Polymorphisms in predicted miRNA binding sites and osteoporosis

Authors

  • Shu-Feng Lei,

    1. Laboratory of Molecular and Statistical Genetics and the Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, Hunan, People's Republic of China
    2. Department of Basic Medical Science, School of Medicine, University of Missouri–Kansas City, Kansas City, MO, USA
    3. Human Genetics/Genomics Program, Department of Orthopedic Surgery, School of Medicine, University of Missouri–Kansas City, Kansas City, MO, USA
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  • Christopher J Papasian,

    1. Department of Basic Medical Science, School of Medicine, University of Missouri–Kansas City, Kansas City, MO, USA
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  • Hong-Wen Deng

    Corresponding author
    1. Laboratory of Molecular and Statistical Genetics and the Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, Hunan, People's Republic of China
    2. Department of Basic Medical Science, School of Medicine, University of Missouri–Kansas City, Kansas City, MO, USA
    3. Human Genetics/Genomics Program, Department of Orthopedic Surgery, School of Medicine, University of Missouri–Kansas City, Kansas City, MO, USA
    4. Center of Systematic Biomedical Research, University of Shanghai for Science and Technology, Shanghai, People's Republic of China
    5. College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, People's Republic of China
    • Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, People's Republic of China.
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Abstract

MicroRNAs (miRNAs) regulate posttranscriptional gene expression usually by binding to 3'-untranslated regions (3'-UTRs) of target message RNAs (mRNAs). Hence genetic polymorphisms on 3'-UTRs of mRNAs may alter binding affinity between miRNAs target 3'-UTRs, thereby altering translational regulation of target mRNAs and/or degradation of mRNAs, leading to differential protein expression of target genes. Based on a database that catalogues predicted polymorphisms in miRNA target sites (poly-miRTSs), we selected 568 polymorphisms within 3'-UTRs of target mRNAs and performed association analyses between these selected poly-miRTSs and osteoporosis in 997 white subjects who were genotyped by Affymetrix Human Mapping 500K arrays. Initial discovery (in the 997 subjects) and replication (in 1728 white subjects) association analyses identified three poly-miRTSs (rs6854081, rs1048201, and rs7683093) in the fibroblast growth factor 2 (FGF2) gene that were significantly associated with femoral neck bone mineral density (BMD). These three poly-miRTSs serve as potential binding sites for 9 miRNAs (eg, miR-146a and miR-146b). Further gene expression analyses demonstrated that the FGF2 gene was differentially expressed between subjects with high versus low BMD in three independent sample sets. Our initial and replicate association studies and subsequent gene expression analyses support the conclusion that these three polymorphisms of the FGF2 gene may contribute to susceptibility to osteoporosis, most likely through their effects on altered binding affinity for specific miRNAs. © 2011 American Society for Bone and Mineral Research.

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