Insulin-like growth factors have fundamental roles in metabolism and apoptosis. Circulating IGF-I and IGF-II are primarily sequestrated with IGFBP-3 in ternary complexes with the acid-labile subunit. We hypothesized that polymorphisms of the IGFBP3 gene may impact circulating IGF-II concentrations.
Methods: 478 Caucasian patients were selected from the Salford Diabetes Cohort for analysis. Thirteen haplotype tagging single nucleotide polymorphisms (SNPs) were selected across the IGFBP3 gene using HapMap and Ensembl. Genotyping was performed using the Sequenom iPlex platform. Seven SNPs passed quality assurance and were in Hardy-Weinberg equilibrium. Serum IGF-II concentration was measured using an in-house ELISA assay(inter-assay and intra-assay CVs of 9.2% and 6%, analytical sensitivity=10 ng/ml) and plasma IGFBP-3 using the commercial Immulite assay (interassay CV<10%, within-assay CV<6%, analytical sensitivity 0.1 mg/l). Quality assurance and statistical analysis was done using SNP Variation Suite 7.
Results: Mean IGF-II concentration was 603.8 ng/ml (range 189.31366.3). Minor alleles of five IGFBP3 SNPs were associated with IGF-II concentration four (rs2854744, rs3110697, rs2854747 and rs2132571) achieved significance at P<0.001 while the rs2471551 polymorphism was nominally associated with IGF-II concentration (P=0.022). rs2854744 was positively associated with IGF-II concentration while the association was negative for the other SNPs. The first four SNPs remained significantly associated after Bonferroni correction (<0.05). Variants of two SNPs, rs2854747 (associated with IGF-2 concentrations in our study and with IGFBP-3 concentrations in other studies) and rs924140 were nominally associated with circulating IGFBP-3 concentrations (negative association P=0.049 and positive association P=0.011 respectively) but lost on Bonferroni correction.
Discussion: We report novel associations of IGFBP3 gene polymorphisms and circulating IGF-II concentration. Three of these SNPs (rs2854744, rs3110697 and rs2854747) have been previously correlated with circulating IGFBP-3. Polymorphisms in the IGFBP3 gene thus influence IGF-II bioavailability with implications in diabetes complications and neoplasia.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.