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.
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 September 29, 2020.
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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/