Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production, multiple organ involvement, strong genetic predisposition and specifically, to be associated with Class II alleles within the Major Histocompatibility Complex (MHC). Immunochemistry studies have shown that specific antibodies often occur years before clinical diagnosis and accrue new specificities through preclinical and clinical phases of SLE. More specifically, specific epitopes appear to be unique to SLE patients early in the course of disease evolution, even compared to other rheumatic diseases. The goal of our study was to better characterize the role of the genes within the MHC by assessing genetic association between antibodies to early epitopes of SmB’, SmD1 and 60kD Ro (termed here GMR, GRx4 and Ro169, respectively) in 703 SLE European-American (EA) and 557 African American (AA) SLE cases. We also assessed genetic association with autoantibodies directed against the parent lupus autoantigens, Sm and 60kD Ro, in both races.
Methods: Standardized ELISA assays tested serum samples for binding of SmB’: amino acid sequence PPPGMRPP (GMR); SmD1: Glycine Arginine repeat sequence (GRx4); 60kD Ro: amino acids 169-180 (Ro169). Levels of anti-Sm and anti-Ro60 were determined by Bio-Rad Bioplex2200 ANA testing. All data are semi-quantitative and only measured in SLE patients. This is in contrast to previous studies, which assessed genetic association of the dichotomous trait, positive versus negative by immunodiffusion asays.
We evaluated > 50,000 SNPs within the MHC in both EA and AA samples. SNP data were collected from Affymetrix Genome-Wide Human SNP Array 5.0, Illumina iSelect Infinium II, and Immunochip and imputed with IMPUTE2. Quality control included removing of SNPs with call rate <90%, minor allele frequency <0.01 and Hardy-Weinberg proportion tests P < 0.001.
Results: Autoantibodies against the GRx4) yielded a novel association within the Class I region, with the most significant SNP near TRIM40/TRIM15 in EAs (P < 5 x10-7) and near TRIM39 in AAs (P < 5 x10-5). The Ro169 was also strongly associated in EAs at this location (P < 5 x10-5). Autoantibodies against the GMR showed no association with Class I genes but was significant for Class II (P < 5 x10-4, nearest DQB1) in the same race. Both Sm and 60kd Ro autoantibody responses were also significantly associated within the Class I region (P < 5 x10-5 and P < 5 x10-4, respectively) in the EAs. 60kD Ro was also highly significant (P < 5 x10-8) within the Class II region at DRB1, DQB1 and DQA1 in EAs. Further conditional analysis showed the driving effect to be within HLA-DQA1. The AA sample was significant for DQB1 and DQA1 (P < 5 x10-6) for the 60kD Ro epitope.
Conclusion: Our genetic study of the MHC region identified novel association between autoantibody responses against some of the earliest epitopes of lupus, their parent proteins and Class I variants. We further confirmed and more specifically characterized association between Class II variants and 60kd Ro. These findings and other investigations into the genetic mechanisms underlying early lupus autoimmunity will give significant insight into disease etiology.
Disclosure:
G. Dumancas,
None;
C. P. Lin,
None;
I. Adrianto,
None;
J. A. Kelly,
None;
S. B. Glenn,
None;
J. Anderson,
None;
J. B. Harley,
None;
T. J. Vyse,
None;
R. P. Kimberly,
None;
M. E. Alarcon-Riquelme,
None;
C. D. Langefeld,
None;
B. P. Tsao,
None;
L. A. Criswell,
None;
C. O. Jacob,
None;
P. M. Gaffney,
None;
K. Sivils,
None;
J. A. James,
None;
C. Montgomery,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-novel-genetic-associations-within-major-histocompatibility-complex-mhc-class-i-and-class-ii-in-systemic-lupus-erythematosus-sle-patients-an-examination-of-epitopes-of-earl/