Research led by Peking University shows treatments targeting both apolipoprotein C3 and low-density lipoprotein (LDL) cholesterol linked genes could give better outcomes for patients at high risk for coronary heart disease (CHD).
The researchers assessed this using a proxy genetic measure in a large cohort of people and found that those with genetically low levels of apolipoprotein 3 and proprotein convertase subtilisin-kexin type 9 (PCSK9), a protein that regulates LDL cholesterol levels, had lower risk of heart disease.
For many years, early treatment and prevention of CHD has focused on reducing LDL cholesterol with drugs such as statins that target 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and also those targeting PCSK9. While this works well for many people, it does not eliminate all cardiovascular risks as other lipids like triglycerides also contribute to this type of disease, and heart disease still kills a large number of people every year.
“Apolipoprotein C3 (APOC3) is a key regulator of plasma triglyceride metabolism by inhibiting lipoprotein lipase,” explained Xinwei Hua and Yi Da Tang, both researchers at Peking University Third Hospital, and colleagues, in the journal JAMA Cardiology.
“Genetic epidemiological evidence suggests that loss-of-function gene variants of APOC3 are associated with lower levels of triglycerides and consequently lower risks of cardiovascular disease.”
Indeed, earlier this year the FDA approved Ionis’s Tryngolza (olezarsen) to treat familial chylomicronemia syndrome, a rare genetic disorder characterized by extremely high triglyceride levels and people are interested in using these therapies more broadly to treat high triglycerides.
In this study, the research team analyzed data from 401,548 UK Biobank participants (54% female) aged 57 years on average.
They found that people with genetically predicted lower APOC3 had a 4% lower risk of CHD and a 3% lower risk of type 2 diabetes than those with higher levels. If individuals had genetically lower APOC3 and PCSK9 they had a 10% lower risk for CHD compared with those with higher levels of these two proteins. Genetically lower levels of HMGCR were also linked to lower CHD risk and had a cumulative 7% reduction in risk when combined with low APOC3 levels.
“Future studies are warranted to investigate the therapeutic potential of these combined therapies,” concluded the authors.
“Our findings provided genetic evidence for future trials evaluating APOC3-targeted therapies that can specifically investigate long-term cardiovascular outcomes in high-risk populations (i.e., those unable to reach treatment targets with existing LDL lowering options) and provided evidence for the efficacy of combined therapy.”
