Lack of association between SLCO1B1 polymorphisms and clinical myalgia following rosuvastatin therapy

doi:10.1016/j.ahj.2013.01.025

American Heart Journal

Volume 165, Issue 6, June 2013, Pages 1008-1014

https://doi.org/10.1016/j.ahj.2013.01.025 Get rights and content

Background

Carriers of the rs4363657C and rs4149056C alleles in SLCO1B1 have increased myopathic complaints when taking simvastatin. Whether rosuvastatin has a similar effect is uncertain. This study assesses whether SLCO1B1 polymorphisms relate to clinical myalgia after rosuvastatin therapy.

Methods

In the JUPITER trial, participants without prior cardiovascular disease or diabetes who had low-density lipoprotein cholesterol <130 mg/dL and C-reactive protein ≥2 mg/L were randomly allocated to rosuvastatin 20 mg or placebo and followed for the first cardiovascular disease events and adverse effects. We evaluated the effect of rs4363657 and rs4149056 in SLCO1B1, which encodes organic anion–transporting polypeptide OATP1B1, a regulator of hepatic statin uptake, on clinically reported myalgia.

Results

Among 4,404 participants allocated to rosuvastatin, clinical myalgia occurred with a rate of 4.1 events per 100 person-years as compared with 3.7 events per 100 person-years among 4,378 participants allocated to placebo (hazard ratio [HR] 1.13, 95% CI 0.98-1.30). Among those on rosuvastatin, there were no differences in the rate of myalgia among those with the rs4363657C (HR 0.95, 95% CI 0.79-1.14 per allele) or the rs4149056C allele (HR 0.95, 95% CI 0.79-1.15 per allele) compared with those without the C allele. Similar null data were observed when the myalgia definition was broadened to include muscle weakness, stiffness, or pain. None of the 3 participants on rosuvastatin or the 3 participants on placebo with frank myopathy had the minor allele at either polymorphism.

Conclusion

There appears to be no increased risk of myalgia among users of rosuvastatin who carry the rs4363657C or the rs4149056C allele in SLCO1B1.

Section snippets

Methods

Details of JUPITER, a randomized, double-blind, placebo controlled trial evaluating rosuvastatin 20 mg in the prevention of first-ever cardiovascular events among men and women free of diabetes or prior cardiovascular disease (NCT00239681) that was conducted between 2003 and 2008 in 26 countries, have been presented elsewhere.⁸ The primary eligibility criteria for JUPITER were a low level of low-density lipoprotein cholesterol (LDL-C) (<130 mg/dL) and an elevated level of high sensitivity

Results

As anticipated and consistent with prior data (dbSNP Build 135),¹³ the MAFs for both SLCO1B1 variants were lower among self-reported black participants (MAF 0.05 for rs4363657, MAF 0.01 for rs4149056) than among white participants (MAF 0.18 for rs4363657, MAF 0.17 for rs4149056). Thus, as specified on an a priori basis to avoid issues of population stratification, we conducted our analysis among white participants only.

Among those allocated to rosuvastatin, there were 417 participants who had

Discussion

Prior data indicate that myalgia and rhabdomyolysis occur with greater frequency among participants receiving simvastatin who carry specific genetic polymorphisms in the SLCO1B1 gene.1, 2 Among those allocated to 80 mg of simvastatin in the SEARCH Study, those with the rs4363657 C and rs4149056 C alleles had 4-fold higher risk of severe myopathy with increasing carriage of the rare allele and a 17-fold higher risk when comparing the rarer CC to the more common TT homozygotes.¹ Similarly, in

Acknowledgements

This research was supported by research funds from AstraZeneca to P.M.R. and D.I.C. Dr Danik has received support from the National Heart, Lung, and Blood Institute (HL-076443) and the American Heart Association (D005113). Dr Ridker reports that he currently or in the past 5 years has received research funding support from not-for-profit entities including the National Heart, Lung, and Blood Institute; the National Cancer Institute; the American Heart Association; the Doris Duke Charitable

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A hybrid decision tree/Markov model was developed to simulate patients post-PCI for ACS requiring antiplatelet therapy (CYP2C19 to guide antiplatelet selection), statin therapy (SLCO1B1 to guide statin selection), and anticoagulant therapy in those that develop atrial fibrillation (CYP2C9/VKORC1 to guide warfarin dose) over 12 months, 24 months, and lifetime. The primary outcome was cost (2016 US dollar) per quality-adjusted life years (QALYs) gained. Costs and QALYs were discounted at 3% per year. Probabilistic sensitivity analysis (PSA) varied input parameters (event probabilities, prescription costs, event costs, health-state utilities) to estimate changes in the cost per QALY gained.
Base-case–discounted results indicated that the cost per QALY gained was $59 876, $33 512, and $3780 at 12 months, 24 months, and lifetime, respectively, for multigene testing compared with standard of care. Single-gene testing was dominated by multigene testing at all time horizons. PSA-discounted results indicated that, at the $50 000/QALY gained willingness-to-pay threshold, multigene testing had the highest probability of cost-effectiveness in the majority of simulations at 24 months (61%) and over the lifetime (81%).
On the basis of projected simulations, multigene testing for Medicare patients post-PCI for ACS has a higher probability of being cost-effective over 24 months and the lifetime compared with single-gene testing and standard of care and could help optimize medication prescribing to improve patient outcomes.
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Evaluation of serum SLCO1B1 levels and genetic variants of SLCO1B1 rs4149056 and rs2306283 in patients with early and exudative age-related macular degeneration
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Citation Excerpt :
In recent years, an increasing number of studies have begun to explore the role of SLCO1B1 polymorphisms in statin-induced ADRs. However, the results remain inconsistent (de Keyser et al., 2014; Marciante et al., 2011; Danik et al., 2013; Carr et al., 2013; Santos et al., 2012; Brunham et al., 2012; Oshiro et al., 2010; Wilke et al., 2012; Li et al., 2012). There are also many studies analyzing SLCO1B1 gene polymorphisms associations with other pathologies.
To determine SLCO1B1 rs4149056 and rs2306283 gene polymorphisms and SLCO1B1 serum levels in patients with early and exudative age-related macular degeneration.
The study enrolled 206 patients with exudative AMD, 253 patients with early AMD and 301 control subjects. DNA was extracted from peripheral venous blood leukocytes using commercial kits. Genotyping of SLCO1B1 rs4149056 and rs2306283 was carried out using a real-time polymerase chain reaction (RT-PCR) method. Serum SLCO1B1 levels were measured using SLCO1B1 ELISA kit.
We found statistically significant differences in genotype (T/T, T/C and C/C) distribution of SLCO1B1 rs4149056 variant between the patients with exudative AMD and control group (52.4%, 47.6% and 0% vs. 64.8%, 31.6% and 13.7%, respectively, p < 0.001). Univariate binary logistic regression analysis showed that age was a risk factor for exudative AMD development. Also, T/C variant was associated with 1.9-fold increased Odds ratio of exudative AMD development under a codominant model (OR = 1.863; 95% CI: 1.290;2.689; p < 0.001). The results remained of the same statistical significance after multivariate analysis. On the other hand, C allele was associated with 1.6-fold increased odds ratio of exudative AMD development (OR = 1.563; 95% CI: 1.035;2.359; p = 0.034) only after adjustment for age. No significant associations were found in analysis of genotypes and alleles at rs2306283.
Serum SLCO1B1 concentration was significantly higher in early AMD patients than in healthy controls (median, IQR: 2.92 ng/ml, 5.01 ng/ml versus 1.26 ng/ml, 2.63 ng/ml, respectively, p = 0.025), as well as in exudative AMD patients than in controls (median, IQR: 2.72 ng/ml, 5.71 ng/ml versus 1.26 ng/ml, 2.63 ng/ml, respectively, p = 0.002). Furthermore, subjects with rs4149056 T/C genotype had higher SLCO1B1 serum levels than those with T/T genotype (median, IQR: 3.73 ng/ml, 3.14 ng/ml versus 1.23 ng/ml, 1.47 ng/ml, respectively, p = 0.037).
Our study determined that SLCO1B1 (c.521 T > C) rs4149056 T/C genotype and C allele may be associated with exudative age-related macular degeneration, as well as with elevated serum SLCO1B1 levels. Also, higher serum SLCO1B1 levels were found to be associated with early and exudative age-related macular degeneration.
Real-world pharmacogenetics of statin intolerance: effects of SLCO1B1, ABCG2, and CYP2C9 variants
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Clinical InvestigationGeneticsLack of association between SLCO1B1 polymorphisms and clinical myalgia following rosuvastatin therapy

Background

Methods

Results

Conclusion

Section snippets

Methods

Results

Discussion

Acknowledgements

J Am Coll Cardiol

Am J Hum Genet

Clin Ther

J Biol Chem

Drug Metab Pharmacokinet

Atherosclerosis

Drug Metab Pharmacokinet

J Pharm Sci

Atherosclerosis

SLCO1B1 variants and statin-induced myopathy—a genomewide study

N Engl J Med

SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid

Pharmacogenet Genomics

Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin

Clin Pharmacol Ther

High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1)

Pharmacogenetics

Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment

Clin Pharmacol Ther

Influence of OATP1B1 genotype on the pharmacokinetics of rosuvastatin in Koreans

Clin Pharmacol Ther

Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein

N Engl J Med

A randomized trial of rosuvastatin in the prevention of venous thromboembolism

N Engl J Med

Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial

Circulation

Clinical Investigation
Genetics
Lack of association between SLCO1B1 polymorphisms and clinical myalgia following rosuvastatin therapy