Background: Insulin-like growth factor I (IGF-I) is one of the important hormonal mediators of human growth. Circulating IGF-I exists in a ternary complex bound to the acid-labile subunit (ALS) and one of its six binding proteins (BPs). IGF-I bound to ALS and BPs needs to be liberated by either Pregnancy Associated Plasma Protease A (PAPP-A) or A2 (PAPP-A2) to reach its receptor. Stanniocalcin 2 (STC2) is a potent inhibitor of both PAPP-A and PAPP-A2. Genome-wide association studies have linked PAPP-A, PAPP-A2, and STC2 to adult stature, and mutations in PAPPA2 lead to short stature. Although these components are key regulators of the bioavailability of IGF-I, little is known about their concentrations throughout childhood. We aimed to evaluate the normal serum concentrations of bioactive IGF-I, PAPP-A2, and STC2 throughout childhood and the relationship between their concentrations and anthropometric measurements.
Methods: We studied serum from 838 individuals (Age: 318, Male: 48%, Caucasian: 83%) who participated in the Cincinnati Genomic Control Cohort, a study of generally healthy children. Subjects were evaluated at a single visit. Height and weight were measured and a blood sample was taken for serum isolation. We measured total IGF-I, bioactive IGF-I, PAPP-A2, and STC2 using ELISA kits at Ansh Laboratories. Patients on medications known to affect growth or with significant medical comorbidities were excluded. Descriptive statistics for each factor by age and sex were estimated; correlation multiple regression was used to assess associations with age, body mass index z-score (BMIz) and height z-score (HAz). Log transformation was used for analysis of the factors, where appropriate. Statistical analysis was performed using SAS®, version 9.4.
Result: Mean bioactive IGF-I, PAPP-A2, and STC2 was slightly higher in females than males. Log PAPP-A2 concentration was inversely correlated with age (r=−0.46, −0.53; (M,F), P=<0.0001). STC2 and intact BP3 concentration were positively correlated with age (r=0.26, 0.34; 0.74, 0.69; (M,F), P=<0.0001). In a multiple regression model, controlling for age and sex, log STC2 and log PAPP-A2 concentration were associated with BMI z-score (β=0.03, P=0.02; β=−0.11, P<0.0001). Log bioactive IGF-I was associated with HAz (β=0.03, P=0.01).
Conclusions: This is the first study describing PAPP-A2 and STC2 concentrations throughout childhood. Bioactive IGF-I levels increased with age as expected. Surprisingly, PAPP-A2, a positive modulator of IGF-I bioavailability, decreased with age, while STC2, a negative modulator, increased with age. Sex differences were detected suggesting differences in regulation of IGF-I bioavailability between sexes throughout childhood.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology