Influence of Genetic Polymorphisms on Response to Statin Therapy

Jordan Dellborg^*
*Correspondence: Jordan Dellborg, Department of Biomedical Sciences for Health, University of Milan, Milan, Italy, Email:

Introduction

The therapeutic use of statins, also known as HMG-CoA reductase inhibitors, represents a cornerstone in the management of hypercholesterolemia and the prevention of Cardio Vascular Disease (CVD). Despite their efficacy, a wide inter-individual variability in response to statin therapy is frequently observed in clinical settings, with some patients experiencing significant cholesterol-lowering effects while others show suboptimal response or adverse effects such as myopathy. This variability has prompted the investigation into pharmacogenetics, particularly the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of statins. Genetic variants can influence how statins are absorbed, metabolized, transported and how they exert their lipid-lowering effects. Among the key genes implicated are those encoding drug-metabolizing enzymes (like CYP3A4, CYP2C9), drug transporters (such as SLCO1B1, ABCB1) and the drug target itself, HMGCR [1].

Description

The variability in statin response begins with the absorption and hepatic uptake of the drug. One of the most studied genes in this context is SLCO1B1, which encodes the Organic Anion-Transporting Polypeptide 1B1 (OATP1B1), a transporter responsible for statin uptake into hepatocytes. The SLCO1B1 c.521T>C (rs4149056) polymorphism has been associated with reduced transporter function, leading to decreased hepatic uptake and increased plasma concentrations of statins such as simvastatin and atorvastatin. This can result in higher systemic exposure and a greater risk of adverse effects like statin-induced myopathy. Clinical studies, such as those from the SEARCH trial, have shown that individuals carrying the C allele are at a significantly increased risk of statin-related muscle toxicity. Consequently, pharmacogenetic guidelines recommend dose adjustments or alternative statin choices for individuals with this genotype. In terms of metabolism, statins are primarily processed in the liver through cytochrome P450 enzymes, particularly CYP3A4, CYP3A5 and CYP2C9. Variations in these genes can influence the metabolic clearance of statins. For example, CYP3A5 expressers (carrying the CYP3A5 1 allele) may have a faster metabolism of drugs like atorvastatin, leading to lower plasma concentrations and reduced efficacy. In contrast, poor metabolizers of CYP2C9 such as those with CYP2C9 2 or 3 alleles may exhibit slower clearance of fluvastatin, potentially increasing the risk of adverse events. The influence of these polymorphisms, however, is statin-specific, as each statin has a unique metabolic pathway. For instance, pravastatin and rosuvastatin are minimally metabolized by cytochrome P450 enzymes, making them less susceptible to variations in these genes.

Polymorphisms in drug efflux transporters also contribute to variability in statin response. The ABCB1 gene, encoding P-glycoprotein, plays a role in limiting intestinal absorption and facilitating biliary excretion of statins. Variants such as C3435T (rs1045642) in ABCB1 have been linked to altered protein expression and function, impacting statin bioavailability and clinical outcomes. Additionally, genes involved in cholesterol metabolism and statin pharmacodynamics, such as HMGCR the target enzyme of statins also harbor polymorphisms that may influence therapeutic efficacy. The HMGCR haplotype 7 has been associated with a diminished LDL-C lowering response to statins, suggesting a direct effect on drug-target interaction. Beyond these pharmacokinetic and pharmacodynamic factors, other genes associated with lipid homeostasis and inflammatory response may further modulate statin effectiveness. For example, variants in APOE, particularly the ε4 allele, have been shown to influence baseline lipid levels and response to statin therapy. Similarly, polymorphisms in PCSK9, which encodes a protein that regulates LDL receptor degradation, may impact LDL-C levels and response to treatment. Furthermore, Genome-Wide Association Studies (GWAS) have identified multiple Single Nucleotide Polymorphisms (SNPs) associated with lipid response to statins, offering broader insights into the polygenic nature of statin pharmacogenetics [2].

Conclusion

In conclusion, genetic polymorphisms significantly influence individual responses to statin therapy, affecting both the efficacy and safety profiles of these widely prescribed lipid-lowering agents. Key genes involved in drug transport (SLCO1B1, ABCB1), metabolism (CYP3A4, CYP2C9, CYP3A5) and pharmacodynamics (HMGCR, APOE) harbor variants that can modulate statin plasma levels, cholesterol-lowering efficacy and the risk of adverse effects. As pharmacogenetic knowledge expands, integrating genetic testing into clinical decision-making offers a promising path toward personalized statin therapy. By tailoring treatment based on a patientâ??s genetic profile, clinicians can optimize outcomes, minimize adverse events and improve adherence. Nonetheless, challenges such as the need for broader population validation, cost-effectiveness analyses and integration into clinical workflows must be addressed to realize the full potential of pharmacogenomics in statin therapy. Ultimately, the convergence of genetic insights with clinical practice heralds a new era of individualized cardiovascular care, where therapies are designed not only around disease characteristics but also around the unique genetic blueprint of each patient.

Acknowledgment

None.

Conflict of Interest

None.

References

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