Whole genome analysis on the genetic backgrounds associated with the secondary failure to etanercept in patients with rheumatoid arthritis

Abstract

Objectives: Etanercept is effective for the treatment of rheumatoid arthritis (RA). However, some of the patients eventually lose efficacy (secondary failure) despite the absence of neutralizing antibodies. We aimed to explore single nucleotide polymorphisms (SNPs) associated with secondary failure.

Methods: We recruited RA patients given etanercept at 50 mg/week for ≥6 months from the Matsubara Mayflower Hospital RA registry. They were assigned to responders, secondary failure patients, and non-responders according to Disease Activity Score. Genome-wide association study (GWAS) was performed using Illumina HumanHAP300k BeadChips and the results were analyzed with Plink software. Clinical backgrounds were compared by ANOVA and contingency table analysis. The protocol was approved by IRB and written informed consent was obtained.

Results: Ninety, 27 and 17 patients were assigned to responders, secondary failure patients, and non-responders, respectively. No significant differences were observed regarding clinical backgrounds among the groups. GWAS revealed that six and 37 SNPs may be associated with secondary failure to etanercept with p< 10⁻⁶ and <10⁻⁵, respectively.

Conclusion: While our preliminary results with borderline significance should be validated by studies with a greater population size, some of the SNPs detected by our GWAS may be involved in the development of secondary failure to etanercept.

Keywords:

• Etanercept
• Rheumatoid arthritis
• Secondary failure
• Single nucleotide polymorphisms

Acknowledgments

The authors would like to thank clinical research coordinators of Matsubara Mayflower Hospital for collecting clinical data of patients participating in the present study and Ms. Carol Matsubara for proofreading the manuscript.

Conflict of interest

We used no specific funding for conducting the present study. No funding was received from either corporations or the Japanese government for this study. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.