The concept of actionability in genetics is frequently associated with identifying genetic variants that directly inform therapeutic intervention. In pharmacogenomics, actionability often means using genetic information that may inform treatment selection and dosing for an individual.
Cholesterol management is an excellent example.
Although low-density lipoprotein (LDL), a lipoprotein particle that carries cholesterol, is often referred to as “bad cholesterol,” cholesterol itself is essential for life. Every cell in the body requires cholesterol to build cell membranes, produce hormones, synthesize bile acids, and support many normal biological functions. Because cholesterol is not water-soluble and cannot travel freely through the bloodstream, it is transported within lipoprotein particles, such as LDL, throughout the body. The liver removes these LDL particles from circulation with LDL receptors on the surface of liver cells, allowing the cholesterol they contain to be recovered, recycled, and reused for normal physiological processes. The number of LDL receptors on liver cells directly influences how efficiently LDL cholesterol is removed from the bloodstream.
When medication is indicated for elevated LDL cholesterol, a statin is often the first choice of treatment. Statins work by inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. As hepatic cholesterol levels decline, liver cells increase the expression of LDL receptors on their surface. This allows the liver to remove more LDL particles from the bloodstream through receptor-mediated uptake, recovering the cholesterol they contain, and helping maintain cholesterol homeostasis. The net effect is a reduction in circulating LDL cholesterol levels.
But not everyone responds to statins in the same way, and genetics can help explain why.
One important gene is SLCO1B1, which encodes the hepatic uptake transporter called organic anion transporting polypeptide 1B1 (OATP1B1), a protein responsible for moving certain statins into liver cells. Reduced-function SLCO1B1 variants can increase systemic exposure to certain statins and may increase the risk of statin-associated muscle toxicity, with the strongest established association involving simvastatin. When available, a patient’s SLCO1B1 genotype result may provide additional information for statin and dose selection. The result should be considered together with the patient’s medical history, other medications, treatment plan, and clinical response.
But tolerability is only one part of the story.
Another important gene is PCSK9. The protein encoded by this gene is an important component of normal cholesterol homeostasis, regulating plasma LDL cholesterol levels by controlling LDL receptor degradation within liver cells. These receptors play a central role in controlling blood cholesterol levels by binding LDL particles, the primary carriers of cholesterol in circulation. PCSK9 binds to LDL receptors and directs them toward degradation, reducing the number of receptors available to return to the liver cell surface.
Gain-of-function variants in the PCSK9 gene result in enhanced PCSK9 protein activity, increased degradation of LDL receptors, and thus fewer LDL receptors on the surface of liver cells. As a result, fewer LDL receptors are available to remove LDL cholesterol from the bloodstream, leading to persistently elevated LDL cholesterol levels. Because statins lower LDL cholesterol in part by increasing LDL receptor expression, enhanced PCSK9 activity can reduce the number of receptors available for LDL clearance, contributing to persistently elevated LDL cholesterol levels.
The development of PCSK9 inhibitors was driven by a landmark genetic discovery linking PCSK9 to autosomal dominant familial hypercholesterolemia (1). Researchers found that PCSK9 gain-of-function variants were associated with substantially elevated LDL cholesterol levels and hypercholesterolemia (1,2), whereas reduced-function variants were associated with lifelong reductions in LDL cholesterol and a markedly lower risk of coronary heart disease, without apparent adverse health effects (3,4). Collectively, these discoveries established the biological foundation for the development of PCSK9 inhibitor therapies to lower LDL cholesterol and reduce cardiovascular risk.
SLCO1B1 and PCSK9 illustrate two complementary forms of genomic actionability. Pharmacogenomic information can contribute to medicine in different ways. Some findings, such as SLCO1B1 results, may help clinicians select an appropriate statin and dose while considering the risk of statin-associated muscle symptoms. Other findings, such as those involving PCSK9, may identify disease mechanisms and support the development of therapeutic targets without independently determining whether a particular medication should be prescribed. Together, they illustrate how human genomics information can contribute to understanding medication response, inherited disease mechanisms, and the discovery of therapeutic targets.
SLCO1B1 answers one question: Could this patient’s genotype provide information relevant to statin selection or dosing?
PCSK9 answers another: Could this patient’s genotype help explain inherited high cholesterol and provide context for therapies that target the PCSK9 pathway?
This illustrates the value of genomic medicine. Rather than providing a single answer, genomic information can generate insights that may guide clinical decision-making, from identifying genetic factors that may influence the risk of adverse drug reactions to improving our understanding of disease biology and potential therapeutic targets. Published evidence demonstrates that certain PCSK9 gain-of-function variants may cause familial hypercholesterolemia; however, a PCSK9 genotype alone does not determine eligibility for, or expected response to PCSK9-targeting therapy. Clinical decisions also consider factors such as the patient’s diagnosis, LDL cholesterol level, cardiovascular risk, and response to previous treatments. When supported by appropriate evidence and interpreted within the broader clinical context, genomic insights may contribute to a more individualized approach to patient care.
References
1. Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003 Jun;34(2):154-6. doi: 10.1038/ng1161. PMID: 12730697.
2. Elguindy A, Yacoub MH. The discovery of PCSK9 inhibitors: A tale of creativity and multifaceted translational research. Glob Cardiol Sci Pract. 2013 Dec 30;2013(4):343-7. doi: 10.5339/gcsp.2013.39. PMID: 24749106; PMCID: PMC3991204.
3. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005 Feb;37(2):161-5. doi: 10.1038/ng1509. Epub 2005 Jan 16. Erratum in: Nat Genet. 2005 Mar;37(3):328. PMID: 15654334.
4. Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL, Cohen JC, Hobbs HH. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet. 2006 Mar;78(3):410-22. doi: 10.1086/500615. Epub 2006 Jan 20. PMID: 16465619; PMCID: PMC1380285.
Important limitations
This article is provided for scientific and educational purposes and is not medical advice or a substitute for professional clinical judgment. The clinical significance of a genomic finding depends on the specific variant, its classification, the strength of the supporting evidence, the medication and dose involved, and the patient’s clinical circumstances. Not every variant in SLCO1B1 or PCSK9 is clinically meaningful or actionable. An SLCO1B1 result may provide information relevant to statin selection or dosing but does not independently predict whether an individual will experience muscle symptoms. A PCSK9 result may provide information about inherited cholesterol biology, but a PCSK9 genotype alone does not determine eligibility for or predict response to PCSK9-targeting therapy. Treatment decisions should be made by a qualified healthcare professional using current prescribing information, clinical guidelines, and the patient’s complete clinical history. References to genes, variants, and therapies illustrate published scientific concepts and should not be interpreted as claims regarding the performance or intended use of any particular laboratory test.