ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2035

Dosage Contribution of a Non-Classical HLA Gene, HLA-Doa, to the Risk of Rheumatoid Arthritis

Yukinori Okada1, Akari Suzuki2, Katsunori Ikari3, Chikashi Terao4, Yuta Kochi2, Koichiro Ohmura5, Koichiro Higasa5, Masato Akiyama2, Kyoto Ashikawa2, Masahiro Kanai2, Jun Hirata1, Naomasa Suita1, Yik-Ying Teo6, Huji Xu7, Sang-Cheol Bae8, Yukihide Momozawa2, koichi Matsuda9, Shigeki Momohara10, Atsuo Taniguchi10, Ryo Yamada5, Tsuneyo Mimori5, Michiaki Kubo2, Matthew A. Brown11, Soumya Raychaudhuri12, Fumihiko Matsuda5, Hisashi Yamanaka10, Yoichiro Kamatani2 and Kazuhiko Yamamoto9, 1Osaka University, Osaka, Japan, 2Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan, 3Inst of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan, 4Departments of Genetics and Rheumatology, Brigham and Women'’s Hospital, Harvard Medical School, Boston, MA, 5Kyoto University Graduate School of Medicine, Kyoto, Japan, 6Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore, 7The Second Military Medical University, Shanghai, Japan, 8Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea, The Republic of, 9The University of Tokyo, Tokyo, Japan, 10Tokyo Women's Medical University, Tokyo, Japan, 11The University of Queensland Diamantina Institute, Brisbane, Australia, 12Brigham and Women's Hospital, Boston, MA

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: , , ,

Session Information

Date: Monday, November 14, 2016

Title: Genetics, Genomics and Proteomics I

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging.

Methods: We conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA), an autoimmune disease with chronic destruction of synovial joints in Japanese (6,244 RA cases and 23,731 controls). We applied the HLA imputation method using the reference panel of the Japanese population (n = 908). We further conducted a multi-ethnic validation study by assessing the MHC fine-mapping analyses of RA in east Asians and Europeans (n = 7,097 and 23,149, respectively).

Results: Our study identified a risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated-protein-autoantibody (ACPA)-positive RA risk (rs378352, odds ratio [OR] = 1.20, P = 1.4×10-9), independently from the risk classical HLA genes (HLA-DRB1, HLA-DPB1, and HLA-B). The HLA-DOA risk variant demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression levels, demonstrating its dosage expression effect on RA risk. Independent risk of the HLA-DOA variant was further validated in east Asians (OR = 1.15, P = 0.0040) and Europeans (OR = 1.06, P = 0.031). Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns between HLA-DOA and HLA-DRB1, which explains the observed HLA-DOA variant risk heterogeneity among ethnicities; which was most evident in Japanese but not in Europeans.

Conclusion: Whilst the previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility of the diseases, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to understanding of HLA immunology in human diseases, and suggests the value of incorporating additional ancestry in MHC fine-mapping.

 

SNP

Gene

Ref /Alt

Population

Cohort

No.

subjects

Ref allele freq

in controls

ACPA+ RA

OR (95%CI)

P

rs378352

(rs369150)

HLA-DOA

A/G

Japanese

BBJ1

16,029

0.26

1.24 (1.13-1.36)

4.6×10-6

BBJ2

3,815

0.26

1.13 (0.96-1.33)

0.15

IORRA

7,207

0.26

1.16 (1.04-1.29)

0.0053

Kyoto

1,799

0.25

1.27 (1.03-1.58)

0.027

Meta

28,850

0.26

1.20 (1.13-1.28)

1.4×10-9

east Asian

–

7,097

0.31

1.15 (1.05-1.27)

0.0040

European

–

23,149

0.26

1.06 (1.01-1.12)

0.031

Disclosure: Y. Okada, None; A. Suzuki, None; K. Ikari, AbbVie, Inc., Asahi Kasei Pharma Corp., Astellas Pharma Inc., Bristol-Myers Squibb Co., Chugai Pharmaceutical Co., Eisai Co., Ltd. Hisamitsu Pharmaceutical Co. Inc., Janssen Pharmaceutical K.K., Kaken Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co.,, 2; C. Terao, None; Y. Kochi, None; K. Ohmura, None; K. Higasa, None; M. Akiyama, None; K. Ashikawa, None; M. Kanai, None; J. Hirata, None; N. Suita, None; Y. Y. Teo, None; H. Xu, None; S. C. Bae, None; Y. Momozawa, None; K. Matsuda, None; S. Momohara, None; A. Taniguchi, None; R. Yamada, None; T. Mimori, None; M. Kubo, None; M. A. Brown, None; S. Raychaudhuri, None; F. Matsuda, None; H. Yamanaka, None, 4; Y. Kamatani, None; K. Yamamoto, UCB Pharma, Pfizer, Abbott, Santen, Mitsubishi-Tanabe, Eisai, 2,UCB Pharma, Pfizer, Abbott, Bristol-Myers Squibb, Roche, Chugai, Mitsubishi-Tanabe, Eisai, 5.

To cite this abstract in AMA style:

Okada Y, Suzuki A, Ikari K, Terao C, Kochi Y, Ohmura K, Higasa K, Akiyama M, Ashikawa K, Kanai M, Hirata J, Suita N, Teo YY, Xu H, Bae SC, Momozawa Y, Matsuda K, Momohara S, Taniguchi A, Yamada R, Mimori T, Kubo M, Brown MA, Raychaudhuri S, Matsuda F, Yamanaka H, Kamatani Y, Yamamoto K. Dosage Contribution of a Non-Classical HLA Gene, HLA-Doa, to the Risk of Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/dosage-contribution-of-a-non-classical-hla-gene-hla-doa-to-the-risk-of-rheumatoid-arthritis/. Accessed .

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/dosage-contribution-of-a-non-classical-hla-gene-hla-doa-to-the-risk-of-rheumatoid-arthritis/