title: Regulation of IGFBP3 gene expression in short children born small for gestational age.
abstract: OBJECTIVE
  Approximately 6% of newborns at term are small for gestational age (SGA) and present a birth weight and/or length less than -2SD from the mean. SGA infants are at increased risk for perinatal morbidity, associated psychological and/or mental problems, persistent short stature (about 15% of subjects) and metabolic alterations. Insulin-like growth factors (IGFs), their common receptor (IGF1R) and their binding proteins (IGFBPs) play a critical role in fetal and postnatal growth. In these genes common polymorphisms, such as single nucleotide polymorphisms and variable number of tandem repeats, have been investigated with conflicting results with respect to SGA-related outcomes, and the functional role of these gene variants remains to be elucidated.
  
  
  METHODS
  The study group consisted of 100 pre-pubertal short children born SGA and 94 healthy controls, matched for sex and age, recruited at the Department of Biomedicine of Development Age of the Bari University and at the Paediatric Department of the Messina Hospital. In the present study we analyzed the allelic frequency of the polymorphisms -795 G/A, -667 G/A, -396 C/T in the IGFBP3 in SGA children and their influence on the basal and insulin-stimulated transcriptional activity of the gene.
  
  
  RESULTS
  We found that the polymorphisms -667 G/A and -396 C/T in the IGFBP3 promoter region are capable of having an effect on the transcriptional activity of the gene, although with opposing effects. Interestingly, the -667 G/A polymorphism has a negative impact on the IGFBP3 transcription, while the -396 C/T polymorphism determines an increase of the transcriptional activity of the IGFBP3 gene promoter. Interestingly, we found that the -396 C/T polymorphism correlates with lower birth length in SGA children. Most importantly, while the diminished IGFBP3 transcriptional activity induced by the -667A polymorphism was significantly recovered after insulin administration (p-value<0.05), the increased transcriptional activity caused by the -396T polymorphism was not restored to baseline levels by insulin.
  
  
  CONCLUSIONS
  Altogether our results demonstrated that the -667 G/A and the -396 C/T polymorphisms in IGFBP3 promoter region influence the basal transcriptional activity of the gene.
authors: Department of Biomedicine of Developmental Age, University of Bari, Italy.
authors: M F
authors: MF
authors: Faienza
authors: F
authors: F
authors: Marzano
authors: A M
authors: AM
authors: Ventura
authors: M
authors: M
authors: Wasniewska
authors: M
authors: M
authors: Valenzise
authors: A
authors: A
authors: Valletti
authors: M F
authors: MF
authors: Caratozzolo
authors: S
authors: S
authors: Cornacchia
authors: E
authors: E
authors: Sbisà
authors: L
authors: L
authors: Cavallo
authors: A
authors: A
authors: Tullo
mesh_terms: D001724:Birth Weight / Q000235:genetics; D001827:Body Height / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D005865:Gestational Age; D045325:HCT116 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007223:Infant; D007230:Infant, Low Birth Weight / Q000378:metabolism*; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age / Q000378:metabolism*; D007328:Insulin / Q000627:therapeutic use; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood / Q000235:genetics*; D007558:Italy; D008156:Luciferases / Q000378:metabolism; D008297:Male; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D004247:DNA; D008156:Luciferases