Late response to rosuvastatin and statin-related myalgia due to SLCO1B1, SLCO1B3, ABCB11, and CYP3A5 variants in a patient with Familial Hypercholesterolemia: a case report

Abstract

Statins are the most widely used cholesterol-lowering drugs for cardiovascular diseases prevention.However, some patients are refractory to treatment, whereas others experience statin-related adverse events (SRAE). It has been increasingly important to identify pharmacogenetic biomarkers for predicting statin response and adverse events. This case report describes a female patient with familial hypercholesterolemia (FH) who showed late response to rosuvastatin and experienced myalgia on statin treatment. In the first visit (V1), the patient reported myalgia to rosuvastatin 40 mg, which was interrupted for a 6-week wash-out period. In V2, rosuvastatin 20 mg was reintroduced, but her lipid profile did not show any changes after 6 weeks (V3) (LDL-c: 402 vs. 407 mg/dL). Her lipid profile markedly improved after 12 weeks of treatment (V4) (LDL-c: 208 mg/dL), suggesting a late rosuvastatin response. Her adherence to treatment was similar in V1 and V3 and no drug interactions were detected. Pharmacogenetic analysis revealed that the patient carries low-activity variants in SLCO1B1*1B and*5, SLCO1B3 (rs4149117 and rs7311358), and ABCB11 rs2287622, and the non-functional variant in CYP3A5*3. The combined effect of variants in pharmacokinetics-related genes may have contributed to the late response to rosuvastatin and statin-related myalgia. Therefore, they should be considered when assessing a patient's response to statin treatment. To the best of our knowledge, this is the first report of a pharmacogenetic analysis on a case of late rosuvastatin response.

Association Study of SLCO1B3 and ABCC3 Genetic Variants in Gallstone Disease

“…The SLCO1B3 gene rs4149117 and rs7311358 polymorphisms have been shown to affect the efficacy of statin treatment in patients with hypercholesterolemia. Additionally, these polymorphisms are associated with an increased risk for acute rejection and allograft failure in lung transplant recipients treated with mycophenolic acid [ 31 , 32 ]. To date, the above polymorphisms have not been investigated in relation to diseases of the liver and the gastrointestinal tract.…”

Pharmacogenomics Variability of Lipid-Lowering Therapies in Familial Hypercholesterolemia

“…Mutations in the ATP-binding cassette transmembrane mediator (ABC) have been significantly correlated with impaired efflux of statins as well as cholesterols from cells. The attenuated activity of ABCA1, ABCA11, and ABCG2 was found to reduce the excretion of statin and increase its intrahepatic levels, thereby increasing hepatotoxicity as well as myopathy to statin adverse consequences [41,52]. Oral lipid-antagonists enter the circulatory system via the enteric SLC and ABC gene-transporters.…”

“…The hepatic absorption of statins is mediated primarily by the solute carrier organic anion transporter 1B1 (encoded via SLCO1B1 ). Loss-of-function SLCO1B1 *5 (c.521T>C) and SLCO1B1 *1B (c.388A>G) SNPs remarkably diminish plasma LDL-C transporting to the liver and raise the systemic exposure to statin [ 52 ]. This results in a greater incidence of rhabdomyolysis risk and a negligible cholesterol optimizing effect.…”

“…The byproduct of these enzymes has a principal role in inhibiting the HMGR protein, indirectly promoting statin effectiveness. Therefore, nonfunctional CYP3A5*3 mutations were reported to lower the rosuvastatin efficacy in decreasing the LDL-C [ 52 ]. On the contrary, Rosales et al have reported that CYP3A4 polymorphism rs2740574 (-290A>G) enhances atorvastatin therapeutic response in subjects with FH [ 44 ].…”

Genetic Variant ABCC1 rs45511401 Is Associated with Increased Response to Statins in Patients with Familial Hypercholesterolemia

“…SLCO1B1 rs2306283 (c.388A>G), for example, was associated with a more pronounced reduction in LDL-c after treatment with atorvastatin and may be a predictor of therapeutic response [ 15 ]. We also recently found that SLCO1B1*15 and variants in SLCO1B3 and ABCB11 delayed rosuvastatin response in an FH patient, without jeopardizing LDL-c reduction after 12 weeks of treatment [ 16 ]. Furthermore, variants in drug-metabolizing enzymes, such as CYP3A4*22 , have been associated with higher LDL-c reduction [ 17 ], whereas our group reported that CYP3A5*3 (rs776746) was associated with a lower reduction in total cholesterol, LDL-c, and HDL cholesterol (HDL-c) [ 18 ].…”