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Disclaimer: This article is for informational purposes only and is not intended for diagnostic use. LifeDNA does not provide diagnostic reports on any traits discussed. Genetics is just one piece of the puzzle; please consult a healthcare professional for comprehensive guidance on any health condition.
Statins are among the most widely prescribed drugs globally. Statins are used to lower blood cholesterol levels and reduce the risk of cardiovascular disease. Despite their broad usage and proven efficacy, not everyone responds to statins in the same way. Genetic differences among individuals play a key role in determining how well statins work, how they are metabolized, and the risk of side effects. Understanding the genetic response to statins is a step toward more personalized and effective treatments for cardiovascular health.
The primary goal of statins is to reduce blood cholesterol levels.
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Cholesterol is made in the liver through a step-by-step chemical process that starts with a molecule called acetyl-CoA. Acetyl-CoA comes from the breakdown of fats and sugars. These molecules are combined and processed through a pathway called the mevalonate pathway.Â
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A key step in this process is controlled by an enzyme called HMG-CoA reductase. HMG-CoA reductase helps convert acetyl-CoA into mevalonate. Mevalonate is an early form (precursor) of cholesterol. From there, the body goes through several more steps to finally produce cholesterol. Cholesterol is an important component of cell membranes- the outermost layer of our cells. Cholesterol is also the starting point to make hormones, like testosterone and estrogen, and vitamin D.
However, as we all know by now, excess cholesterol, especially in the form of low-density lipoprotein (LDL) cholesterol, often called “bad cholesterol,” can build up in the walls of your arteries over time. This buildup forms plaques that narrow the arteries and make them stiff. This condition is called atherosclerosis. If a plaque breaks open, your body treats it like an injury and sends platelets to the area. The platelets form a clot. This clot can block blood flow and lead to a heart attack or stroke. So, while cholesterol is essential for your body, having too much of it in the wrong places can seriously increase the risk of cardiovascular disease.
Statins function by inhibiting HMG-CoA reductase. By blocking this enzyme, statins reduce levels of LDL. Lowering LDL levels helps prevent the buildup of plaques in arteries, thus reducing the risk of heart attack and stroke.
Several genetic studies have reported that around 9% of the treatment effect of statins can be explained by genetic variations. Several genetic markers have been shown to influence our response to statins.Â
The SLCO1B1 gene encodes a liver transporter protein. This protein helps statins enter liver cells where they exert their effect. A common variant, SLCO1B1 c.521T>C (rs4149056), reduces the function of this transporter, leading to increased blood levels of statins like simvastatin. Increased levels of statin in the blood can heighten the risk of statin-associated muscle symptoms (SAMS), including myopathy and, rarely, rhabdomyolysis.
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A 2012 case-controlled study researchers studied over 5,000 older adults who took either statin pravastatin or a placebo for about three years. They focused on specific gene variations in LXRA and SLCO1B1. They found that the SLCO1B1 variant rs4149056-C, was also linked to a weaker response to the drug. And people with this variant had a smaller drop in LDL cholesterol compared to those without it.Â
This gene encodes an enzyme that is involved in the metabolism of statins like atorvastatin, simvastatin, and lovastatin. Variations in this gene can alter how quickly statins are cleared from the body. Reduced-function alleles (such as CYP3A5*3) can result in higher plasma statin concentrations, increasing the risk of side effects but potentially enhancing efficacy.
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A 2021 systematic review analyzed data from eight studies involving 1,614 patients to examine whether the specific genetic variation CYP3A5*3, is linked to a reduced enzyme function and increased statin levels in the blood. The analysis found that individuals with the CYP3A5 *3/*3 genotype had a 1.4 times higher risk of experiencing statin-related side effects compared to those with other genotypes.Â
The ABCG2 gene encodes a transporter protein involved in drug clearance from the body. The rs2231142 (Q141K) variant is associated with higher statin concentrations in plasma, especially rosuvastatin, and may influence both efficacy and side effect profiles.
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A 2024 systematic review analysed 15 studies involving over 34,000 people found that a specific genetic variant, the A-allele of ABCG2 rs2231142, affects cholesterol levels and statin response. People with this variant tend to have lower “good” HDL cholesterol and higher “bad” LDL and total cholesterol. However, in Asian individuals with high cholesterol (dyslipidemia), this same variant makes the statin rosuvastatin work more effectively at lowering lipid levels. The study suggests that this genetic difference has the most impact in Asian populations and that using rosuvastatin preventively in those with the variant could help lower the risk of developing coronary artery disease.
Statin intolerance refers to the inability to tolerate statin medications, usually due to side effects that make continued use difficult or impossible. The most common symptoms are muscle-related, such as pain, weakness, or cramps (known as statin-associated muscle symptoms or SAMS). In some cases, people may also experience liver enzyme abnormalities, digestive issues, or headaches. It often leads to patients stopping the medication or reducing the dose, which may increase their risk of heart disease if cholesterol levels are not well managed by other means.
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Genetic testing, particularly for SLCO1B1 variants, is being increasingly used to predict the risk of statin-associated side effects. For example, a 2023 study showed that people with the SLCO1B1 c.521C/C genotype are more likely to have problems with simvastatin.
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The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides guidelines for tailoring statin therapy based on SLCO1B1 genotype.
Pharmacogenomic testing isn’t yet standard for all statin prescriptions, but its utility is growing. Patients with a history of side effects or those requiring high-intensity therapy could particularly benefit. Integrating genetic data with clinical information, such as age, liver and kidney function, and other medications, can help clinicians make more informed choices about which statin to prescribe, at what dose, and with what monitoring.
The genetic response to statins is a compelling example of how genomic insights can refine and personalize medicine. Variants in genes such as SLCO1B1, CYP3A4, CYP3A5, and ABCG2 can significantly influence how patients metabolize and respond to statins, affecting both efficacy and safety. As pharmacogenomic tools become more accessible and cost-effective, they are likely to become an integral part of routine cardiovascular care—ensuring that the right patient gets the right statin at the right dose.
