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.

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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/