rs4149056 — SLCO1B1 *5

SLCO1B1 - The Statin Safety Gene

SLCO1B1 encodes the organic anion transporting polypeptide 1B1 (OATP1B1), a liver uptake transporter that moves statins from the blood into liver cells where they exert their cholesterol-lowering effect. When this transporter does not work properly, statins accumulate in the blood and muscle tissue instead of entering the liver, dramatically increasing the risk of myopathy¹¹ Myopathy: disease of muscle tissue, ranging from mild pain to serious breakdown.

The Mechanism

The SLCO1B1*5 variant²² rs4149056 causes a valine-to-alanine substitution at position 174³³ Amino acid change: valine to alanine at position 174 (V174A) in a transmembrane domain of the transporter. This reduces the transporter's ability to move statins into liver cells. The C allele produces a transporter with markedly reduced function, leading to higher systemic statin exposure -- approximately 40% higher simvastatin acid levels⁴⁴ 40% higher simvastatin acid levels
CPIC guideline for SLCO1B1 in heterozygous carriers.

The SEARCH Trial

The landmark SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) trial⁵⁵ SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) trial
SEARCH Collaborative Group. NEJM, 2008 identified SLCO1B1*5 as the primary genetic determinant of statin-induced myopathy. Homozygous carriers (CC) had a 17-fold increased risk of myopathy on simvastatin 80mg (OR 16.9, 95% CI 4.7-61.1), while heterozygous carriers (CT) had a 4.5-fold increased risk (OR 4.5, 95% CI 2.6-7.7). This finding led to the FDA limiting the maximum recommended dose of simvastatin to 40mg.

Not All Statins Are Equal

The risk varies significantly by statin type. Simvastatin is the highest risk because it relies heavily on SLCO1B1 for liver uptake. Pravastatin is the safest alternative because it enters liver cells through multiple pathways and is less dependent on SLCO1B1. Rosuvastatin has intermediate risk. Atorvastatin uses SLCO1B1 but has a wider therapeutic window than simvastatin. The 2022 CPIC guideline update⁶⁶ 2022 CPIC guideline update
Cooper-DeHoff RM et al. CPIC guideline for statins and SLCO1B1, ABCG2, CYP2C9. Clin Pharmacol Ther, 2022 now covers all statins, not just simvastatin.

Practical Implications

If you carry the C allele and ever need statin therapy, this information can prevent a potentially serious adverse reaction. Statin-induced myopathy ranges from mild muscle aches to rhabdomyolysis⁷⁷ Rhabdomyolysis: severe muscle breakdown that releases proteins into the blood, potentially damaging the kidneys. Choosing the right statin and dose based on your SLCO1B1 genotype is one of the clearest wins in clinical pharmacogenomics.