Leptin is known to be an adipokine of key importance to the regulation of body composition throughout life. However, little work has so far be done to identify the effects of genetic polymorphisms within the genes encoding leptin and the leptin receptor. In particular, no study has previously assessed the effect of LEP and LEPR polymorphisms on fetal growth trajectories.

The Developmental Origins of Health and Disease (DOHaD) theory is now well established, linking intrauterine and early-life growth with adult cardiovascular and other disease, with increasing evidence for the role of gene-environment interactions underlying this association.

We hypothesise that the leptin pathway plays a significant role in the modification of both fetal growth and adult cardiovascular disease risk, and may therefore represent one of the genetic mechanisms underlying DOHaD. This study aims to test this hypothesis by identifying associations between single nucleotide polymorphisms in the LEP and LEPR genes with:

(1) antenatal growth trajectories; and,

(2) adolescent cardiovascular disease precursors.

Further to this, we aim to investigate the association of LEP and LEPR SNPs with serum leptin concentration at six time points throughout the life course, which will help describe the mechanism by which leptin polymorphisms act to effect growth and cardiovascular risk.

This project will utilise the resources of four international cohorts:

(1) The Western Australian Pregnancy (Raine) Cohort will be studied for the associations between LEP and LEPR SNPs and fetal growth trajectories, age 14 and 17 cardiovascular disease precursors, and leptin concentrations in maternal blood during pregnancy, umbilical cord blood from the time of birth, and adolescent serum at 17 years.

(2) The ALSPAC cohort will be studies for the associations with age 9 serum leptin concentrations in approximately 3000 subjects.

(3) The Helsinki Birth Cohort Study will be studied for the associations with adult (age about 60years) serum leptin concentration in 2000 subjects.

(4) The Generation R cohort will be studied in an attempt to replicate the antenatal growth associations found in Raine.

Preliminary analysis of the data from the Raine cohort suggests significant genetic associations with all of the proposed outcomes and identifies two potential biologically plausible mechanisms by which leptin polymorphisms may result in DOHaD outcomes