Polymorphisms of the human TGF-β1 gene

• Main Author: Heathcote, Kirsten
• Published: University of Cambridge 1999
• Subjects: 616.042
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603934

Experimental evidence has implicated a function for TGF-β1 in many pathological processes, including atherosclerosis, cancer, fibrotic diseases and osteoporosis. In this study 1115 bp of the TGF-β1 promoter, the 5' untranslated region and exons 1, 2 and 3 were screened by single stranded conformational polymorphism analysis. Four polymorphisms were identified in the TGF-β1 gene at -800 and -509 of the promoter and at +869 (codon 10) and +914 (codon 25) of exon 1. A simple non-radioactive assay was developed for each of these polymorphisms and also for a polymorphism located at +1628 (exon 5, codon 263) which was reported in the literature. These polymorphisms were analysed in a study of postmenopausal female twins and the -800, -509 and +869 polymorphisms were associated with the concentration of TGF-β1 in the serum detected by ELISA. The TGF-β1 promoter polymorphisms (-509 and -800) were associated with increased and decreased serum TGF-β1 respectively in the twin study. These promoter isoforms were assayed <I>in vitro</I> to establish whether there was a functional effect of the polymorphisms on the basal activity of the TGF-β1 promoter. However, the activity of the TGF-β1 promoter was weak, and in the cell line studied no difference in activity between the isoforms of the TGF-β1 promoter was observed. The five TGF-β1 polymorphisms were analysed in 457 subjects recruited to the St. George's Heart Disease study. None of the polymorphisms showed any association with either coronary artery disease or hypertension in this study. However, strong linkage disequilibrium was observed at the TGFB1 locus and haplotypes of the locus were also considered in this study. The haplotype G(-800)C(-509)T(+869)G(+914)C(+1628) arose more frequently in the control subjects than the coronary artery disease cases (p=0.024), suggesting that it may be cardioprotective. The -509 and -800 TGF-β1 promoter polymorphisms were analysed in subjects of a breast cancer study. Subjects homozygous for the -800A allele appeared to have an increased risk for breast cancer in this study (relative risk 3.9, 95% confidence interval 0.90-17), but few homozygotes were observed and this risk was not insignificant.