Background Patients with RA have a higher prevalence of osteoporosis and hip fracture than healthy individuals. Although several clinical factors influence osteoporotic fracture¹, multiple genetic loci are also involved in the pathogenesis². Elevated levels of circulating homocysteine have been reported to inhibit the formation of collagen cross-links, resulting in fragile bones and the occurrence of osteoporotic fracture³. The activity of the methylene tetrahydrofolate reductase (MTHFR) enzyme affects levels of circulating homocysteine, but association of the MTHFR gene with osteoporotic fracture has been conflicting among studies. Previously, we reported no association of the MTHFR C677T polymorphism with incident fracture risk⁴. In the present study, we extended the dataset to enhance the statistical power and reviewed the association between the C677T polymorphism and the occurrence of hip fracture in Japanese patients with RA.

Objectives The purpose of this study was to investigate the association of the MTHFR C677T polymorphism with the occurrence of hip fracture in Japanese patients with RA.

Methods This study included 2282 Japanese patients with RA, who participated in the Institute of Rheumatology Rheumatoid Arthritis cohort study (IORRA). The MTHFR C677T polymorphism was genotyped in the DNA samples. The occurrence of hip fracture after enrollment in IORRA was determined from the response to a patient questionnaire every 6 months from October 2000 to October 2010. The data were confirmed by review of medical records. A total of 40 hip fractures in 40 patients were identified and included in this study. A multivariate Cox proportional hazards model was performed in order to examine the association between the number of risk alleles of the C677T polymorphism with the occurrence of hip fracture.

Results A multivariate Cox proportional hazards model showed that patients with more risk alleles of the C677T polymorphism had a higher risk of hip fracture (HR [95% CI] =1.63 [1.06 to 2.50], P =0.025).

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Conclusions Our results demonstrated that the MTHFR C677T polymorphism was significantly associated with the occurrence of hip fracture. Extending the dataset to 2282 patients with RA resulted in a different finding from the previous study. The present data support evidence that the C677T polymorphism contributes to an increased risk of hip fracture.

References

1. Furuya T, et al. Risk factors associated with the occurrence of hip fracture in Japanese patients with rheumatoid arthritis: a prospective observational cohort study. Osteoporos Int. 2013 Apr;24(4):1257-1265.

2. Styrkarsdottir U, et al. Multiple genetic loci for bone mineral density and fractures. N Eng J Med. 2008 May 29;358(22):2355-2365.

3. van Meurs JB, et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med. 2004 May 13;350(20):2033-2041.

4. Urano W, et al. Associations between methotrexate treatment and methylenetetrahydrofolate reductase gene polymorphisms with incident fractures in Japanese female rheumatoid arthritis patients. J Bone Miner Metab. 2009;27(5):574-583.

Acknowledgements We thank all DNA donors for making this study possible. We appreciate all the members of Institute of Rheumatology, Tokyo Women's Medical University for their effort on the IORRA cohort. We are also grateful to Ms Kaori Arai, Ms Nao Satomi and Ms Yuka Sato for their technical assistance.

Disclosure of Interest S. Yoshida: None declared, K. Ikari: None declared, T. Furuya: None declared, A. Taniguchi: None declared, H. Yamanaka Grant/research support from: Abbott, AbbVie, Asahikasei, Astellas, AstraZeneca, Bristol-Myers Squib, Chugai, Daiichi Sankyo, Eisai, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, MSD, Nippon Kayaku, Pfizer, Santen, Taishotoyama, Takeda, Teijin Consultant for: Abbott, AbbVie, Astellas, AstraZeneca, Bristol-Myers Squib, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Nippon Kayaku, Pfizer, Takeda, Teijin, Consultant for: Abbott, AbbVie, Astellas, AstraZeneca, Bristol-Myers Squib, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Nippon Kayaku, Pfizer, Takeda, Teijin., Speakers bureau: Abbott, AbbVie, Astellas, Bristol-Myers Squib, Chugai, Eisai, Mitsubishi Tanabe, Pfizer, Takeda, Teijin.S., S. Momohara Speakers bureau: Abbvie Japan, Chugai Parmaceutical, Eisai, Mitsubishi Tanabe Parma, Takeda Parmaceutical