Background Vitamin D is important for the maintenance of the musculoskeletal system, is positively associated with muscle strength and physical performance, and is inversely associated with fall and fracture risk. The major determinants of serum vitamin D concentration are sunlight exposure and intake from diet or supplements; however, genetic variants affecting serum vitamin D concentration were recently identified in a meta-analyses of genome-wide association studies in Caucasian populations.1,2 We investigated the genetic variants associated with serum vitamin D concentration and the occurrence of hip fracture in Japanese rheumatoid arthritis (RA) patients.
Objectives The purpose of this study is to identify the genetic variants associated with serum vitamin D concentration and the occurrence of hip fracture in Japanese RA patients.
Methods We obtained DNA samples of 2068 Japanese RA patients from the IORRA (Institute of Rheumatology Rheumatoid Arthritis cohort study) DNA collection. IORRA is a project of a large-scale observational RA cohort. All of the patients who donated DNA samples consented to participate in this study in accordance with the process approved by the Tokyo Women’s Medical University Genome Ethics Committee. All of the patients satisfied the American College of Rheumatology 1987 revised criteria for the classification of RA. Five of the single nucleotide polymorphisms (SNPs) reported by Wang TJ, et al.1 and Ahn J, et al.2 were selected: rs2282679 in GC, rs12785878, rs1790349, rs3829251 in or near DHCR7/NADSYN1, and rs10741657 near CYP2R1. SNP genotyping was performed using the TaqMan fluorogenic 5’ nuclease assay (Applied Biosystems, Tokyo, Japan). In 933 of 2068 Japanese RA patients, serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured. The occurrence of hip fracture was picked up from the patient questionnaires performed in IORRA, and confirmed by review of medical records and radiographs. Eventually we included 97 hip fractures in 97 patients in this study. Univariate regression analyses for serum 25(OH)D concentration were performed in 933 Japanese RA patients. Prediction analysis for the occurrence of hip fracture was performed using multivariate Cox proportional hazards regression models in 2068 Japanese RA patients.
Results Univariate linear regression analyses showed that rs2282679 was associated with progression of lower serum 25(OH)D concentration in Japanese RA patients (β=-1.25, p=8.73 × 10-5). The other SNPs showed no such association. Multivariate Cox proportional hazards regression models indicated that the occurrence of hip fracture was significantly increased in the recessive model [HR (95% CI): 2.5 (1.04 to 6.13); p=0.04].
Conclusions A significant association was observed between genetic variants in GC and serum vitamin D concentration in Japanese RA patients. In addition, our data indicated that GC gene polymorphism is the risk for hip fracture in Japanese RA patients.
Wang TJ, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 2010 Jul 17; 376(9736):180-8.
Ahn J, et al. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet. 2010 Jul 1; 19(13):2739-45.
Disclosure of Interest S. Yoshida: None Declared, K. Ikari Speakers bureau: Abbott Japan Co. Ltd., Astellas Pharma Inc., Eisai Co. Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K. Japan, Mitsubishi Tanabe Pharma Corporation, T. Furuya: None Declared, Y. Toyama: None Declared, A. Taniguchi: None Declared, H. Yamanaka Grant/research support from: The IORRA cohort was supported by non-restricted research grants from following companies; Abbott Japan Co. Ltd., Asahikasei Kuraray Medical Co. Ltd., Asahikasei Pharma Corporation, Astellas Pharma Inc., AstraZeneca K.K., Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd., Daiichi Fine Chemical Co. Ltd., Daiichi Sankyo Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd., Dentsu, Sudler & Hennessey Inc., Eisai Co. Ltd., GlaxoSmithKline K.K., Hisamitsu Pharmaceutical Co. Inc., Janssen Pharmaceutical K.K. Japan, Tobacco Inc., Kaken Pharmaceutical Co. Ltd., Kissei Pharmaceutical Co. Ltd., Kowa Pharmaceutical Co. Ltd., Maruho Co. Ltd., Mitsubishi Chemical Medience Corporation, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd., MSD K.K., Mundipharma K.K., Nippon Chemiphar Co. Ltd., Nippon Shinyaku Co. Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co. Ltd., Pfizer Japan Inc., Sanofi-Aventis K.K., Santen Pharmaceutical Co. Ltd., Sanwa Kagaku Kenkyusho Co. Ltd., Sekisui Medical Co. Ltd., Shionogi Co. Ltd., Taishotoyama Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Torii Pharmaceutical Co. Ltd., UCB Japan Co. Ltd., ZERIA Pharmaceutical Co. Ltd., Speakers bureau: Abbott Japan Co. Ltd., AstraZeneca K.K., Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Janssen Pharmaceutical K.K. Japan, Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Teijin Pharma Limited, UCB Japan Co. Ltd., S. Momohara: None Declared