LAUSR

Abstract Insulin-like growth factor I (IGF-I) is one of the essential hormonal mediators of human growth. Circulating IGF-I exists in a ternary complex bound to the acid-labile subunit (ALS) and an IGF binding protein, predominantly IGFBP-3. Pregnancy Associated Plasma Protein-A2 (PAPP-A2), which cleaves intact IGFBP-3, liberates IGF-I from the ternary complex to interact with cell surface receptors. Genome-wide association studies have linked PAPPA2 to adult stature, and mutations in PAPPA2 cause short stature with decreased IGF-I bioavailability. As little is known about PAPP-A2 concentrations throughout childhood and its association with IGF-I bioavailability, we evaluated normal serum concentrations of free IGF-I, intact IGFBP-3, and PAPP-A2 throughout childhood and their relationship with anthropometry. We assessed serum samples from 838 individuals (Age: 3-18, Male: 48%, Caucasian: 83%) who participated in the Cincinnati Genomic Control Cohort, a population-based study of generally healthy children. Patients on medications known to affect growth or with significant medical comorbidities were excluded. Subjects were evaluated at a single visit. Height and weight were measured and a blood sample was drawn. Serum samples were aliquoted and stored at −80 ° C without thawing until the current assays were performed. Total and free IGF-I, total and intact IGFBP-3 and PAPP-A2 were measured using ELISA kits developed by Ansh Laboratories. Age-specific reference interval curves were generated by sex. Correlation and regression analyses were used to examine relationships among analytes and association between each analyte and age, sex, race, height, and BMI. Statistical analyses were performed using SAS®, version 9.4. Free IGF-I increased with age. Serum PAPP-A2 consistently decreased throughout childhood. Serum intact IGFBP-3 increased from early childhood into adolescence with a more marked rise than total IGFBP-3. In multiple regression analysis, height Z-score was positively associated with free and total IGF-I (P=0.01; P<0.0001). Free IGF-I was positively associated with total IGF-I (M; F, r=0.32; r=0.39, P<0.0001). Intact IGFBP-3 was negatively associated with PAPP-A2 (M; F, r=−0.58; r=−0.65, P<0.0001) and the percentage of free to total IGF-I in both sexes (r=−0.53, P<0.0001). PAPP-A2 was positively associated with the percentage of free to total IGF-I (M; F, r=0.18; r=0.38, P<0.001) but not with absolute free IGF-I levels. In conclusion, this is the first study describing PAPP-A2 and intact IGFBP-3 concentrations throughout childhood. Surprisingly, PAPP-A2, a positive modulator of IGF-I bioavailability, decreased with age, but was not positively associated with absolute levels of free IGF-I. Higher levels of PAPP-A2 led to more cleavage of intact IGFBP-3 and thus increased the percentage of free to total IGF-I in this population.