Loss-of-function mutations in the APOC3 gene are associated with reduced risk of coronary heart disease and ischaemic cardiovascular disease.

The lowdown: Two large-scale genetic validation studies have pointed the way to another putative cardiovascular target.

Credit: S.Harris/NPG

In a first study, members of the Exome Sequencing Project examined a cohort of 3,734 participants for mutations that were associated with low plasma triglyceride levels, a measure that has previously been associated with reduced cardiovascular risk. Carriers of a rare APOC3 mutation had plasma triglyceride levels that were 39% lower than those of non-carriers. When the researchers cross-validated the results by looking at the clinical importance of 4 loss-of-function APOC3 mutations in 110,970 participants from 14 studies, they found that the 498 participants that were heterozygous for loss-of-function mutations had a 40% lower risk of coronary heart disease than did non-carriers (N. Engl. J. Med. 371, 22–31; 2014).

In an independent study, Anders Berg Jørgensen from the University of Copenhagen, Denmark, and his colleagues found that loss-of-function APOC3 mutations were associated with a 44% reduction in non-fasting levels of triglycerides. Clinical follow-up of participants showed that the incidences of ischaemic vascular disease and ischaemic heart disease were reduced in carriers by 41% and 36%, respectively (N. Engl. J. Med. 371, 32–41; 2014).

“The results of our study highlight the potential usefulness of naturally occurring loss-of-function mutations in guiding the selection of therapeutic targets,” write the members of the Exome Sequencing Project. They compare their findings to the discovery of loss-of-function mutations in the gene coding for proprotein convertase subtilisin kexin 9 (PCSK9), which sparked the development of a highly anticipated class of antibody therapies for hypercholesterolaemia (Nature Rev. Drug Discov. 11, 817–819; 2012).

These data may be particularly important for Isis, which has an antisense APOC3 inhibitor in Phase II development for the treatment of elevated plasma triglycerides.