Genetic determinants of lipidomic variation and their role in CVD risk

This project is a collaboration with Eric Moses, Phillip Melton, Joseph Hung, Gemma Cadby and Gerald Watts (University of Western Australia); John Blangero (South Texas Diabetes and Obesity Institute); John Beilby (Pathwest Laboratory Medicine); Marie-Pierre Dube (Montreal Heart Institute) and Frank Van Bockxmeer (Royal Perth Hospital)

Cardiovascular disease (CVD) is the leading cause of death in the world, including Australia. Genetics has a major role in the risk of CVD, but overall this is poorly understood. Evidence is now emerging that rare genetic variation is a likely major contributor to heritable risk of CVD. Large, densely affected families, in combination with massively parallel sequencing, is now proving to be an optimal study design for rare variant discovery in complex diseases. However, suitable families are rare themselves, largely because they require a major financial investment (tens of millions of dollars) and a long time (decades) to collect.

In a major innovation we have transformed the iconic long running (50 years) Busselton Health Study into a unique Australian family resource optimal for genetic dissection of CVD and other complex diseases. In this flagship project we will utilise large empirically defined BHS family lineages to identify rare causal variants for CVD. These findings will be validated on independent CVD patient studies through our national and international collaborators. Our overall objective is translation of this knowledge to improve human health and as a first step we will evaluate the clinical utility of novel risk variants in familial hypercholesterolaemia, the most common cause of high cholesterol.

The potential benefit to human health from the genetic discoveries arising from this initiative will be among the biggest contributions to the field internationally.

We hypothesise that genetic analysis of the plasma lipidome in large families enriched for CVD events, with a focus on identifying rare mutations, will identify novel CVD risk factors of large effect. These risk factors will have clinical utility in the diagnosis and prediction of CVD.

There are six specific aims:

1. To determine whole genome sequence (WGS) for 1000 BHS individuals in extended family lineages.
   We will obtain WGS for (up-to) 1000 individuals in family lineages from the BHS that we have empirically defined using existing high-density SNP genotypes.
2. To determine the plasma lipidome in BHS family lineages.
   We will perform targeted lipidomic profiling (>400 lipid species) on plasma samples from 4671 BHS individuals for whom we have empirically derived family lineage relationships.
3. To identify lipid endophenotype QTLs for CVD risk in BHS family lineages.
   We will identify heritable lipid endophenotypes genetically correlated with CVD events in BHS family lineages and perform genetic analyses to identify quantitative trait loci (QTLs) for CVD risk.
4. To identify causal variants/genes underlying QTLs influencing CVD risk.
   We will statistically and bioinformatically evaluate sequence variants at QTLs influencing CVD risk to prioritise those variants/genes most likely to be functionally relevant.
5. To validate genetic associations with CVD risk in other cohorts.
   In collaboration with leading North American investigators, we will validate novel variant/gene associations with CVD risk in a large selected cohort of coronary artery disease (CAD) patients under study at the Montreal Heart Institute and in the unselected SAFHS Mexican American family cohort.
6. To evaluate the clinical utility of novel rare CVD risk variants in familial hypercholesterolemia (FH).
   In collaboration with leading European and South American investigators we will evaluate the clinical utility of the novel risk variants we identify in the diagnosis of FH and the prediction of CVD in FH.