title: A functional common polymorphism in the vitamin D-responsive element of the GH1 promoter contributes to isolated growth hormone deficiency.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  The common -57G-->T polymorphism contributes to IGHD susceptibility, indicating that it may have a multifactorial etiology.
authors.affiliation: Laboratory of Human Genetics, Department of Medical Sciences, University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy. mara.giordano@med.unipmn.it
authors.forename: Mara
authors.initials: M
authors.lastname: Giordano
authors.forename: Michela
authors.initials: M
authors.lastname: Godi
authors.forename: Simona
authors.initials: S
authors.lastname: Mellone
authors.forename: Antonella
authors.initials: A
authors.lastname: Petri
authors.forename: Daniela
authors.initials: D
authors.lastname: Vivenza
authors.forename: Luigi
authors.initials: L
authors.lastname: Tiradani
authors.forename: Yari
authors.initials: Y
authors.lastname: Carlomagno
authors.forename: Daniela
authors.initials: D
authors.lastname: Ferrante
authors.forename: Teresa
authors.initials: T
authors.lastname: Arrigo
authors.forename: Ginevra
authors.initials: G
authors.lastname: Corneli
authors.forename: Simonetta
authors.initials: S
authors.lastname: Bellone
authors.forename: Francesca
authors.initials: F
authors.lastname: Giacopelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Santoro
authors.forename: Gianni
authors.initials: G
authors.lastname: Bona
authors.forename: Patricia
authors.initials: P
authors.lastname: Momigliano-Richiardi
mesh_terms: D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006239:Haplotypes; D019382:Human Growth Hormone / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020218:Response Elements; D014807:Vitamin D / Q000502:physiology*
chemical_list: D019382:Human Growth Hormone; D014807:Vitamin D