Objective: IGF1 is essential for human growth and mediates its effects through the type 1 IGF receptor (IGF1R). Our objective was to determine the frequency of certain previously reported IGF1R gene variants in the normal population and their effect on stature.
Design: A cross-sectional study was conducted in a population of 2500 children enrolled in public school grades 5 through 12 for whom DNA and anthropometric data were available. Subjects were genotyped at five previously reported loci that affect receptor abundance or function.
Methods: The frequency of the following IGF1R variants Arg108Gln, Lys115Asn, Arg59stop, Arg481Gln, and Arg605His was measured by a PCR-based assay. Circulating concentrations of IGF1 or IGF binding protein-3 (IGFBP3) were measured by ELISA in those affected and matched controls.
Results: A scan of 1300 subjects detected none with Arg108Gln, Lys115Asn, or Arg59stop mutations. In contrast, nucleotide changes leading to heterozygosity at codon 605 were identified in nine of 2500 subjects and six of 1800 subjects at codon 481. These individuals were, on average, 4 cm shorter than the others. There were no differences in circulating concentrations of IGF1 or IGFBP3 between those with the gene variants and controls matched for sex, ethnicity, age, and BMI.
Conclusion: Rare IGF1R variants exerting a moderate effect on stature are present in the general population, supporting the importance of IGF1R function in growth control and indicating that variation in height within healthy individuals may be explained, in some cases, by larger effects of a small subset of gene variants.