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Meta-analyses of cohorts and population-based sequencing studies have investigated whether genes for lipoprotein lipase and proteins that interact with it, such as apolipoprotein (apo) A-V, apo C-III and the angiopoietin-like proteins 3 and 4, are associated with cardiovascular disease risk. The evidence to date shows that triglyceride-raising variants of these genes showed generally strong associations with clinical cardiovascular endpoints. However, these findings are confounded by the association of elevated triglycerides with low high-density lipoprotein cholesterol (HDL-C). Thus, while the evidence from these genetic studies points to a potential causal association with cardiovascular risk, further study is needed to tease out this confounding with low HDL-C. Ultimately, what is needed to resolve this uncertainty is outcomes studies with novel agents specifically aimed at targeting elevated triglycerides via inhibition of apoCIII or angiopoietin-like protein 3. This week’s Landmark study offers new hope.