The Million Veteran Program (MVP) is a large-scale multiethnic biobank launched in 2011 to investigate the role of genetic, behavioural and environmental factors in complex diseases. In a new study, Themistocles Assimes and his team used genetic and clinical data from 312,571 MVP participants to identify genetic variants associated with blood lipid levels; these findings could facilitate the emergence of new strategies for the prevention of atherosclerotic cardiovascular disease (CVD).

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Previous genome-wide association studies (GWAS) have already linked variants to lipid levels. “Other groups have identified genetic variants and associations that influence lipids levels, many of which are under investigation as potential therapeutic targets. However, it was clear that there was room for additional discovery through the study of larger and more diverse populations,” says Assimes.

By performing a GWAS on the MVP cohort and combining the results with existing data, the investigators identified 826 lipid-associated variants across 118 novel and 268 previously identified loci. Some variants were shared among the African, European and Hispanic ethnicities, whereas novel coding variants were associated with lipid levels only in the non-European population. These new insights into the genetics of dyslipidaemia provide additional therapeutic targets to prevent CVD.

The investigators also identified new variants associated with the risk of coronary artery disease (CAD) in genes already targeted by pharmaceutical agents, including ANGPTL4, LPL and PCSK9. Interestingly, the mutation in ANGPTL4 was also associated with a reduced risk of type 2 diabetes mellitus, and individuals carrying a loss-of-function mutation in PCSK9 had a reduced risk of abdominal aortic aneurysm compared with individuals with the wild-type allele. “Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors of lipids that are either already on the market or under development,” explains study investigator Derek Klarin.

A loss-of-function variant in PDE3B was associated with lower plasma levels of triglycerides and a decreased risk of CAD. “To date, no pharmacotherapy has been clearly shown to reduce the risk of CAD by reducing triglyceride levels,” explains Klarin. Although studies have shown that treatment with cilostazol, an inhibitor of the phosphodiesterase encoded by PDE3B, reduces triglyceride levels in humans, the effects of the drug on the risk of CAD have not yet been investigated.

we propose novel indications for pharmaceutical inhibitors of lipids that are either already on the market or under development

The investigators plan to explore further the possibility of repurposing cilostazol to prevent CAD. “If observational studies confirm our hypothesis, we may have enough evidence to launch a clinical trial to provide the ultimate proof of the clinical utility of the drug in this context,” concludes Assimes.