title: Molecular genetic analysis of a human insulin-like growth factor 1 promoter P1 variation.
abstract: Insulin-like growth factor 1 (IGF1) exerts important endocrine and paracrine functions in the cardiovascular system. We identified the common variant -1411C>T in the IGF1 upstream promoter P1, located within several overlapping transcription factor binding sites. Using transient transfection assays, we identified this site as a functional enhancer. The T allele-carrying enhancer, compared with the C allelic portion, exerts significantly reduced or even abrogated activity, respectively, in SaOs-2 and HepG2 (all P<0.0001) as well as in differentiated THP-1 macrophages. Electrophoretic mobility shift assay and subsequent supershift experiments in HepG2 identified c-Jun as the binding partner exclusively to the T allele, whereas CCAAT/enhancer-binding protein delta and interferon consensus site-binding protein/interferon-regulating factor 8 interacted only with the C allelic promoter portion. Furthermore, genotyping in a case-control study for essential hypertension (n=745 hypertensive patients; n=769 normotensive control subjects) for this variant revealed an odds ratio for hypertension of 0.73 (95% confidence interval 0.58-0.91, P=0.006) associated with the T allele, and normotensive subjects carrying the protective T allele displayed a significant decrease in diastolic (P=0.036) and systolic (P=0.024) blood pressure levels. We here report detection of a functional enhancer module in the upstream IGF1 promoter region, which might play a key role in local IGF1 bioavailability. Whether -1411C>T is also associated with other IGF1-related disease phenotypes should be evaluated further in population studies.
authors.affiliation: Department of Molecular Genetics of Cardiovascular Disease, Leibniz-Institute for Arteriosclerosis Research, University of Münster, Domagkstrasse 3, 48149 Münster, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Telgmann
authors.forename: Corinna
authors.initials: C
authors.lastname: Dördelmann
authors.forename: Eva
authors.initials: E
authors.lastname: Brand
authors.forename: Viviane
authors.initials: V
authors.lastname: Nicaud
authors.forename: Claudia
authors.initials: C
authors.lastname: Hagedorn
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: François
authors.initials: F
authors.lastname: Cambien
authors.forename: Laurence
authors.initials: L
authors.lastname: Tiret
authors.forename: Martin
authors.initials: M
authors.lastname: Paul
authors.forename: Stefan-Martin
authors.initials: SM
authors.lastname: Brand-Herrmann
mesh_terms: D001483:Base Sequence; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019295:Computational Biology; D016384:Consensus Sequence; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D050835:Interferon Regulatory Factors / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic / Q000502:physiology; D000099185:Interferon Regulatory Factor-8
chemical_list: D051743:CCAAT-Enhancer-Binding Protein-delta; D007334:Insulin-Like Growth Factor I; D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8