title: Allelic diversity in the TGFB1 regulatory region: characterization of novel functional single nucleotide polymorphisms.
abstract: Altered TGF-beta1 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-beta1 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-beta1 related diseases.
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC 20007, USA.
authors.forename: Riddhish
authors.initials: R
authors.lastname: Shah
authors.forename: Brad
authors.initials: B
authors.lastname: Rahaman
authors.forename: Carolyn Katovich
authors.initials: CK
authors.lastname: Hurley
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Posch
mesh_terms: D001741:Black or African American / Q000235:genetics; D000483:Alleles; D001665:Binding Sites; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004742:Enhancer Elements, Genetic; D005091:Exons; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; C497121:SP3 protein, human; D016329:Sp1 Transcription Factor; D053773:Transforming Growth Factor beta1; D051705:Sp3 Transcription Factor; D008156:Luciferases