Shah Riddhish, Rahaman Brad, Hurley Carolyn Katovich, Posch Phillip E
Department of Oncology, Georgetown University Medical Center, Washington, DC 20007, USA.
Hum Genet. 2006 Mar;119(1-2):61-74. doi: 10.1007/s00439-005-0112-y. Epub 2005 Dec 14.
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.
由于多态性导致的转化生长因子β1（TGF-beta1）表达改变会影响多种正常细胞和疾病进程，如T细胞活化与增殖、肿瘤进展以及哮喘。在本研究中，对TGFB1启动子区域和外显子1（-2,665至+423）进行了功能和多样性的全面检测。通过鉴定一个远端片段（-2,665至-2,204）的强增强子活性，将已知的TGF-beta1启动子扩展至包含463个碱基。鉴定出了10个新的多态性和14个新的等位基因。除了c.-768_-769insC和c.+74G > C以及一组在非洲裔人群的单个等位基因中出现的5个新多态性外，大多数单核苷酸多态性（SNP）似乎是随机关联的。基于常见的功能性SNP c.-1347C > T（通常称为-509C-T）和c.+29T > C（通常称为+869T-C），TGFB1等位基因聚为三个系统发育组，提示存在三个表型组。非裔美国人特有的两个SNP影响TGFB1调控区域。启动子中的c.-1287G > A SNP改变了两种未鉴定转录因子复合物的结合亲和力，这转化为报告基因表达的显著差异，而5'非翻译区（UTR）中的c.-387C > T SNP改变了刺激蛋白1和3的结合。因此，TGFB1拥有一个高度多态的广泛调控区域，可能影响众多与TGF-beta1相关疾病的发病机制。
