The biological basis of the observed associations between early growth and adult metabolic phenotypes remains to be explained. Whilst there is strong evidence, from rodent models, that metabolic programming consequent on poor fetal nutrition is involved, a complementary explanation attributes these associations to the effect of variation in genes with pleiotropic effects on both fetal and adult phenotypes. Proof of principle for such genetic links between fetal growth and adult disease comes from the analysis of monogenic forms of diabetes and other metabolic phenotypes. However, these rare variants cannot account for the observed epidemiological associations.
Studies on the insulin gene, by our group and others, are starting to shed light on the mechanisms whereby common genomic variants influence both early growth and adult metabolic phenotypes. Insulin gene related susceptibility effects have been shown for type 2 diabetes, polycystic ovarian syndrome and childhood obesity - in each case susceptibility is restricted to the paternally transmitted allele. Preliminary data support similar parent-of-origin effects in the regulation of early growth. These data are consistent with the maternal imprinting of the INS-IGF2 locus and strengthen the mechanistic links between early growth and adult metabolic disease. Preliminary studies by our group in a large Nordic birth cohort (which allows us to study fetal growth parameters and adult metabolic phenotypes in the same population) reinforce these findings, and indicate complex relationships between insulin gene variation, the control of fetal and infant growth, and the development of adult metabolic phenotypes.
Hattersley, A.T., and Tooke, J.E. The fetal insulin hypothesis an alternative explanation of the association of low birth weight with diabetes and vascular disease. Lancet, 353, 1789-1792, 1999.
Huxtable, S.J., Saker, P.J., Haddad, L., Walker, M., Frayling, T.M., Levy, I.C., Hitman, G.A., O'Rahilly, S., Hattersley, A.T., and McCarthy, M.I. Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class Ill variable number tandem repeat alleles. Diabetes, 49, 126-130, 2000.
Le Stunff, C., Fallin, D., and Bougnères, P. Paternal transmission of the very common class I INS VNTR alleles predisposes to childhood obesity. Nat. Genet. 29, 96-99, 2001.