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Molecular genetic analysis of a human insulin-like growth factor 1 promoter P1 variation

Ralph Telgmann^*, Corinna Dördelmann^*, Eva Brand, Viviane Nicaud, Claudia Hagedorn^*, Hermann Pavenstädt, François Cambien, Laurence Tiret, Martin Paul and Stefan-Martin Brand-Herrmann^*,1

^* Department of Molecular Genetics of Cardiovascular Disease, Leibniz-Institute for Arteriosclerosis Research, University of Münster, Münster, Germany;

University Hospital Münster, Internal Medicine and Nephrology D, Münster, Germany;

INSERM, UMR S 525, Paris, France; and

Faculty of Health, Medicine, and Life Science, Maastricht University, Maastricht, The Netherlands

¹ Correspondence: Leibniz-Institute for Arteriosclerosis Research at the University of Münster, Department of Molecular Genetics of Cardiovascular Disease, Domagkstraße 3, 48149 Münster, Germany. E-mail: brandher{at}uni-muenster.de

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 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.—Telgmann, R., Dördelmann, C., Brand, E., Nicaud, V., Hagedorn, C., Pavenstädt, H., Cambien, F., Tiret, L., Paul, M., Brand-Herrmann, S.-M. Molecular genetic analysis of a human insulin growth factor 1 promoter P1 variation.

Key Words: gene expression • hypertension • bandshift assay • reporter gene • transcription factor • functional analysis

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