Human Molecular Genetics Advance Access originally published online on March 3, 2005
Human Molecular Genetics 2005 14(8):1009-1017; doi:10.1093/hmg/ddi093
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A functional single nucleotide polymorphism in the core promoter region of CALM1 is associated with hip osteoarthritis in Japanese
1Laboratory for Bone and Joint Diseases and 2Laboratory for SNP Analysis, Research Groups of Personalized Medicine, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan, 3Pharmaceutical Research Laboratories I, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, Osaka 532-8686, Japan, 4Department of Orthopaedic Surgery, Sumitomo Hospital, Nakanoshima 5-3-20, Kita-ku, Osaka 530-0005, Japan, 5Department of Orthopaedic Surgery, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan, 6Department of Orthopaedic Surgery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan, 7Department of Orthopaedic Surgery, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan, 8Laboratory for Genotyping and 9Laboratory for Medical Informatics, SNP Research Center, RIKEN, 1-7-22 Suehirocho, Tsurumi-ku, Yokohama 230-0045, Japan and 10Tumor Suppression and the Functional Genomics Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
* To whom correspondence should be addressed. Tel: +81 354495393; Fax: +81 354495393; Email: sikegawa{at}ims.u-tokyo.ac.jp
Received December 27, 2004; Revised February 14, 2005; Accepted February 22, 2005
Osteoarthritis (OA), a common skeletal disease, is a leading cause of disability among the elderly populations. OA is characterized by gradual loss of articular cartilage, but the etiology and pathogenesis of OA are largely unknown. Epidemiological and genetic studies have demonstrated that genetic factors play an important role in OA. To identify susceptibility genes for OA, we performed a large-scale, case–control association study using gene-based single nucleotide polymorphisms (SNPs). In two independent case–control populations, we found significant association (P=9.8x10–7) between hip OA and a SNP (IVS3–293C>T) located in intron 3 of the calmodulin (CaM) 1 gene (CALM1). CALM1 was expressed in cultured chondrocytes and articular cartilage, and its expression was increased in OA. Subsequent linkage-disequilibrium mapping identified five SNPs showing significant association equivalent to IVS3–293C>T. One of these (–16C>T) is located in the core promoter region of CALM1. Functional analyses indicate that the susceptibility –16T allele decreases CALM1 transcription in vitro and in vivo. Inhibition of CaM in chondrogenic cells reduced the expression of the major cartilage matrix genes Col2a1 and Agc1. These results suggest that the transcriptional level of CALM1 is associated with susceptibility for hip OA through modulation of chondrogenic activity. Our findings reveal the CALM1-mediated signaling pathway in chondrocytes as a novel potential target for treatment of OA.
Present address: Department of Orthopaedic Surgery, Osaka Rosai Hospital, 1179-3 Nagasone-cho, Sakai, Osaka 591-8025, Japan
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