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.
Major Histocompatibility Complex Association to Rheumatoid Arthritis Is Explained by Polymorphic Amino Acids In the Binding Grooves of HLA-DRB1, HLA-B, and HLA-DPB1.
Raychaudhuri1, Soumya, Stahl1, Eli A., Jia1, Xiaoming, Alfredsson2, Lars, Padyukov3, Leonid, Siminovitch4, Katherine A., Klareskog5, Lars
Brigham and Women's Hospital, Boston, MA
Institute of Environmental Medicine, Unit of Cardiovascular Epidemiology, Karolinska Institutet, Stockholm, Sweden
Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden
Mount Sinai Hospital, Toronto, ON
Karolinska Institutet, Stockholm, Sweden
University of Manchester, Manchester, United Kingdom
Feinstein Institute Medical Reschearch, Manhasset, NY
Rheumatoid arthritis (RA) is a common autoimmune disease that affects up to 1% of the general adult population worldwide. While the RA association at the major histocompatibility complex (MHC) has been noted for >20 years, there has been controversy about other associations outside DRB1, and the causal alleles within DRB1 itself.
In order to fine-map the MHC association, we used a strategy previously described (Pereyra et al., Science, 2010) to impute classical types and amino acid polymorphisms for the classical HLA-A, HLA -B, HLA-C, DPA1, DPB1, DQA1, DQB1, and DRB1 loci along with 2,537 SNPs across the MHC in 5,018 anti-CCP+ cases and 14,974 controls from 6 GWAS data sets (Stahl et al., Nature Genetics, 2010). Using logistic regression across all 6 data sets jointly, we performed conditional analyses to identify independent variants, correcting for 5 principal components in each GWAS.
We compared imputed classical alleles to DRB1 4-digit genotypes for 1150 overlapping individuals from two cohorts; the imputation was 96.5% and 85.4% accurate for 2-digit and 4-digit types, respectively. We also observed that classical DRB1 associations were identical to previously reported effect sizes. The strongest signal mapped to the presence of a valine or leucine in position 11 of DRB1 (OR=3.7, p<10-500), accounting in itself for 9% of the phenotypic variance. With conditional haplotype analysis we found that most of the DRB1 signal can be parsimoniously explained by 3 amino acid positions within DRB1 (11, 71, 74), refining the "shared epitope" hypothesis to include position 11, located at the floor of the binding groove, but to exclude positions 70, 72, and 73. We also confirmed an independent effect due to a single amino acid polymorphism in HLA-B (OR=2.1; p=2×10-38, Asp at position 9), corresponding to HLA-B*08, and identified a novel independent effect at HLA-DPB1 (OR=1.3; p=5×10-22, Phe at position 9). Controlling for all of these variants leaves no additional significant associations within the MHC (p>10-6).
In each case, the amino acid residues at these positions point into the binding groove of the HLA molecule, highlighting the importance of these residues in presenting auto-antigens to the immune system. In aggregate, these independent variants account for almost all of the known MHC signal in RA, and explain ~15% of the phenotypic variance, a significant increase relative to the most recent genome-wide meta-analysis in RA.
To cite this abstract, please use the following information:
Raychaudhuri, Soumya, Stahl, Eli A., Jia, Xiaoming, Alfredsson, Lars, Padyukov, Leonid, Siminovitch, Katherine A., et al; Major Histocompatibility Complex Association to Rheumatoid Arthritis Is Explained by Polymorphic Amino Acids In the Binding Grooves of HLA-DRB1, HLA-B, and HLA-DPB1. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1682