzyme-linked immunosorbent assays (ELISA) to quantify levels of autoantibody response directed against each epitope. Box and Cox transformation was applied to epitope variables that did not fulfill the normality assumption. Genome-wide imputation was performed using IMPUTE2 and the phase III Hapmap panel for 659,676 observed single-nucleotide polymorphisms (SNPs). After quality control, the final genotype sample comprised 581,509 SNPs. We tested for association between the epitopes as quantitative traits and the genetic variants using multiple linear regression under an additive model, adjusting for gender and global ancestry.
After performing stringent quality control, no effects met the Bonferroni corrected threshold of p < 8.60×10-8. However, several regions were significant at a suggestive level (p< 1×10-4) in RYR2 (p=1.95×10-6), GTDC1 (p=1.06×10-5) and NAALADL2 (p=1.72×10-6) for anti-Sm B', anti-Sm D1 and anti-60kD Ro epitopes, respectively. Genes previously shown to be associated with SLE were also evident in the study, particularly JAZF1 (p=0.000456) for anti-Sm B', KIAA1542 (p=0.000204) and XKR6 (p=0.0001) for anti-Sm D1 and PXK (p=0.00058) for anti-60kD Ro epitopes.
Our results demonstrate the potential power gained by examining more precise phenotypes and refines the association of previously reported SLE genes to the production of these antigenic responses. Overall, our study presents the first evidence of genetic associations with early lupus autoimmunity. It also highlights the importance of examining sub-phenotypes of a complex disease and further supports the involvement of gene by environment interactions toward initiating specific lupus autoimmune responses.
To cite this abstract, please use the following information:
Lin, Chee Paul, Adrianto, Indra, Hale, Jessica J., Kelly, Jennifer A., Glenn, Stuart B., Anderson, Jourdan, et al; Genome-Wide Association Scan of Antigenic Epitopes of Lupus Specific Autoantibodies in European Americans. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :649