Blood cholesterol levels are linked to cardiovascular disease. However, recent studies suggest that it is not LDL cholesterol that mediates cardiovascular risk, but its neighbour apoB instead.
Lowering blood levels of low-density (LDL) cholesterol has been linked to reducing cardiovascular risk, including the risk of heart attacks. Statins are a type of drug typically used to lower LDL cholesterol. However, recent research has shown that lowering LDL cholesterol via statin use is not enough to reduce cardiovascular risk. This suggests that either we do not know how it is that statins actually work to reduce that risk, or that lowering LDL cholesterol is not enough. One major challenge is that we do not understand the interactions between genetics, statins, LDL cholesterol, and cardiovascular risk.
Ference and colleagues recently published a study in the Journal of the American Medical Association investigating how the interactions between genetics and statin functioning may be influencing the effectiveness of statins in reducing cardiovascular risk. To do so, the researchers looked at the CETP gene and its variants, along with the HMGCR gene and its variants, and compared the association between these genes, blood cholesterol levels, and cardiovascular risk.
To quantify CETP and HMGCR scores, researchers calculated the number of mutations associated with high-density (HDL) cholesterol levels in each individual. They split individuals into two groups based on these scores, allocating them to either high or low HDL-associated mutation groups. They used a sample of 102,837 individuals to develop a model of the relationship between these factors, which they then tested on a sample of 189,539 different individuals. The entire sample was derived from the National Center for Biotechnology Information database and included data of cardiovascular conditions and events.
The researchers found that certain individuals with more high HDL-associated variants in the CETP gene tended to have higher HDL cholesterol, lower LDL cholesterol and apoB (apolipoprotein B: a protein that binds to fat and cholesterol), and lower cardiovascular risk. When combined with HMGCR, individuals who had higher HDL-associated variants in both genes had higher HDL cholesterol and lower LDL cholesterol, but the decrease in cardiovascular risk was lower than expected based on the differences in cholesterol levels alone. Rather, these individuals had a lower than expected reduction of apoB which was proportional to the decrease in cardiovascular risk. Individuals with certain CETP variants further gained some benefits from using statins, but it was less than expected based on their LDL cholesterol levels.
The most important finding of this surprising study is that cardiovascular risk is mediated by apoB rather than by LDL cholesterol levels directly. This is contrary to much of our current thinking about cardiovascular disease. These two molecules are typically highly correlated in the bloodstream, and the difference in their effects is only obvious when their levels diverge, as in individuals with multiple CETP and HMGCR mutations. These results suggest that some therapies, like statins, may be successful only through their indirect effects on apoB, and that drugs that target only LDL cholesterol without also causing a reduction in apoB may be ineffective for lowering cardiovascular risk. Further, it suggests that some individuals with particular genotypes may benefit more or less from specific therapies.
Written by C. I. Villamil
Reference: Ference et al. 2017. JAMA. Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk.