Genotyping IGFBP3 gene polymorphism improves the diagnostic efficiency of IGFBP-3 measurements in the differential diagnosis between growth hormone deficiency (GHD) and idiopathic short stature (ISS ).

DOMENÉ H; SCAGLIA P; MARTÍNEZ A; KESELMAN A; PIPMAN V; BENGOLEA V; KARABATAS L; ROPELATO M; BALLERINI M; HEINRICH J; JASPER H

Praga, República Checa

Congreso; 41st Internacional KIGS Symposium on Endocrinology and Metabolism; 2009

Pharmacia Symposia

Genotyping IGFBP3 gene polymorphism improves the diagnostic efficiency of IGFBP-3 measurements in the differential diagnosis between growth hormone deficiency (GHD) and idiopathic short stature (ISS ). Domené H, Scaglia P, Martínez A, Keselman A, Pipman V, Bengolea V,  Karabatas L, Ropelato M, Ballerini M, Heinrich J, Jasper H, Centro de Investigaciones Endocrinológicas (CEDIE-CONICET), División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina. Background: Serum levels of markers of GH action such as IGF-I, IGFBP-3 and ALS have been proposed for the diagnosis of GHD during infancy. However, as low IGF-I, IGFBP-3, and ALS levels are found in some children with idiopathic short stature, this results in a reduction of the diagnostic efficiency (DE) of these markers. Objective: The aim of this study was to determine the DE for GHD of IGF-I, IGFBP-3, and ALS levels before and after taking in consideration the effect of genetic polymorphyc variants in the genes encoding these proteins. Subjects and Methods: We enrolled 187 normal (N) (4.9-16.6 y), 86 ISS (3.1-17.6 y) and 24 GHD (3.1-17.6 y) children. Serum IGF-I and ALS were determined by RIA and IGFBP-3 by IRMA and expressed in SDS in relation to normal controls. The following polymorphisms were determined: IGF1.PCR1 and rs6220 (C/T) in the IGF1 gene, rs2854744 (-202 A/C) and rs13241830 (-185 C/T) in the IGFBP3 gene, and rs3751893 (C/T, D70D), and 5 SNPs in the promoter region, all in the IGFALS gene. Cut off levels for maximal DE were calculated by ROC analysis. Results: The only statistically significant association between serum level and polymorphism was found for IGFBP-3 and the -202 A/C polymorphism. In N [AA: 0.34±0.16 (mean±sem), AC: 0.13±0.11, CC: −0.30±0.11; ANOVA: p= 0.0032; AA>CC, and AC>CC, p<0.05; LT (linear trend): p=0.0036] and ISS (AA:−0.14±0.28, AC:-0.81±0.17, CC:−1.25±0.22; ANOVA: p=0.0147; AA>CC, p<0.05, LT: p= 0.0039). In GHD children there was a non-significant trend (AA:−1.87±0.36, AC:−2.47±0.52, CC:−2.87±0.55). Table   Test Cut-off SDS Sensitivity % Specificity % Diagnostic Efficiency (%) IGF-I -2.12 66.7 79.1 77.3 ALS -2.74 66.7 91.9 86.4 IGFBP-3 -1.69 70.8 83.7 80.9 Genotypes AA AC CC -1.26 -1.73 -2.56 70.8 89.5 85.4     Conclusion: ALS levels showed the higher specificity and the higher overall DE, but it also presented a relatively poor sensitivity. Genotype specific IGFBP-3 cut-off levels improved specificity and DE of IGFBP-3 measurements, reaching similar DE than ALS measurements but with a slightly higher sensitivity. Moreover, this study extends the association of IGFBP-3 levels with the −202 IGFBP3 gene polymorphism to ISS children.