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Abstract Number: 2918

Fine-Mapping Major Histocompatibility Complex Associations in ACPA-Positive Rheumatoid Arthritis Identified Shared HLA Amino Acid Polymorphisms in Asian and European Populations

Yukinori Okada1, Kwangwoo Kim2, Buhm Han3, Nisha E. Pillai4, Rick T-H. Ong4, Woei-Yuh Saw4, Ma Luo5, Lei Jiang6, Jian Yin6, So-Young Bang7, Hye-Soon Lee7, Matthew A. Brown8, Sang-Cheol Bae2, Huji Xu9, Yik-Ying Teo4, Paul IW. de Bakker10 and Soumya Raychaudhuri3, 1Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan, 2Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea, 3Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 4National University of Singapore, Singapore, Singapore, 5University of Manitoba, Winnipeg, MB, Canada, 6The Second Military Medical University, Shanghai, China, 7Department of Rheumatology, Hanyang University Guri Hospital, Guri, South Korea, 8University of Queensland Diamantina Institute, Brisbane, Australia, 9Shanghai Changzheng Hospital, Shanghai, China, 10Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands

Meeting: ACR/ARHP Annual Meeting 2014

Keywords: , , ,

Session Information

Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis II: Citrullination, Autoantibodies and Genes

Session Type: Abstract Submissions (ACR)

Background/Purpose: Rheumatoid arthritis (RA) risk is strongly associated with variations within the major histocompatibility complex (MHC) region, and in particular to HLA-DRB1 alleles. We aimed to fine-map RA risk alleles within the MHC in Asian populations and conduct trans-ethnic risk comparison to those in European populations.

Methods: We analyzed 2,782 anti-citrullinated protein antibodies (ACPA)-positive RA cases and 4,315 controls from Chinese and Korean populations. We applied HLA imputation to infer genotypes at eight class I and II HLA genes (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, HLA-DPB1) using SNP2HLA software and a newly constructed pan-Asian imputation reference panel.

Results: We obtained highly accurate imputation of HLA classical alleles with this reference panel (95.1% and 82.4% concordance for two and four digit classical alleles respectively). We observed the most significant association in HLA-DRb1 at amino acid position 13 (Pomnibus = 6.9×10-135), located outside the classical shared epitope (SE). The individual residues at position 13 have relative effects that are consistent with published effects in European populations (His>Phe>Arg>Tyr≈Gly>Ser) – but Asian effects are generally smaller. Applying stepwise conditional analysis, we identified additional associations at positions 57 (conditional Pomnibus = 2.2×10-33) and 74 (conditional Pomnibus = 1.1×10-8). Outside of HLA-DRb1, we observed independent effects for amino acid polymorphisms within HLA-B (Asp9, conditional P = 3.8×10-6) and HLA-DPb1 (Phe9, conditional P = 3.0×10-5) concordant with European populations. While a common set of amino-acid residue effects in three HLA genes are shared between European and Asian populations, these same effects can induce different classical allelic associations (e.g. HLA-DRB1*09:01) in the two populations due to differences in allele frequencies.

Conclusion: Our trans-ethnic study reveals that a common set of amino-acid residue effects in three HLA genes are largely shared between European and Asian populations. Our study illustrates the value of high-resolution imputation for fine-mapping causal variants in the MHC.

Disclosure:

Y. Okada,
None;

K. Kim,
None;

B. Han,
None;

N. E. Pillai,
None;

R. T. H. Ong,
None;

W. Y. Saw,
None;

M. Luo,
None;

L. Jiang,
None;

J. Yin,
None;

S. Y. Bang,
None;

H. S. Lee,
None;

M. A. Brown,
None;

S. C. Bae,
None;

H. Xu,
None;

Y. Y. Teo,
None;

P. I. de Bakker,
None;

S. Raychaudhuri,
None.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/fine-mapping-major-histocompatibility-complex-associations-in-acpa-positive-rheumatoid-arthritis-identified-shared-hla-amino-acid-polymorphisms-in-asian-and-european-populations/