A functional common polymorphism in the vitamin D-responsive element of the GH1 promoter contributes to isolated growth hormone deficiency

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 -57G → T polymorphism contributes to IGHD susceptibility, indicating that it may have a multifactorial etiology.