Muscle aches are the most common reason people stop taking statins. A common variant in SLCO1B1, the liver transporter that pulls statins out of the bloodstream, is linked to higher statin levels and higher myopathy risk.
Statins are cholesterol-lowering medicines and among the most prescribed drugs in the world. They work well and they prevent cardiovascular disease. Their most common side effect is muscle-related — collectively called statin-associated musculoskeletal symptoms, or SAMS. This matters more than "a bit of muscle ache" suggests, because muscle symptoms are a leading reason people stop taking statins, and stopping means losing the cardiovascular protection the drug was prescribed for.
SAMS covers a spectrum. At the common end is myalgia — muscle pain without laboratory evidence of muscle breakdown — which affects roughly one in ten people on a statin. Less common, at roughly one in two thousand, is myopathy, where muscle damage is detectable in blood tests. Rare, at fewer than one in ten thousand, is rhabdomyolysis, severe muscle breakdown that can injure the kidneys. Most of these cases appear to depend on how much statin is circulating in the body — which is exactly where genetics enters the picture.
The transporter. The gene SLCO1B1 encodes a protein usually called OATP1B1, which sits on liver cells and pulls statins out of the bloodstream and into the liver. The liver is where statins are meant to act, so this transporter is doing two jobs at once: delivering the drug to its site of action, and clearing it from general circulation. When the transporter works less well, more statin stays in the blood and reaches other tissues, including muscle. That elevated systemic exposure is the leading explanation for the link between this gene and muscle symptoms.
The variant on this page, rs4149056, changes a single amino acid in the transporter and reduces its function. It is the most studied variant in the gene. Its significance became clear in a 2008 genome-wide study of patients on a high dose of simvastatin, which found a strong association with myopathy: the odds of myopathy rose several-fold per copy of the reduced-function version, and were substantially higher again in people carrying two copies compared with those carrying none. That study reported the variant at about 15% in the population it examined, and more than 60% of the myopathy cases in it were attributable to the variant.
What the guideline addresses. There is a formal, published clinical guideline on this — from CPIC, covering SLCO1B1 along with two other genes, ABCG2 and CYP2C9, and all the commonly used statins. Two things about it are worth understanding correctly. First, it is a guide for choosing which statin and what intensity when genetic results are already available; it does not tell clinicians whether to order genetic testing in the first place. Second, and importantly, the guideline is explicit that statin therapy should not be stopped or avoided on the basis of these genotypes in someone who has an indication for a statin. The point of the genetics is to help pick an option that is better tolerated so that people can stay on treatment — not to talk anyone out of it.
The other two genes play narrower roles. ABCG2 encodes a different transporter and is relevant mainly to rosuvastatin, where a common variant is associated with substantially higher drug exposure. CYP2C9 is a metabolising enzyme relevant mainly to fluvastatin. MyGeneLog currently reports the SLCO1B1 variant only.
A note on interpretation: not all muscle pain in someone taking a statin is caused by the statin. Clinical trials that compare statins with placebo find lower rates of muscle complaints than everyday practice does, and a nocebo effect — symptoms arising from the expectation of side effects — is part of that gap. There is also a distinct, uncommon autoimmune muscle condition involving antibodies against HMGCR that is a separate entity from the concentration-dependent muscle symptoms discussed here.
This page is educational and is not medical advice. It contains no dosing information and should not be used to start, stop, switch, or change the dose of any statin. Muscle symptoms while taking a statin are worth raising with the prescriber or pharmacist managing the therapy, who can weigh them against the cardiovascular benefit of continuing.
Guideline. Cooper-DeHoff RM, Niemi M, Ramsey LB, et al. The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms. Clin Pharmacol Ther. 2022;111(5):1007-1021 (PMID 35152405). This document replaces both the 2012 CPIC guideline for SLCO1B1 and simvastatin-induced myopathy and its 2014 update, extending coverage to ABCG2 and CYP2C9 and to all statins. It remains the current CPIC statin guideline. Its recommendations are based on the effect of genetic variation on SAMS risk, and it is framed as guidance for statin and dose selection when pharmacogenetic results are available — not as guidance on whether to test.
Mechanism. SLCO1B1 (solute carrier organic anion transporter family member 1B1; protein also known as OATP1B1 or OATP-C) mediates hepatic uptake of all statins as well as endogenous substrates including bilirubin. Decreased transporter function — whether inherited or acquired through drug-mediated inhibition — can markedly increase systemic statin exposure, which the guideline identifies as the putative causal factor underlying the link to SAMS. The gene locus spans about 109 kb at 12p12.2.
Allele nomenclature. rs4149056 is c.521T>C, producing p.Val174Ala. It is contained within the SLCO1B1*5 and *15 haplotypes. The *17 designation no longer exists — PharmVar has merged it into *15 — so older reports and literature citing *17 should be read accordingly. The minor C allele is associated with decreased transport function in vitro and increased systemic exposure to several drugs in vivo. CPIC states that all SLCO1B1 genetic tests should interrogate c.521T>C.
Phenotype assignment (CPIC, Table 1). SLCO1B1 predicted phenotypes are assigned from star-allele diplotypes, with no activity score: increased function — two increased-function alleles (e.g. *14/*14); normal function — two normal-function alleles or one normal plus one increased (e.g. *1/*1, *1/*14); decreased function — one normal or increased-function allele plus one no-function allele (e.g. *1/*5, *1/*15); possible decreased function — one no-function allele plus one uncertain/unknown-function allele (e.g. *5/*6, *15/*10); poor function — two no-function alleles (e.g. *5/*5, *5/*15, *15/*15); and indeterminate — one normal-function allele plus one uncertain/unknown, or combinations of uncertain/unknown alleles.
SAMS definitions and background rates. The guideline stratifies SAMS as myalgia — pain without evidence of muscle degradation, creatine kinase below three times normal — at roughly 1 in 10; myopathy — evidence of muscle degradation with or without myalgia, CK at or above three times normal — at roughly 1 in 2,000; and rhabdomyolysis — severe muscle damage with risk of acute kidney injury — at fewer than 1 in 10,000. Most SAMS cases are considered statin concentration-dependent, based on extrapolation from dose-response and drug-drug interaction data. Autoimmune-mediated necrotising myopathy with anti-HMGCR autoantibodies is explicitly excluded from the guideline's definition of SAMS. The guideline also notes that observed SAMS frequency in practice exceeds that in blinded placebo-controlled trials, attributable to differences in enrolled populations, trial run-in periods, and a potential nocebo effect.
Key clinical validity evidence. SEARCH Collaborative Group; Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy — a genomewide study. N Engl J Med. 2008;359(8):789-799 (PMID 18650507). A GWAS of 85 cases with definite or incipient myopathy versus 90 controls, all on simvastatin 80 mg daily within a 12,000-participant trial, yielded a single strong association at rs4363657 in SLCO1B1 (P = 4x10-9), in near-complete linkage disequilibrium (r² = 0.97) with the non-synonymous rs4149056. The odds ratio for myopathy was 4.5 (95% CI 2.6-7.7) per copy of the C allele and 16.9 (95% CI 4.7-61.1) for CC versus TT homozygotes; more than 60% of myopathy cases were attributable to the C variant, and the association replicated in a 20,000-participant trial of simvastatin 40 mg daily.
Scope of evidence across genes. CPIC found the highest levels of evidence for SLCO1B1 across all statins, ABCG2 for rosuvastatin, and CYP2C9 for fluvastatin, and these form the basis of the therapeutic recommendations. No recommendations are provided for CYP3A4, CYP3A5 or HMGCR on the grounds of weak evidence and lack of conclusive genotype-based action.
Population frequency. 1000 Genomes Phase 3 (Ensembl) frequency of the c.521C decreased-function allele: EUR 0.161, AMR 0.134, EAS 0.123, SAS 0.043, AFR 0.014 — consistent with the roughly 15% prevalence reported in the SEARCH cohort.
Regulatory status. The FDA's Table of Pharmacogenetic Associations places SLCO1B1 with simvastatin in Section 2 (associations with potential impact on safety or response), describing 521 TC or CC as intermediate or poor function transporters resulting in higher systemic concentrations and higher myopathy risk, with risk greater at the 80 mg dose than at lower doses. SLCO1B1 with atorvastatin and with rosuvastatin appears in Section 3 (associations that may affect pharmacokinetic properties only), for 521 CC.
Incidental findings. SLCO1B1 variation also influences hepatic uptake of other substrates including methotrexate, and of endogenous compounds including bilirubin; combined complete SLCO1B1 and SLCO1B3 deficiency is associated with Rotor syndrome.
No dosing guidance is given on this page. CPIC's own position is that statin therapy should neither be discontinued nor avoided on the basis of SLCO1B1, ABCG2 or CYP2C9 genotype in patients with an indication for statin therapy.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Statin-Associated Muscle Symptoms and SLCO1B1 comes down to these specific, well-studied positions — not a diagnosis.
Research-derived gene–drug associations only — not a prescription, dosing guide, or medical advice. Always follow your prescriber's guidance.
| Gene | Drug | What the research shows |
|---|---|---|
| SLCO1B1 | Statins (simvastatin, atorvastatin, lovastatin, pravastatin, pitavastatin, rosuvastatin, fluvastatin) | SLCO1B1 encodes OATP1B1, the liver transporter that takes statins up from the blood into liver cells. Reduced transporter function leaves more statin circulating in the body, which CPIC identifies as the likely reason for the link to statin-associated musculoskeletal symptoms. The rs4149056 (c.521T>C, p.Val174Ala) variant is the main decreased-function change and is carried within the *5 and *15 haplotypes. CPIC assigns phenotypes of increased function, normal function, decreased function, possible decreased function, poor function and indeterminate, based on the combination of alleles a person carries. A 2008 genome-wide study of patients on high-dose simvastatin found myopathy odds of 4.5 per copy of the C allele and 16.9 for two copies versus none. CPIC states that statin therapy should not be stopped or avoided because of these genotypes in someone who has an indication for a statin. No dosing information is given here. (CPIC Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms. Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022;111(5):1007-1021 (PMID 35152405); SEARCH Collaborative Group, N Engl J Med. 2008;359(8):789-799 (PMID 18650507).) |
| ABCG2 | Rosuvastatin | ABCG2 encodes BCRP, an efflux transporter that moves compounds out of cells and shapes how rosuvastatin is absorbed and distributed. The common rs2231142 (c.421C>A, p.Gln141Lys) variant is associated with reduced protein expression, and rosuvastatin exposure has been reported as substantially higher in people with two copies than in those with none. CPIC assigns normal, decreased and poor function phenotypes for this gene and its recommendations for it are specific to rosuvastatin. Not currently reported by MyGeneLog. (CPIC Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms. Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022;111(5):1007-1021 (PMID 35152405).) |
| CYP2C9 | Fluvastatin | CYP2C9 is a metabolising enzyme, and among the statins its genetic variation is relevant mainly to fluvastatin, where reduced-function alleles are associated with increased drug exposure. CPIC classifies CYP2C9 into normal, intermediate and poor metabolizer phenotypes using an activity score derived from the person's two alleles. The pharmacokinetics of the other statins are not meaningfully affected by CYP2C9 variation. Not currently reported by MyGeneLog. (CPIC Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms. Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022;111(5):1007-1021 (PMID 35152405).) |
They are a spectrum. Myalgia — muscle pain with no laboratory sign of muscle breakdown — is the common form, affecting roughly one in ten people taking a statin. Myopathy, where muscle damage shows up in blood tests, is far less common at roughly one in two thousand. Rhabdomyolysis, severe muscle breakdown that can injure the kidneys, is rare at fewer than one in ten thousand.
SLCO1B1 encodes OATP1B1, a transporter on liver cells that pulls statins out of the bloodstream and into the liver. When that transporter works less efficiently, more statin remains in general circulation and reaches tissues including muscle. CPIC identifies that increased systemic exposure as the likely reason reduced-function variants are linked to muscle symptoms.
No — and CPIC says so explicitly. The guideline states that statin therapy should neither be discontinued nor avoided on the basis of SLCO1B1, ABCG2 or CYP2C9 genotype in a person who has an indication for a statin. The purpose of the genetics is to help a clinician choose an option a person is more likely to tolerate, so treatment can continue. This page contains no dosing information and is not medical advice; muscle symptoms are worth raising with your prescriber or pharmacist.
All of them. The original 2012 CPIC guideline and its 2014 update were limited to SLCO1B1 and simvastatin. The 2022 guideline replaced both and extended coverage to simvastatin, atorvastatin, lovastatin, pravastatin, pitavastatin, rosuvastatin and fluvastatin, and added the genes ABCG2 (relevant to rosuvastatin) and CYP2C9 (relevant to fluvastatin).
Not necessarily. Muscle pain is common in the general population, and CPIC notes that SAMS is reported more often in everyday practice than in blinded placebo-controlled trials — differences in the patients enrolled, trial run-in periods, and a nocebo effect all contribute. There is also a distinct autoimmune muscle condition involving antibodies against HMGCR that the guideline treats as a separate entity. Working out the cause of muscle symptoms is a clinical assessment, not something a genotype settles.
Free to reuse. This page's text is original writing from freely-available research, licensed CC BY 4.0 — reuse it, including commercially, with attribution to MyGeneLog. It's general research-derived information, not medical advice or a diagnosis — see Terms of Use.