Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Multiple Independent Major Histocompatibility Complex Associations with Nephritis and Autoantibody Production in Systemic Lupus Erythematosus.

Chung7,  Sharon A., Taylor7,  Kimberly E., May10,  Suzanne L., Ramsay9,  Patricia P., Quach9,  Hong L., Lane2,  Julie A., Nititham8,  Joanne

Children's Hospital Cincinnati Medical Center, Cincinnati, OH
University of California, Berkely, CA
University of California, Davis, CA
Children's Hospital Oakland Research Institute, Oakland, CA
Genentech, Inc., South San Francisco, CA
Oklahoma Medical Research Foundation, Oklahoma City, OK
Oklahoma Medical Research Foundation, Oklahoma City, OK
Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, San Francisco, CA
Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco
Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, CA
University of California, Berkeley, CA

Background:

The most significant genetic associations with systemic lupus erythematosus (SLE) have been with the major histocompatibility complex (MHC), a gene dense region on chr6p21 spanning >5Mb. Prior attempts to identify MHC associations independent of HLA-DRB1 (the most consistently associated MHC locus) were limited, in part, by the region's extensive linkage disequilibrium. In addition, MHC associations with SLE manifestations such as nephritis and autoantibody production have not been fully explored. Therefore, we performed high-density single nucleotide polymorphism (SNP) genotyping to identify MHC associations with lupus nephritis, anti-dsDNA, and anti-Ro/La (SSA/SSB) autoantibody production among SLE patients.

Methods:

Using the Illumina Combined MHC panel, we genotyped 1,610 SLE cases of European descent for 2,360 MHC SNPs. SLE cases were also genotyped for HLA-DRB1 and 384 ancestry informative markers. Lupus nephritis and autoantibody status was obtained from medical record review. We identified associations with HLA-DRB1 alleles using a relative predispositional effects (RPE) method. Forward selection with conditional logistic regression (CLR) based on haplotypes was used to identify SNPs associated with particular SLE manifestations that were independent of each other and HLA-DRB1.

Results:

After applying stringent quality control criteria (including removal of SLE cases with <90% northern European ancestry), we analyzed 1,974 SNPs in 1,125 SLE cases. Thirty-two percent (32%) had lupus nephritis, 50% had anti-dsDNA autoantibodies, and 27% had anti-Ro/La (SSA/SSB) autoantibodies. RPE analysis showed that different HLA-DRB1 alleles were associated with lupus nephritis as compared to anti-Ro/La (SSA/SSB) autoantibody production (*1501 and *1302 for nephritis vs. *0301, *0401, *0404, *1301, and *0101 for anti-Ro/La). No HLA-DRB1 alleles were significantly associated with anti-dsDNA autoantibody production (global c2 p>0.05). CLR analysis identified associations independent of HLA-DRB1 in the HLA-DOB, HLA-A/HCG9, and LEMD2 regions with lupus nephritis (OR for the most associated haplotype [ORhs] 3.04, haplotype-specific p [phs]=3.1E-04). HLA-DRB1-independent associations were observed in the HLA-DPA1/HLA-DOA, C6orf205, and OR2H2 regions with anti-Ro/La (SSA/SSB) autoantibody production (ORhs 3.23, phs=1.6E-08). SNPs in or near TAP2, C6orf10, and TRIM40/TRIM15 were associated with anti-dsDNA autoantibody production (ORhs 2.82, phs=1.5E-08).

Conclusions:

We have identified several significant MHC associations with lupus nephritis and autoantibody production that are independent of HLA-DRB1. Of interest, different genes/genetic regions were associated with these specific SLE manifestations. These results indicate that MHC genetic variation contributes significantly to disease heterogeneity in SLE.

To cite this abstract, please use the following information:
Chung, Sharon A., Taylor, Kimberly E., May, Suzanne L., Ramsay, Patricia P., Quach, Hong L., Lane, Julie A., et al; Multiple Independent Major Histocompatibility Complex Associations with Nephritis and Autoantibody Production in Systemic Lupus Erythematosus. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :502
DOI: 10.1002/art.28271

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