Functional Interaction Between SNPs and Microsatellite in the Transcriptional Regulation of Insulin-Like Growth Factor 1

Authors

  • Holly Y. Chen,

    1. Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
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  • Wei Huang,

    1. Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Vincent H. K. Leung,

    1. Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
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  • Simon L. M. Fung,

    1. Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
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  • Suk Ling Ma,

    1. Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
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  • Hongling Jiang,

    1. Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
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  • Nelson L. S. Tang

    Corresponding author
    1. Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
    2. Laboratory of Genetics of Disease Susceptibility, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
    3. Functional Genomics and Biostatistical Computing laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
    4. KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, China
    • Correspondence to: Nelson L.S. Tang, Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China. E-mail: nelsontang@cuhk.edu.hk

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  • Communicated by Nancy B. Spinner

  • Contract grant sponsors: Research Grants Council (RGC), Hong Kong SAR government (CUHK4437/06M); Sir Michael and Lady Kadoorie Funded Research Into Cancer Genetics and Direct Grant, the Chinese University of Hong Kong.

ABSTRACT

A CA-repeat microsatellite in insulin-like growth factor 1 (IGF1) promoter was associated with interindividual variation of circulating IGF1 level. Previously, we reported that such association was due to variation of haplotype unit in a linkage disequilibrium block composed of microsatellite and single-nucleotide polymorphisms (SNPs), suggesting the presence of an interaction between them. In this study, reporter assays were performed to investigate the regulatory effect and interaction of genetic variants on gene expression. We used an in vitro system to compare the transcriptional activities of haplotypes (rs35767:T>C, the CA-repeat microsatellite, rs5742612:T>C, and rs2288377:T>A) in evolutionarily conserved region of IGF1 promoter. In haplotype C-T-T, a longer microsatellite had a lower transcriptional activity (17.6 ± 2.4-fold for 17 repeats and 8.3 ± 1.1-fold for 21 repeats), whereas in haplotype T-C-A, such trend could not be observed, as the microsatellite with 21 repeats had the highest transcriptional activity (17.5 ± 2.3-fold). Because the microsatellite and SNPs affected the transcriptional activity of each other, there may be an interaction between them in the regulation of IGF1 expression. For the first time, we demonstrated that a noncoding microsatellite polymorphism could act as a functional unit and interact with SNPs in the regulation of transcription in human genome.

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