SNP rs6265 Regulates Protein Phosphorylation and Osteoblast Differentiation and Influences BMD in Humans

Authors

  • Fei-Yan Deng,

    1. Center of Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, Jiangsu, PR China
    2. Center for Bioinformatics and Genomics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
    3. Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
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  • Li-Jun Tan,

    1. Center for Bioinformatics and Genomics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
    2. Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
    3. Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, PR China
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  • Hui Shen,

    1. Center for Bioinformatics and Genomics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
    2. Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
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  • Yong-Jun Liu,

    1. Center for Bioinformatics and Genomics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
    2. Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
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  • Yao-Zhong Liu,

    1. Center for Bioinformatics and Genomics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
    2. Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
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  • Jian Li,

    1. Center for Bioinformatics and Genomics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
    2. Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
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  • Xue-Zhen Zhu,

    1. Center for Systematic Biomedical Research, Shanghai University of Science and Technology, Shanghai, PR China
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  • Xiang-Ding Chen,

    1. Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, PR China
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  • Qing Tian,

    1. Center for Bioinformatics and Genomics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
    2. Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
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  • Ming Zhao,

    1. Center for Bioinformatics and Genomics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
    2. Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
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  • Hong-Wen Deng

    Corresponding author
    1. Center for Bioinformatics and Genomics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
    2. Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
    3. Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, PR China
    4. Center for Systematic Biomedical Research, Shanghai University of Science and Technology, Shanghai, PR China
    • Address correspondence to: Hong-Wen Deng, PhD, Center for Bioinformatics and Genomics, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, Suite 2001, New Orleans, LA 70112, USA. E-mail: hdeng2@tulane.edu

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ABSTRACT

Bone mineral density (BMD) is a major index for diagnosing osteoporosis. PhosSNPs are nonsynonymous SNPs that affect protein phosphorylation. The relevance and significance of phosSNPs to BMD and osteoporosis is unknown. This study aimed to identify and characterize phosSNPs significant for BMD in humans. We conducted a pilot genomewide phosSNP association study for BMD in three independent population samples, involving ∼5000 unrelated individuals. We identified and replicated three phosSNPs associated with both spine BMD and hip BMD in Caucasians. Association with hip BMD for one of these phosSNPs, ie, rs6265 (major/minor allele: G/A) in BDNF gene, was also suggested in Chinese. Consistently in both ethnicities, individuals carrying the AA genotype have significantly lower hip BMD than carriers of the GA and GG genotypes. Through in vitro molecular and cellular studies, we found that compared to osteoblastic cells transfected with wild-type BDNF-Val66 (encoded with allele G at rs6265), transfection of variant BDNF-Met66 (encoded with allele A at rs6265) significantly decreased BDNF protein phosphorylation (at amino acid residue T62), expression of osteoblastic genes (OPN, BMP2, and ALP), and osteoblastic activity. The findings are consistent with and explain our prior observations in general human populations. We conclude that phosSNP rs6265, by regulating BDNF protein phosphorylation and osteoblast differentiation, influences hip BMD in humans. This study represents our first endeavor to dissect the functions of phosSNPs in bone, which might stimulate extended large-scale studies on bone or similar studies on other human complex traits and diseases. © 2013 American Society for Bone and Mineral Research.

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