Pregnancy has been conceptualised as a metabolic challenge, since the normal physiological/hormonal response to pregnancy - high oestrogens and cortisol levels - results in a temporary metabolic like syndrome.(1) These changes are likely to be hormonally driven through acquisition of fat in early pregnancy and its rapid mobilisation later, and it has been hypothesised that women with greater weight gain during pregnancy are likely to be at greater risk of extreme metabolic and vascular changes during pregnancy and increased risk of the later development of diabetes and CVD.(1;2) There is also increasing evidence that greater weight gain in pregnancy is associated with offspring obesity risk in childhood and early adulthood,(3-10) and from a recent study conducted by the PI of this application that this association results in greater blood pressure in offspring.(3) At the extreme, the metabolic and vascular changes of pregnancy are manifest as clinically diagnosed gestational diabetes and hypertensive disorders of pregnancy (HDP: preeclampsia and gestational hypertension) both of which are associated with a wide range of other adverse (for mother or general populations in non-pregnant states) vascular, metabolic and inflammatory changes during pregnancy and with future glucose intolerance, diabetes, dyslipidaemia, hypertension and cardiovascular disease risk in the mother,(1;2;11-15) and her offspring in later life.(2;3;16-18)

The mechanisms that link pregnancy related characteristics to later cardiovascular and metabolic phenotypes in women are unclear. Our proposal will contribute to understanding the extent to which two hypothesised mechanisms for this association might be responsible.(19) These two hypotheses are (i) that an existing predisposition (in part a genetic predisposition) for adverse vascular and metabolic outcomes is unmasked by the stress test of pregnancy(1;20) and (ii) that adverse vascular and metabolic changes are caused by pregnancy in some women and these changes remain permanent and therefore increase the risk of future disease in later life. In the latter fetal genotype might drive the maternal changes in order to increase their nutrition during intrauterine development, particularly in the situation of placental underperfusion.(19;21) If the first hypothesis has a substantial role in explaining the association of pregnancy with later life maternal phenotypes then we would anticipate similar genetic variation to be associated with both pregnancy and non-pregnancy (later life) phenotypes. If the second has a substantial role then we would anticipate some maternal genetic variation to be associated only with non-pregnant phenotypes and we might expect some fetal (offspring) genetic variation to be associated with maternal pregnancy phenotypes. We will be able to test these possibilities in this proposal.

We will also be able to explore the extent to which intrauterine (developmental origin) mechanisms or shared genetic heritability contribute to the link between maternal pregnancy characteristics and offspring metabolic and vascular phenotypes. If intrauterine factors are important then we would anticipate that maternal genetic variation that is associated robustly with her phenotypes (e.g. weight change in pregnancy) to be associated with offspring phenotypes even after controlling for the offspring's own genotype. Whereas if genetic inheritance explains the intergenerational association we would anticipate the association of mother's genotype with offspring phenotype to be attenuated to the null upon adjustment for offspring genotype.