Triglyceride-lowering alleles in the LPL pathway are associated with a decreased risk of both coronary disease and type 2 diabetes. As the authors of the new study noted, there is increased interest in targeting LPL-mediated lipolysis to prevent cardiovascular outcomes, but it has been unclear whether such a treatment would provide an additional benefit when used in conjunction with LDL-C-lowering treatments like statins.
A University of Cambridge-led team turned to natural genetic variations found within LPL and LDL-Clinked alleles to gauge whether their mechanisms are intertwined or independent. As they reported in the medical journal JAMA Cardiology in September 19th, 2018, (jamanetwork.com/journals/jamacardiology/fullarticle/2702977), the researchers found that the link between triglyceride-lowering alleles in the LPL pathway and decreased coronary disease and type 2 diabetes risk is independent from LDL-Clowering mechanisms. "These findings provide human genetics evidence to support the development of agents that enhance LPL-mediated lipolysis for further clinical benefit in addition to LDL-C–lowering therapy," senior author Nicholas Wareham from Cambridge and his colleagues wrote in their paper.
In a genetic association analysis drawing on data from more than 392,000 individuals from numerous consortia, the researchers found that triglyceride-lowering alleles in LPL were linked to both lower type 2 diabetes risk and lower coronary risk. Similarly, they found that triglyceride-lowering alleles in ANGPTL4 — an LPL inhibitor — were associated with decreased disease risk. The researchers divided their population up based on the alleles they carried. One group contained individuals with genetically lower triglyceride levels due to their LPL alleles, another with lower LDL-C levels due to variants in 58 different LDL-C-linked loci, and one group with both genetically lower triglyceride and LDL-C levels. A fourth group served as a reference.
People with genetically lower triglycerides did indeed have lower triglyceride levels than the reference group and had similar LDL-C levels as the reference, the researchers reported. They also noted that people with genetically lower triglycerides, those with genetically lower LDL-C levels, or both had a lower coronary disease risk than the reference group, with the individuals with both genetically lower triglyceride and genetically lower LDL-C levels having the lowest odds of disease.