Genetics of familial hypercholesterolemia: a tool for development of novel lipid lowering pharmaceuticals?

Familial hypercholesterolemia is characterized by high LDL cholesterol and an elevated risk to develop coronary heart disease. Mutations in LDL receptor-mediated cholesterol uptake are the main cause of familial hypercholesterolemia. However, multiple mutations in various other genes are also associated with high LDL cholesterol and even familial hypercholesterolemia. Thus, pharmaceuticals that target these genes and proteins might be attractive treatment options to reduce LDL cholesterol. This review provides an overview of the recent developments and clinical testing of such pharmaceuticals.

About 80 genes are associated with hypercholesterolemia but only pharmaceuticals that inhibit cholesteryl ester transfer protein (CETP), angiopoietin-related protein 3 (ANGPTL3), and apolipoprotein C-III (apoC-III) have recently been tested in clinical trials. Inhibition of CETP and ANGPTL3 lowered LDL cholesterol. ANGPTL3 inhibition had the largest effect and was even effective in familial hypercholesterolemia patients. The effect of apoC-III inhibition on LDL cholesterol is not conclusive.

Of the many potential pharmaceutical targets involved in LDL cholesterol, only a few have been studied so far. Of these, pharmaceuticals that inhibit CETP or ANGPTL3 are promising novel treatment options to reduce LDL cholesterol but the effect of apoC-III inhibition requires more research.