Association of PCSK9 Variants With the Risk of Atherosclerotic Cardiovascular Disease and Variable Responses to PCSK9 Inhibitor Therapy

Genetic polymorphisms or variations, randomly distributed in a population, may cause drug-gene response variations. Investigation into these polymorphisms may identify novel mechanisms contributing to a specific disease process. Such investigation necessitates the use of Mendelian randomization, an analytical method that uses genetic variants as instrumental variables for modifiable risk factors that affect population health.¹ In the past decade, advances in our understanding of genetic polymorphisms have enabled the identification of genetic variants in candidate genes that impact low-density lipoprotein cholesterol (LDL-C) regulating pathways and cardiovascular disease (CVD) outcomes. A specific candidate gene of interest is that of the LDL receptor degrading protein, PCSK9. In fact, loss-of-function genetic variants for the PCSK9 gene are what first highlighted this pathway as a candidate for pharmacologic inhibition. PCSK9 inhibitors (PCSK9i) are a class of cholesterol-lowering medications that provide significant reductions in LDL by inhibiting the degradation of LDL receptors (LDLR). These inhibitors have also been found to reduce production and enhance clearance of lipoprotein A (Lp[a]), an LDL-like particle currently under study as a separate risk factor for atherosclerotic CVD. Here, we discuss the promise of personalized medicine in developing a more efficacious and individualized pharmacogenomics-based approach for the use of PCSK9i that considers genetic variation and targets different patient populations. This review explores the pharmacogenomics of PCSK9i in the context of PCSK9 allele variants related to drug-metabolizing enzymes and responses since more studies are demonstrating that some patients are hyporesponsive or non–responsive to PCSK9i.² In summary, the pharmacogenomics of PCSK9 are a promising therapeutic target and genetic information from prospective randomized clinical trials is warranted to gain a full understanding of the efficacy and cost-effectiveness of such allele and/or gene-guided PCSK9i therapy.