Exon 3-deleted genotype of growth hormone receptor (GHRd3) positively influences IGF-1 increase at generation test in children with idiopathic short stature

• Published in: Clinical endocrinology (Oxford) 2007-10, Vol.67 (4), p.500-504
• Main Authors: Toyoshima, Marcos T. K., Castroneves, Luciana A., Costalonga, Everlayny F., Mendonca, Berenice B., Arnhold, Ivo J. P., Jorge, Alexander A. L.
• Format: Article
• Language: English
• Subjects: Age Factors; Biological and medical sciences; Body Height; Body Mass Index; Case-Control Studies; Chi-Square Distribution; Child; Endocrinopathies; Exons - genetics; Female; Fundamental and applied biological sciences. Psychology; Genotype; Growth; Growth Disorders - blood; Growth Disorders - genetics; Growth Disorders - physiopathology; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 3 - blood; Insulin-Like Growth Factor I - analysis; Insulin-Like Growth Factor I - secretion; Male; Medical sciences; Parents; Receptors, Somatotropin - genetics; Regression Analysis; Sequence Deletion; Vertebrates: endocrinology
• ISSN: 0300-0664; 1365-2265
• DOI: 10.1111/j.1365-2265.2007.02915.x

Summary Context   A GHR‐exon 3 polymorphism has been reported to influence the growth response to hGH therapy in short stature children. None of these studies provided data on IGF‐1 generation test. Objective   To evaluate the influence of the GHR‐exon 3 polymorphism on the generation test in children with idiopathic short stature (ISS). Design and patients   A total of 45 prepubertal ISS children were submitted to IGF‐1 and IGFBP‐3 generation test (4 days of hGH 33 µg/kg/day). Children were genotyped for GHR‐exon 3: full‐length (fl) and exon 3‐deleted (d3) alleles. Measurements   IGF‐1 and IGFBP‐3 increment as absolute values and standard deviation scores (SDS). Results   Basal clinical and laboratory data were similar among patients with different genotypes (fl/fl vs. fl/d3 or d3/d3). All patients presented IGF‐1 increase ≥ 15 µg/l at generation test. Children with GHRd3 allele, as a group, presented a statistically significant higher IGF‐1 SDS increase at generation test than children homozygous for GHRfl allele (1·0 ranging from 0·1 to 3·7 for fl/fl vs. 1·2 ranging from 0·3 to 4·4 for fl/d3 and d3/d3; P = 0·037). Multiple linear regression found a positive association between increase in IGF‐1 SDS with chronological age (P = 0·007) and GHR genotype (P = 0·027), which together explain 24% of the variability of IGF‐1 SDS increment at generation test. There was no difference in IGFBP‐3 generation test between the two genotype groups. Conclusion   This study demonstrates that ISS children carrying the GHRd3 allele, as a group, present a slightly higher GH sensitivity regarding short‐term IGF‐1 generation during hGH stimulus than children homozygous for GHRfl allele.