The effect of polymorphisms at the IGFBP3 and GHR genes on the IGF system and height in normal and short children.

HORACIO M. DOMENÉ; ALICIA S. MARTÍNEZ; PAULA A. SCAGLIA; MARIANA GUTIÉRREZ; MARÍA G. ROPELATO; VIVIANA R. PIPMAN; SONIA V. BENGOLEA; ANA C. KESELMAN; PATRICIA G. BEDECARRÁS; MARÍA G. BALLERINI; LILIANA M. KARABATAS; MAURICIO ARCOS-BURGOS; JUAN J. HEINRICH; HÉCTOR G. JASPER

Boston, USA

Congreso; 88th Annual Meeting of the Endocrine Society; 2006

Endocrine Society

Circulating levels of IGF-I and IGFBP-3 vary considerably in healthy children. Up to 50% of this variability could be explained by genetic factors. Polymorphisms of genes of the GH-IGF axis may be responsible for some of this variability. The aim of this study was to determine the effect of IGFBP-3 and GHR gene polymorphisms on the levels of IGFBP-3, IGF-I, and height in normal and short children. Seventy seven children of normal height, aged 2.4 to 16.5 years, 38 males; and 35 children with idiopathic short stature (ISS), aged 2.4 to 16.9 years, 28 males, were studied. All ISS children presented height < 2.0 SD and normal GH response after arginine-clonidine test (> 7.0 mg/L). Clinical causes of short stature were ruled out. Height, IGF-I (RIA), and IGFBP-3 (IRMA) levels were expressed in SDS. We studied two single nucleotide polymorphisms (SNPs) in the promoter region of the IGFBP-3 gene by restriction fragment length polymorphism(-202 A/C and –185 C/T), and a GHR gene polymorphism by multiplex PCR (exon 3 deletion, DEL). One-way ANOVA (A) followed by Tukey´s test or linear trend (LT) were used for statistical analysis. In normal children a correlation between the –202 A/C SNP and IGFBP-3 levels (A p=0.0015; LT p=0.0009; AA: 0.57±0.28 [mean±sem] vs. CC: -0.46±0.17; p=0.01; AC: 0.18±0.14 vs. CC: p<0.05) and IGF-I (A p=0.0309; AC:0.26±0.15 vs. CC: -0.37±0.19; p<0.05) was found. Although the CT and TT genotypes were associated to the lower IGF-I and IGFBP-3 levels, did not reach statistical signification. Exon 3 deletion of GHR gene correlated with IGFBP-3 levels (A p=0.0423; FL/FL: 0.38±0.17 vs. FL/DEL: -0.30±0.14; p<0.05). Based upon the association to low levels of IGF-I and/or IGFBP-3, the following genotypes were defined as unfavorable: CC for –202, CT or TT for –185 at the  IGFBP-3 gene, and FL/DEL or DEL/DEL at the GHR gene. There was an additive effect of the number of unfavorable genotypes on IGFBP-3 and IGF-I levels (A p=0.0141; LT p=0.0041; and A p=0.0239; LT p=0.0121, respectively), as well as on height (A p=0.0258; LT p=0.0071). In ISS children no such correlation was found. In conclusion IGF-I, IGFBP-3 levels, and height in normal children seem, surely partially, to be related to genetic polymorphisms on the IGFBP-3 and GHR genes. This effect was not observed in ISS children, suggesting that other physiological or pathological causes might be responsible for this condition.