Premium
Molecular genetic analysis of a human insulin‐like growth factor 1 promoter P1 variation
Author(s) -
Telgmann Ralph,
Dördelmann Corinna,
Brand Eva,
Nicaud Viviane,
Hagedorn Claudia,
Pavenstädt Hermann,
Cambien Franşois,
Tiret Laurence,
Paul Martin,
BrandHerrmann StefanMartin
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-116863
Subject(s) - enhancer , allele , biology , transcription factor , promoter , insulin like growth factor binding protein , microbiology and biotechnology , endocrinology , genetics , growth factor , insulin like growth factor , gene , gene expression , receptor
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, inSaOs‐2 and HepG2 (all p <0.0001) as well as in differentiatedTHP‐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 8 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, 7=0.006) associated with the T allele, and normotensive subjects carrying the protective T allele displayed a significant decrease in diastolic (7=0.036) and systolic (7=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.— Telgmann, R., Dordelmann, C., Brand, E., Nicaud, V., Hagedorn, C., Pavenstadt, H., Cambien, F., Tiret, L., Paul, M., Brand‐Herrmann, S.‐M. Molecular genetic analysis of a human insulin growth factor 1 promoter P1 variation. FASEBJ. 23, 1303–1313 (2009)