Idiopathic short stature: the impact of polymorphic markers of genes encoding the 150-kDa circulating IGFs ternary complex

H DOMENÉ; P SCAGLIA; A MARTÍNEZ; A KESELMAN; D FERNÁNDEZ; V PIPMAN; S BENGOLEA; L KARABATAS; G ROPELATO; G BALLERINI; J HEINRICH; H JASPER

Istanbul, Turkey

Congreso; 47th Annual Meeting, European Society for Pediatric Endocrinology; 2008

European Society for Pediatric Endocrinology

Abstract Title       Idiopathic short stature: The impact of polymorphic markers of genes encoding the 150-kDa circulating IGFs ternary complex.       Abstract Text        Idiopathic short stature (ISS) is a heterogeneous clinical condition, probably comprising several etiologies. Different studies have shown reduced IGF-I levels in a significant proportion of these subjects. Our aim was to determine: 1) if the distribution of some polymorphic markers of the genes encoding for GHR, IGF-I, IGFBP-3, and ALS in ISS differs from normal; 2) if the distribution of these markers differ using two different classifications of ISS: with low or normal IGF-I levels, or with (F-ISS) or without (NF-ISS) family background of short stature. We enrolled 191 normal children, height above -2.0 SDS, aged 5.1 to 16.6 years, and 82 ISS, height below -2.2 SDS, aged 2.0 to 17.6 years, with normal GH response after provocative tests (>7.0 µg/L). Height, IGF-I (RIA), IGFBP-3 (IRMA), ALS (RIA), and ternary complex formation (TCF, size exclusion chromatography) were expressed in SDS. Single nucleotide polymorphisms (SNPs) were determined by RFLP: two in the promoter region of IGFBP3 gene (rs2854744 and rs13241830), one in the 3´-UTR of IGF1 gene (rs6220), and one in the coding region of IGFALS gene (rs3751893), and a GHR gene polymorphism by multiplex PCR (full length or exon 3 deletion). ISS children showed a more frequent reduction (<-2.0 SDS) of IGF-I levels (30.5%), compared to ALS (23.2%), IGFBP-3 (15.9%), and TCF (7.3%), ?2 test p=0.0014; ?2 for trend p<0.0001. Same results were observed for NF-ISS, ?2 test p=0.025; ?2 for trend p=0.0025. The frequency distribution of the 5 polymorphic markers studied did not significantly differ in ISS children compared to normal controls. No difference in these markers were observed in ISS divided either by IGF-I levels or by short stature family background. The affectation of the components of the circulating IGF system suggest a reduced GH secretion/activity or sensitivity as the cause of some cases of ISS. Our results, from a limited number of studied polymorphic markers, do not support a role of subtle genetic variation in the genes encoding for the components of the IGF ternary complex in the etiology of ISS.