Identifying novel lipid and genetic signatures of metabolic disease in early childhood

This project is a collaboration with Bronwyn Kingwell; Neerja Karnani, Gerard Wong, S. Sendhil Velan (Singapore Institute for Clinical Science); Markus Wenk (National University of Singapore); David Burgner, Richard Saffery, Anne-Louise Ponsonby (Murdoch Children’s Research Institute); Peter Vuillermin (Deakin University).

Metabolic diseases can be triggered in early life by both genetic risk factors and environmental exposures.  The antenatal period and early childhood also represents a critical window of high plasticity within the life course, where there is potential for early intervention to prevent the onset of adverse health trajectories.

We hypothesise that plasma lipidomic profiles, combined with genomic profiles, will facilitate the identification of those individuals on adverse health trajectories and provide mechanistic insight to guide preventative interventions. This proposal combines the resources of two unique and well-established birth cohorts from Singapore (Growing Up in Singapore Towards healthy Outcomes, GUSTO) and Australia (The Barwon Infant study, BIS) to examine the early origins of metabolic diseases. GUSTO and BIS are prospective cohorts with largely harmonised study designs, which have both collected maternal and child anthropometric and related measures with repeated longitudinal bio-sampling.

Combining expertise and complementary skill sets, our collaboration aims to:

1. Profile the plasma lipidome in early childhood and examine associations with longitudinal anthropometric measures and growth trajectories.
2. Identify maternal health factors as contributors to suboptimal plasma lipid profiles and adiposity in childhood.
3. Identify genetic risk variants associated with plasma lipidomic profiles and child adiposity.
4. Utilise the ethnic diversity of the two cohorts (Asian and Caucasian) to bring precision and specificity to risk prediction, diagnosis and intervention by population risk stratification.
5. Leverage longitudinal body composition data from GUSTO which includes imaging of fat depots (intramyocellular, hepatic, subcutaneous) from birth to 6 years to define the genetic risk and lipid profiles linked with ectopic fat accumulation in early childhood.
6. Leverage the detailed cardiovascular risk measures in BIS (aortic/carotid intima-media thickness, pulse wave velocity and blood pressure), in order to investigate longitudinal association between blood lipid profiles and early markers of cardiovascular risk.

These goals will be achieved via the collective expertise of an experienced multidisciplinary team across four world-class institutions, (two in Melbourne, two in Singapore). The ten chief investigators have proven track records spanning advanced lipidomics, genomics, physiology, bioinformatics, epidemiology, public health and research translation. This application will expand established collaborations between Melbourne and Singapore to promote significant knowledge transfer, particularly in the fields of lipidomics, integrative ‘omics and bioinformatics.

Through understanding the mechanisms linking genetic risk variants, environmental factors and plasma lipidomic profiles, this multi-cohort collaboration will:

1. Identify early childhood markers of metabolic disease which may herald future risk for development of type 2 diabetes and cardiovascular disease.
2. Elucidate novel molecular mechanisms with the potential to underpin new therapeutic approaches for the prevention and management of metabolic diseases and their complications.

A particular innovation is that the risk markers studied will include those evident in infancy and childhood, but also capture ante- and perinatal factors. The diversity of the combined cohorts which encompass Caucasian, Indian, Chinese and Malay will permit tailoring of risk prediction models by ethnicity. Collectively, the outcomes from this study will delineate risk profiles which identify vulnerable children at an age where early lifestyle interventions can occur at developmental windows of high plasticity, and are therefore potentially highly effective in altering early life programming to mitigate adverse health trajectories.