Circulating IGF1 and IGF2 and SNP genotypes in men and pregnant and non-pregnant women

Abstract

Circulating IGFs are important regulators of prenatal and postnatal growth, and of metabolism and pregnancy, and change with sex, age and pregnancy. Single-nucleotide polymorphisms (SNPs) in genes coding for these hormones associate with circulating abundance of IGF1 and IGF2 in non-pregnant adults and children, but whether this occurs in pregnancy is unknown. We therefore investigated associations of plasma IGF1 and IGF2 with age and genotype at candidate SNPs previously associated with circulating IGF1, IGF2 or methylation of the INS-IGF2-H19 locus in men (n=134), non-pregnant women (n=74) and women at 15 weeks of gestation (n=98). Plasma IGF1 concentrations decreased with age (P<0.001) and plasma IGF1 and IGF2 concentrations were lower in pregnant women than in non-pregnant women or men (each P<0.001). SNP genotypes in the INS-IGF2-H19 locus were associated with plasma IGF1 (IGF2 rs680, IGF2 rs1004446 and IGF2 rs3741204) and IGF2 (IGF2 rs1004446, IGF2 rs3741204 and H19 rs217727). In single SNP models, effects of IGF2 rs680 were similar between groups, with higher plasma IGF1 concentrations in individuals with the GG genotype when compared with GA (P=0.016), or combined GA and AA genotypes (P=0.003). SNPs in the IGF2 gene associated with IGF1 or IGF2 were in linkage disequilibrium, hence these associations could reflect other genotype variations within this region or be due to changes in INS-IGF2-H19 methylation previously associated with some of these variants. As IGF1 in early pregnancy promotes placental differentiation and function, lower IGF1 concentrations in pregnant women carrying IGF2 rs680 A alleles may affect placental development and/or risk of pregnancy complications.

Keywords: IGF1; IGF2; SNP genotype; human; pregnancy.

Figure 1

Schematic of the Homo sapiens INS – IGF2 – H19 locus. Exons are represented as blue boxes with intronic regions between exons as black lines. Black arrows above exons show transcription start sites and direction of transcription. Orange boxes indicate the approximate location of differentially methylated regions (DMRs). The x-axis shows genomic position in base pairs for human chromosome 11 and the position of single-nucleotide polymorphisms (SNPs, denoted by rs number) investigated in this study. This representation is based on human reference genome hg19, dbSNP 138 and RefSeq transcripts.

Figure 2

Circulating plasma IGF1 and IGF2 in men (white squares), non-pregnant women (grey circles) and at 15 weeks of gestation in pregnant women (black circles).

Figure 3

Plasma IGF1 according to IGF2 rs680 SNP genotype in men (white squares), non-pregnant women (grey circles) and at 15 weeks of gestation in pregnant women (black circles). Plasma IGF1 data are estimated means and s.e.m. adjusted to an average age of 26.2 years. Differences between groups are indicated as follows: *P< 0.05; **P<0.01.