NEW YORK (GenomeWeb) – Alleles in the lipoprotein lipase pathway that lower triglyceride levels work independently of genetic mechanisms that lower low-density lipoprotein cholesterol levels, according to a new study.
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-C-linked alleles to gauge whether their mechanisms are intertwined or independent. As they reported in JAMA Cardiology today, 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-C-lowering 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 divvied 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.
Meanwhile, people with genetically lower LDL-C levels had a higher risk of type 2 diabetes than the reference group, which the researchers said was in line with findings from previous studies. However, individuals with genetically lower triglycerides and genetically lower LDL-C levels had a similar type 2 diabetes risk as the reference group, indicating that the lower risk conferred by the LPL alleles cancelled out the higher risk from LDL-C alleles.
When the researchers further stratified their population by the number of different LDL-C lowering alleles they had, they found triglyceride-lowering LPL alleles were strongly associated with protection from coronary disease and type 2 diabetes in both people who harbored many and who harbored few of the LDL-C lowering alleles.
Additionally, the researchers reported that the p.Glu40Lys variant in ANGPTL4 was linked to decreased coronary disease and diabetes risk with an effect nearly identical to that of the LPL alleles, and that ANGPTL3 variants were linked to decreased coronary disease risk even more strongly than were of LDL-C alleles.
Overall, the researchers said their findings suggest that the triglyceride lowering-LPL alleles and LDL-C lowering alleles are independently associated with coronary disease risk and further support the notion that pharmacologically targeting LPL-mediated lipolysis could provide additional cardiovascular benefits as compared to LDL-C lowering treatments alone.
"This is of relevance to the future clinical development and positioning of LPL-enhancing drugs, given that these agents are being developed for use in addition to statins and other existing LDL-C–lowering drugs," the researchers wrote.
The researchers cautioned, though that while their study showed a strong association between LPL alleles and coronary disease and diabetes risk, it does not necessarily mean that drug-induced short-term enhanced lipolysis will lead to clinically relevant changes in disease risk in high-risk adults.