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A Functional Common Polymorphism in the Vitamin D-Responsive Element of the GH1 Promoter Contributes to Isolated Growth Hormone Deficiency

Department of Medical Sciences and Interdisciplinary Research Center of Autoimmune Diseases (M.Gi., M.Go., S.M., L.T., Y.C., D.F., C.S., P.M.-R.), and Unit of Pediatrics (A.P., D.V., G.C., S.B., G.B.), Department of Medical Sciences, University of Eastern Piedmont, 28100 Novara, Italy; Department of Pediatrics (T.A.), University of Messina, 98100 Messina, Italy; and Laboratory of Molecular Genetics (F.G.), Institute G. Gaslini and Department of Pediatrics and Center of Excellence for Biomedical Research, University of Genova, 16100 Genova, Italy

Address all correspondence and requests for reprints to: Mara Giordano, Laboratory of Human Genetics, Department of Medical Sciences, University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy. E-mail: mara.giordano{at}med.unipmn.it.

Context: Causal mutations have been detected only in a minority of isolated GH deficiency (IGHD) patients. Idiopathic IGHD might be the result of the interaction between several low-penetrance genetic factors and the environment.

Objective: The aim of this study was to test the contribution to IGHD of genetic variations in the GH1 gene regulatory regions.

Design and Patients: A case-control association study was performed including 118 sporadic IGHD patients with a nonsevere phenotype (height –4/–1 SD score and partial GH deficiency) and two control groups, normal stature (n = 200) and short-stature individuals with normal GH secretion (n = 113). Seven single-nucleotide polymorphisms in the GH1 promoter, one in the IVS4 region, and two in the locus control region were analyzed.

Results: The –57T allele within the vitamin D-responsive element showed a positive significant association when comparing patients with normal (P = 0.006) or short stature (P = 0.0011) controls. The genotype –57TT showed an odds ratio of 2.93 (1.44–5.99) and 2.99 (1.42–6.31), respectively. The functional relevance of the –57 variation was demonstrated by the luciferase assay in the presence of vitamin D. The vitamin D-induced inhibition of luciferase activity was significantly (P = 0.012) stronger for the promoter haplotype carrying the associated variation –57T [haplotype #1 (hp#1)] with respect to hp#2, bearing –57G. Replacement of the T with a G at –57 on hp#1 abolished the repression, demonstrating that the T at position –57 is necessary to determine the greater vitamin D-induced inhibitory effect of hp#1. EMSA experiments showed a different band-shift pattern of the T and G sequences.

Conclusion: The common –57GT polymorphism contributes to IGHD susceptibility, indicating that it may have a multifactorial etiology.

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