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

K L Gatford,C T Roberts,G K Heinemann,S D Thompson,G A Dekker,J A Owens,S Buckberry,J V Zhang

doi:10.1530/ec-14-0068

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.

Highlights

The insulin-like growth factors (IGFs), IGF1 and IGF2, are important regulators of placental and foetal development, as well as postnatal growth and metabolism
We identified differences in circulating IGF1 between individuals according to common allele numbers in three linked Single-nucleotide polymorphisms (SNPs) in the INS– IGF2–H19 locus
Associations between circulating IGF1 and IGF2 rs[680] genotype remained significant in single SNP models and were consistent among men, non-pregnant women and pregnant women. This suggests that effects of SNP genotype in the INS–IGF2–H19 locus are consistent between sexes and unaffected by pregnancy

Summary

Introduction

The insulin-like growth factors (IGFs), IGF1 and IGF2, are important regulators of placental and foetal development, as well as postnatal growth and metabolism. In humans, circulating IGF1 peaks in adolescence and falls with age, whereas IGF2 concentrations remain fairly stable after puberty (1). The pubertal peak in plasma IGF1 occurs 1–2 years earlier in girls than in boys, resulting in higher circulating IGF1 concentrations in girls than in boys through adolescence (2, 3). Plasma IGF1 concentrations are fairly similar in men and women (2, 4) but slightly lower circulating IGF1 concentration in adult women than in men has been reported in large studies (3, 5).

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Conclusion