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Abstract Number: 1966

A Genome-Wide Association Study of Copy Number Variations Identifies the Deletion Associated with Efficacy of TNF-Alpha Blocker Therapy in Korean Patients with Rheumatoid Arthritis

Ki-Nam Gu 1, So-Young Bang2, Hye-Soon Lee 3, Youngho Park 2, Juyeon Kang 2, Ji-Soong Kim 2, Bora Nam 2, Hyun-Seung Yoo 4, Jung-Min Shin 2, Yeon-Kyung Lee 2, Tae-Han Lee 2, Sehwan Chun 1, Soo-Kyung Cho 2, Chan-Bum Choi 2, Yoon-Kyoung Sung 5, Tae-Hwan Kim 2, Jae-Bum Jun 2, DaeHyun Yoo 2, Kwangwoo Kim 1 and Sang-Cheol Bae 2, 1Kyung Hee University, Seoul, Republic of Korea, 2Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea, 3Department of Internal Medicine, Hanyang University Guri Hospital,Hanyang University School of Medicine, Guri, Korea, Guri, Republic of Korea, 4Hanyang University Hospital, Guri, Republic of Korea, 5Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Copy number variations, rheumatoid arthritis, TNF-α blockers and Drug efficacy

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Session Information

Date: Tuesday, November 12, 2019

Session Title: Genetics, Genomics & Proteomics Poster

Session Type: Poster Session (Tuesday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Copy number variation (CNV) is the most common structural variation defined as large ( >1 kb) genomic deletions and duplications and could yield a high impact on various traits including drug response. In this study, we performed a genome-wide association studies (GWAS) of CNV to investigate the efficacy of treatment with TNF-α blockers in patients with rheumatoid arthritis (RA).

Methods: The study was conducted in 357 Korean RA patients treated with TNF-α blockers. All the study subjects were classified into non-responders and responders based on the change in disease activity indexes at 6 months according to the EULAR response criteria. A multivariate logistic regression analysis performed to fit the response to TNF-α blocker therapy with a CNV adjusting for the top 10 genetic principal components, body mass index, gender, baseline disease activity, and methotrexate use.

Results: The study subjects had 319 common CNVs with the frequency of abnormal-copy carrier ≥ 5% in autosomes and varied in their responses to TNF-α blockers with a wide range of 6-month changes in disease activity indexes. The CNV-response association analysis revealed that the copy number at 2q14.3 was associated with response to TNF-α blockers therapy in the patients with RA (P ≤ 3.2 x 10-4) at a false discovery rate (FDR) threshold of 5%. The loss of copy number in the identified CNV was significantly more in the non-responders than in the responders (7.3 ≤ odds ratio ≤ 8.5), indicating worse response to TNF-α blockers in the deletion carriers. The 3.8-kb deletion at 2q14.3 is located in an intergenic region with the experimentally validated binding sites of two transcription factors, MAFF and MAFK.

Conclusion: This study conducted the first genome-wide CNV analysis to identify which structural variations associated with the varied response to the TNF-α blocker therapy. Here, we identified a novel CNV that explained a proportion of the inter-individual variance in efficacy of biologics based on the common response criteria.


Disclosure: K. Gu, None; S. Bang, None; H. Lee, None; Y. Park, None; J. Kang, None; J. Kim, None; B. Nam, None; H. Yoo, None; J. Shin, None; Y. Lee, None; T. Lee, None; S. Chun, None; S. Cho, None; C. Choi, Eisai Korea, 2; Y. Sung, BMS, Eisai, JW pharmaceuticals, Pfizer; T. Kim, None; J. Jun, None; D. Yoo, Celltrion Healthcare, 8, Celltrion, Inc., 2, 5, 8; K. Kim, None; S. Bae, None.

To cite this abstract in AMA style:

Gu K, Bang S, Lee H, Park Y, Kang J, Kim J, Nam B, Yoo H, Shin J, Lee Y, Lee T, Chun S, Cho S, Choi C, Sung Y, Kim T, Jun J, Yoo D, Kim K, Bae S. A Genome-Wide Association Study of Copy Number Variations Identifies the Deletion Associated with Efficacy of TNF-Alpha Blocker Therapy in Korean Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/a-genome-wide-association-study-of-copy-number-variations-identifies-the-deletion-associated-with-efficacy-of-tnf-alpha-blocker-therapy-in-korean-patients-with-rheumatoid-arthritis/. Accessed January 18, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-genome-wide-association-study-of-copy-number-variations-identifies-the-deletion-associated-with-efficacy-of-tnf-alpha-blocker-therapy-in-korean-patients-with-rheumatoid-arthritis/

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