SLCO1B1 rs4149056: Statin Exposure and Muscle Safety
The rs4149056 single-nucleotide polymorphism is a well-characterized missense variant within the SLCO1B1 gene, located on chromosome 12. Carrying the minor C allele impairs a hepatic influx transporter, leading to reduced hepatic uptake and elevated systemic circulating levels of certain statin medications. As a result, population studies and clinical guidelines link this variant to an increased risk of statin-associated muscle symptoms and toxicity, particularly with high-dose simvastatin.
What each genotype means
Normal transporter function
This genotype is considered the wild-type or normal function profile for the SLCO1B1 gene. Individuals with this profile typically have standard hepatic uptake of statin medications, which is associated with a lower risk of statin-induced muscle toxicity compared to those carrying the C allele. Please discuss your medication options and any muscle-related symptoms with your clinician or pharmacist.
This is the most common genotype across most global populations.
Reduced transporter function
This genotype, often referred to as carrying one copy of the *5 allele, is associated with reduced hepatic uptake of certain statins, particularly simvastatin. Research indicates this may lead to higher systemic exposure to the drug and an increased risk of muscle-related side effects. You should discuss your specific statin dosage or alternative medication options with your healthcare provider.
Carried by a significant portion of the population, with a minor allele frequency of approximately 15% in Europeans and 10-15% in East Asians.
Significantly reduced transporter function
This genotype, representing two copies of the *5 allele, is associated with a marked reduction in the function of the OATP1B1 transporter, which can significantly increase systemic exposure to certain statins like simvastatin. Clinical guidelines identify this profile as having the highest risk for statin-induced myopathy. It is important to consult with your clinician or pharmacist regarding appropriate statin dosing or the selection of alternative lipid-lowering therapies.
This is the least common genotype, occurring in a small percentage of individuals across most ancestries.
Molecular Profile: What rs4149056 Represents
The single-nucleotide polymorphism rs4149056 is a coding variant located within exon 5 of the SLCO1B1 gene on chromosome 12 (12p12.2). At the cDNA level, it is characterized by a thymine-to-cytosine substitution at nucleotide position 521 (c.521T>C). In the resulting protein, this nucleotide change causes an amino acid substitution from valine to alanine at residue 174 (p.Val174Ala). In pharmacogenomic star-allele nomenclature cataloged by resources like [PharmGKB](https://www.pharmgkb.org/gene/PA134865839), rs4149056 defines the key functional core of the SLCO1B1 *5 allele and is also a major component of compound star haplotypes such as *15, *16, and *17. The functional consequence of this missense change is a notable reduction in transporter trafficking or intrinsic uptake activity at the cell membrane of human hepatocytes.
The Biological Role of the SLCO1B1 Transporter
The SLCO1B1 gene encodes the organic anion transporting polypeptide 1B1 (OATP1B1), an influx transport protein predominantly expressed on the sinusoidal (basolateral) membrane of hepatocytes in the liver. OATP1B1 plays an essential role in hepatic clearance by extracting an array of endogenous compounds—such as unconjugated bilirubin, bile acids, and thyroid hormones—as well as numerous medications from portal blood into the liver tissue. Statins, including simvastatin, atorvastatin, and pravastatin, are prime therapeutic substrates of this transport system. Because statins exert their therapeutic cholesterol-lowering effects inside hepatocytes by inhibiting HMG-CoA reductase, hepatic uptake is necessary both for drug efficacy and for first-pass metabolic elimination. When transport efficiency drops, less drug enters the hepatocyte, leaving larger quantities of active drug circulating through peripheral blood and tissues.
Evidence on Statin-Associated Muscle Toxicity
When OATP1B1 function is impaired by the rs4149056 C allele, blood plasma concentrations of sensitive statins rise considerably. Seminal genome-wide association investigations, including the SEARCH study, discovered a strong statistical link between rs4149056 and simvastatin-induced myopathy, observing an odds ratio of approximately 4.5 per copy of the minor C allele in patients receiving high-dose simvastatin (80 mg daily). Independent replications confirmed this risk profile, leading organizations like the Clinical Pharmacogenetics Implementation Consortium ([CPIC](https://cpicpgx.org/guidelines/guideline-for-statins-and-slco1b1-abcg2-and-cyp2c9/)) to issue formal dosing recommendations for simvastatin based on rs4149056 genotype. Although research has explored associations with other statins, such as atorvastatin and lovastatin, the clinical evidence is strongest for simvastatin and shows more variable or modest effects across other statin classes.
Ancestry and Population Distribution
The prevalence of the rs4149056 variant varies substantially across global populations, which shapes how frequently this pharmacogenomic interaction occurs in different communities. In European and Caucasian-descent populations, the minor C allele frequency typically ranges between 12% and 20%, meaning that approximately one in four individuals carries at least one copy of the variant. In East Asian populations, allele frequencies generally fall between 10% and 15%. In contrast, African and African American populations show substantially lower minor allele frequencies, frequently reported between 1% and 5%. Interestingly, population studies in South and Central America, including Indigenous Amerindian groups, have observed C allele frequencies exceeding 25%, highlighting how genetic architecture alters potential statin toxicity risks worldwide.
Clinical Utility and Essential Precautions
Understanding your rs4149056 genotype can provide helpful context regarding how your body processes certain medications, but genetic variation is only one piece of the puzzle. Other critical factors influencing statin safety include patient age, kidney function, thyroid status, physical exertion, specific drug doses, and interacting medications that inhibit hepatic pathways. Having a higher-risk genotype does not guarantee that you will experience muscle aches, nor does a normal genotype eliminate the risk of adverse reactions entirely. Never discontinue, initiate, or adjust statin therapy on your own based on genetic data. If you are taking or considering a statin and have questions about your genotype, consult your prescribing physician or pharmacist to discuss appropriate drug selection and monitoring.
How common is this variant?
The minor C allele is present at approximately 12% to 20% in Europeans, 10% to 15% in East Asians, and about 1% to 5% in individuals of African ancestry, while reaching over 25% in certain Indigenous American populations.
Frequently asked questions
Does having the rs4149056 C allele mean I should not take statins?
No, carrying the C allele does not mean you cannot take statins. Statins are vital medications for reducing cardiovascular risk, and many people with the C allele take them without experiencing adverse side effects. Rather than avoiding statins, clinical guidelines like CPIC suggest choosing a statin less reliant on OATP1B1 or prescribing a lower starting dose under medical supervision.
What is the difference between ordinary muscle soreness and statin myopathy?
Ordinary muscle soreness often stems from exercise, strain, or daily activities and typically resolves with rest over a few days. In contrast, true statin-associated myotoxicity tends to cause persistent, unexplained, symmetrical muscle pain, tenderness, or weakness, and in rare severe cases (rhabdomyolysis) can produce dark urine and elevated creatine kinase levels. Any persistent or severe muscle symptoms should be evaluated by a healthcare professional.
Does rs4149056 affect all statins equally?
No, the impact varies considerably depending on the specific statin. The clinical evidence for increased muscle toxicity is strongest and most established for simvastatin, which relies heavily on OATP1B1 for hepatic entry. Other statins, such as pravastatin, rosuvastatin, and atorvastatin, may show altered blood levels with this variant, but the risk of clinical myotoxicity is generally less pronounced.
Can this genetic variant affect anything other than statins?
Yes, because the OATP1B1 protein transports endogenous molecules as well as drugs, rs4149056 is associated with subtle differences in natural substances like serum bilirubin. In addition, other medications handled by OATP1B1, such as the chemotherapeutic agent methotrexate, can show altered clearance in individuals carrying the decreased-function allele.
Sources & further reading
Educational information only, last refreshed 9/5/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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This missense variant (p.Pro155Thr) is associated with reduced OATP1B1 transporter function, which can lead to increased plasma concentrations of certain statins and higher risk of myopathy.
A regulatory variant in the SLCO1B1 gene influencing statin pharmacokinetics.
Defines the c.388A>G (p.Asn130Asp) variant, which is a component of the SLCO1B1*1B and *15 haplotypes, influencing hepatic statin uptake.
Non-synonymous coding polymorphism (p.Asn130Asp) defining the SLCO1B1*30 allele with modest alteration in hepatic statin uptake.
This variant (c.521T>C) is strongly associated with decreased function of the OATP1B1 transporter, significantly increasing the risk of statin-induced myopathy.
Known as SLCO1B1*1b (p.Asn130Asp), this variant alters hepatic transporter activity and modulates statin exposure and pharmacokinetic clearance.