Protein QTL analysis of IGF-I and its binding proteins provides insights into growth biology

Abstract

The growth hormone and insulin-like growth factor (IGF) system is integral to human growth. Genome-wide association studies (GWAS) have identified variants associated with height and located near the genes in this pathway. However, mechanisms underlying these genetic associations are not understood. To investigate the regulation of the genes in this pathway and mechanisms by which regulation could affect growth, we performed GWAS of measured serum protein levels of IGF-I, IGF binding protein-3 (IGFBP-3), pregnancy-associated plasma protein A (PAPP-A2), IGF-II and IGFBP-5 in 838 children (3–18 years) from the Cincinnati Genomic Control Cohort. We identified variants associated with protein levels near IGFBP3 and IGFBP5 genes, which contain multiple signals of association with height and other skeletal growth phenotypes. Surprisingly, variants that associate with protein levels at these two loci do not colocalize with height associations, confirmed through conditional analysis. Rather, the IGFBP3 signal (associated with total IGFBP-3 and IGF-II levels) colocalizes with an association with sitting height ratio (SHR); the IGFBP5 signal (associated with IGFBP-5 levels) colocalizes with birth weight. Indeed, height-associated single nucleotide polymorphisms near genes encoding other proteins in this pathway are not associated with serum levels, possibly excluding PAPP-A2. Mendelian randomization supports a stronger causal relationship of measured serum levels with SHR (for IGFBP-3) and birth weight (for IGFBP-5) than with height. In conclusion, we begin to characterize the genetic regulation of serum levels of IGF-related proteins in childhood. Furthermore, our data strongly suggest the existence of growth-regulating mechanisms acting through IGF-related genes in ways that are not reflected in measured serum levels of the corresponding proteins.

Research Trends of Stunting Related to Insulin-Like Growth Factor-1: Bibliometric Analysis

“…articles, and Chen L and Li J each published 6 articles. Several publications from 10 authors with the highest number of articles are Association Between the Growth Hormone/Insulin-Like Growth Factor-1 Axis and Muscle Density in Children and Adolescents of Short Stature (Yang et al, 2022), Association between Growth Differentiation Factor-15 and Risk of Cardiovascular Diseases in Patients with Adult Growth Hormone Deficiency (Wu et al, 2021), Protein QTL analysis of IGF-I and its binding proteins provides insights into growth biology (Bartell et al, 2020), and Association Between the Growth Hormone /Insulin-Like Growth Factor-1 Axis and Muscle Density in Children and Adolescents of Short Stature (Yang et al, 2022). The results of keyword analysis using bibliometrics found 4548 keywords which provide important information about the dynamics of the scope and issues that are much larger than this research (Table VII and Figure 8).…”

“…Serum IGF-1 levels are very sensitive to changes in nutritional status, both chronic and short-term, so that in children with poor nutritional status and malnutrition, serum IGF-1 becomes low and has an impact on growth and height development, this is because IGF -1 has a key role in the development and growth of skeletal muscle (Bartell et al, 2020;Flora et al, 2021).…”

SINE Insertion in 5’ Flanking of IGFBP3 May Associated With Gene Expression and Phenotypic Variations

“…Furthermore, IGFBPs function independently of the IGFs in vitro and in vivo as growth modulators [3]. In humans, genetic variation in IGFBPs was associated with height by GWAS [4,5]. For the domestic animals, polymorphisms in IGFBPs were associated with meat quality [6,7], energy balance [8], and other economically-relevant traits [9,10].…”