-Original-

Polymorphism in Organic Anion-Transporting Polypeptide Gene Related to Methotrexate Response in Rheumatoid Arthritis Treatment

Kenji Takahashi¹, Hiroshi Nakamura², Atsushi Watanabe³, Tokifumi Majima⁴, Masahito Koiwa⁵, Toshikazu Kamada⁶ and Shinro Takai⁴

¹Department of Orthopaedic Surgery, International University of Health and Welfare Hospital, Tochigi, Japan
²Department of Orthopaedic Surgery, Sanno Hospital, Tokyo, Japan
³Division of Personalized Genetic Medicine, Nippon Medical School Hospital, Tokyo, Japan
⁴Department of Orthopaedic Surgery, Nippon Medical School, Tokyo, Japan
⁵Department of Orthopaedic Surgery, Shuwa General Hospital, Saitama, Japan
⁶Hara Orthopaedic Hospital, Tokyo, Japan

Background: Methotrexate (MTX) is still the first-choice drug for the treatment of rheumatoid arthritis (RA). In Japan, MTX doses of up to 16 mg/week were approved in 2011. In this study, we aimed to identify the gene polymorphisms that can predict therapeutic effects of MTX in Japanese patients in current clinical settings.
Methods: This study involved 171 patients with RA (all Japanese nationals, age 63.5±10.0 years) who had been administered MTX. The analyzed polymorphisms included 82 single nucleotide polymorphisms (SNPs) involved in the MTX pharmacological pathway or in the pathogenesis of RA. Responders were patients who showed high sustained remission or low disease activity with MTX or conventional disease-modifying anti-rheumatic drugs (DMARDs) treatment beyond 6 months. Non-responders were patients who showed moderate or high disease activity, who were prescribed biological DMARDs. A logistic model was constructed with Responder/Non-responder as the target variable, and minor allele frequency was set as an explanatory variable.
Results: None of the 82 SNPs targeted for analysis met the Bonferroni significance threshold of 6.098×10⁻⁴. However, we identified SLCO1B1 rs11045879 as an SNP that might yield significant results if the number of patients were to be increased (P=0.015).
Conclusions: The rs11045879 minor allele in the SLCO1B1 gene is a potential predictor of non-responders to MTX treatment among Japanese RA patients. In future collaborative research, we will investigate whether the association with SLCO1B1 polymorphism is significant by performing statistical analysis with a larger study population.

J Nippon Med Sch 2019; 86: 149-158

Keywords
genetic polymorphism, rheumatoid arthritis, methotrexate, precision medicine, Japanese

Correspondence to
Kenji Takahashi, MD, PhD, Department of Orthopaedic Surgery, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi 329-2763, Japan
t-kenji@iuhw.ac.jp

Received, September 7, 2018
Accepted, January 22, 2019