Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

Abstract

SummaryThe growth hormone/insulin‐like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF‐related proteins including IGF‐I and IGF‐binding protein‐3 (IGFBP‐3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF‐I and IGFBP‐3 concentrations (IGF1, IGFBP3,GCKR,TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP‐3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF‐I and IGFBP‐3 concentrations. The IGF‐I‐decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity‐associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF‐I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF‐I‐ and IGFBP‐3‐associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF‐I and IGFBP‐3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity‐associated loci.

Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness

“…53), DHEA-S (ref. 54) and IGF-1 levels55, we saw no evidence for a causal association with grip strength (Supplementary Table 11). We saw some indication of causality of insulin resistance and fasting insulin levels in grip strength (Supplementary Table 11) in inverse-variance and median-weighted analyses, although the considerable heterogeneity in inverse-variance weighted results warrants a cautious interpretation (Supplementary Table 11; Supplementary Fig.…”

Recent advances in understanding the role of FOXO3

“…For example, the G allele of a longevity variant of FOXO3 was associated with a 10% reduction in all-cause mortality in a prospective cohort study of 3,584 older American men 55 . Moreover, in a cross-sectional study including more than 30,000 individuals, the G allele of another longevity variant of FOXO3 was associated with a decrease in concentration of circulating insulin-like growth factor-1 (IGF-1), a marker of insulin resistance and chronic disease 56 . Smaller-scale studies have yielded mixed results, albeit showing consistent trends.…”

Immunosenescence Induced by Plasma from Individuals with Obesity Caused Cell Signaling Dysfunction and Inflammation

“…Available data from proteome and genome-wide analyses arrays have identified particular genes or single nucleotide polymorphisms from the signaling glucose pathway, named insulin growth factor (IGF)-1 and IGF binding protein (IGFBP-3) present in plasma, associated with DM2, cancer, mortality (20), and age-related diseases (21). In addition, adipocytes secrete adipokines such as leptin and adiponectin, vascular endothelial growth factor, plasminogen activator inhibitor 1, macrophage migration inhibitory factor, monocyte chemotactic protein 1, C-reactive protein, and proinflammatory cytokines such as TNF-a, IL-1b, IL-8, IL-18, and IL-6 (15).…”