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Allelic diversity in the TGFB1 regulatory region: characterization of novel functional single nucleotide polymorphisms

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Abstract

Altered TGF-β1 expression due to polymorphisms affects a wide variety of normal cellular and disease processes such as T cell activation and proliferation, tumor progression, and asthma. In this study, a comprehensive examination of function and diversity was undertaken for the TGFB1 promoter region and exon 1 (−2,665 to +423). The known TGF-β1 promoter was extended to encompass 463 bases by the identification of a strong enhancer activity for a distal segment (−2,665 to −2,204). Ten novel polymorphisms and 14 novel alleles were identified. Most single nucleotide polymorphisms (SNPs) appear to be randomly associated except c.-768_-769insC and c.+74G>C and a set of five novel polymorphisms present in a single allele in persons of African descent. The TGFB1 alleles clustered into three phylogenetic groups based on the common functional SNPs c.-1347C>T (commonly known as -509C-T) and c.+29T>C (commonly known as +869T-C) suggesting three phenotypic groups. Two SNPs unique to African-Americans affect the TGFB1 regulatory region. The c.-1287G>A SNP in the promoter alters the binding affinity of two unidentified transcription factor complexes which translates into a significant difference in reporter gene expression and the c.-387C>T SNP in the 5′ UTR alters the binding of Stimulating protein 1 and 3. Thus, TGFB1 possesses a highly polymorphic, extensive regulatory region that likely impacts the pathogenesis of numerous TGF-β1 related diseases.

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Abbreviations

Sp1:

Stimulating protein 1

SNP:

Single nucleotide polymorphism

leu:

Leucine

pro:

Proline

arg:

Arginine

IHWS:

International Histocompatibility Workshop

UTR:

Untranslated region

Sp3:

Stimulating protein 3

AP4:

Activator protein 4

YY1:

Yin-yang 1

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Acknowledgements

We would like to thank Dr. Nathalie Gualt for the generous gift of the TGFB1 promoter PGL3 construct. Funding from the Office of Naval Research N00014-99-1-055 and N00014-00-1-0898 to the C. W. Bill Young Marrow Donor Recruitment and Research Program supported this research. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Navy, the Department of Defense or the US Government. This investigation was conducted using a tissue culture core facility constructed with support from the Research Facilities Improvement Grant C06 RR14567 from the National Center for Research Resources, National Institute of Health. The authors have no conflicting financial interests.

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Authors and Affiliations

  1. Department of Oncology, Georgetown University Medical Center, Washington, DC, USA

    Riddhish Shah, Brad Rahaman & Carolyn Katovich Hurley

  2. Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, USA

    Phillip E. Posch

  3. E408 New Research Building, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC, 20007, USA

    Phillip E. Posch

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  1. Riddhish Shah
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  4. Phillip E. Posch
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Correspondence to Phillip E. Posch.

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Shah, R., Rahaman, B., Hurley, C.K. et al. Allelic diversity in the TGFB1 regulatory region: characterization of novel functional single nucleotide polymorphisms. Hum Genet 119, 61–74 (2006). https://doi.org/10.1007/s00439-005-0112-y

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  • DOI: https://doi.org/10.1007/s00439-005-0112-y

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