Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Ankylosing spondylitis (AS) is a highly heritable rheumatic disease causing chronic inflammation of axial spine, joints and various organs. The presence of HLA-B*27 is strongly associated with development of AS, explaining most of the genetic associations between AS and the major histocompatibility complex (MHC) locus on human chromosome 6. Here, we investigated residual effects outside HLA-B within the MHC region.
Methods: We obtained high-density genotyping array Immunochip data for the extended MHC locus in 3,820 unrelated Korean subjects (comprising 654 cases of AS and 3,166 controls) who were ethnically homogeneous and showed no evidence of systemic bias or potential population substructure. The patients with AS satisfied the modified New York criteria for AS diagnosis. Using the SNP2HLA script and the Korean HLA reference panel, we imputed the two- and four-digit classical alleles and amino-acid residues of HLA-A, -B, –C, –DRB1, –DPB1 and –DQB1, as well as MHC SNPs (spanning 25–35 Mb). AS associations of all markers with minor allele frequency ≥1% and imputation quality (PLINK INFO) ≥0.1 were assessed using logistic regression, adding the top ten principal components as covariates. AS associations at HLA amino-acid positions (or multiple markers) were assessed using log likelihood ratio tests (LRT).
Results: We imputed 5,658 polymorphic variations including 158 classical alleles and 663 amino-acid variants in HLA-A, -B, -C, -DRB1, -DPB1 and -DQB1, as well as 4,837 MHC SNPs. The most significant associations were identified at amino-acid positions 97 (PLRT=7.20×10−479) and 114 (PLRT=2.54×10−484) in the epitope-binding site of HLA-B, highlighting the risk effect of the HLA-B*27 allele (OR=243) and the protective effects of other classical alleles (OR≤0.67). A secondary effect was located at the leucine at amino-acid position 116 in the epitope-binding site of HLA-C (p=3.76×10−15) in a conditional logistic regression analysis adding the two amino-acid positions 97 and 114 as covariates. This residue was highly correlated with the HLA-C*15:02 allele and had a large effect in HLA-B*27-negative patients (OR=6.6; 95% CI=3.8-11.4; p=1.52×10−11). After conditioning on the three AS-associated amino-acid positions, we could not find any MHC SNPs or HLA variants associated with AS susceptibility (p>1.32×10−5).
Conclusion: We identified associations of HLA-C in addition to HLA-B with AS susceptibility in the Korean population. This updates the list of AS susceptibility loci and provides new insight into AS pathogenesis mediated by MHC class I molecules.
To cite this abstract in AMA style:Kim K, Bang SY, Lee S, Lee HS, Shim SC, Kang YM, Suh CH, Sun C, Nath S, Bae SC, Kim TH. An HLA-C Amino Acid Variant in Addition to HLA-B*27 Confers Risk for Ankylosing Spondylitis in the Korean Population [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/an-hla-c-amino-acid-variant-in-addition-to-hla-b27-confers-risk-for-ankylosing-spondylitis-in-the-korean-population/. Accessed March 21, 2018.
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