The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin‐Associated Musculoskeletal Symptoms

Cooper‐DeHoff, Rhonda M.; Niemi, Mikko; Ramsey, Laura B.; Luzum, Jasmine A.; Tarkiainen, E. Katriina; Straka, Robert J.; Gong, Li; Tuteja, Sony; Wilke, Russell A.; Wadelius, Mia; Larson, Eric A; Roden, Dan M.; Klein, Teri E.; Yee, Sook Wah; Krauss, Ronald M.; Turner, Richard M.; Palaniappan, Latha; Gaedigk, Andrea; Giacomini, Kathleen M.; Caudle, Kelly E.; Voora, Deepak

doi:10.1002/cpt.2557

Cited by 195 publications

(227 citation statements)

References 50 publications

(104 reference statements)

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“…The effect of SLCO1B1 c.521T>C on simvastatin-induced myopathy and rhabdomyolysis risk is well-known. [2][3][4][5] In order to mitigate the risk of myotoxicity, a simvastatin dose is advisable for patients with decreased OATP1B1 function and the use of simvastatin is best avoided in individuals with poor OATP1B1 function. The effects of SLCO1B1*14 and *20 on the clinical response to simvastatin are not known.…”

Section: Discussionmentioning

confidence: 99%

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Genomewide Association Study of Simvastatin Pharmacokinetics

Mykkänen

Taskinen

Neuvonen

et al. 2022

Clin Pharma and Therapeutics

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We investigated genetic determinants of single‐dose simvastatin pharmacokinetics in a prospective study of 170 subjects and a retrospective cohort of 59 healthy volunteers. In a microarray‐based genomewide association study with the prospective data, the SLCO1B1 c.521T>C (p.Val174Ala, rs4149056) single nucleotide variation showed the strongest, genomewide significant association with the area under the plasma simvastatin acid concentration‐time curve (AUC; P = 6.0 × 10−10). Meta‐analysis with the retrospective cohort strengthened the association (P = 1.6 × 10−17). In a stepwise linear regression candidate gene analysis among all 229 participants, SLCO1B1 c.521T>C (P = 1.9 × 10−13) and CYP3A4 c.664T>C (p.Ser222Pro, rs55785340, CYP3A4*2, P = 0.023) were associated with increased simvastatin acid AUC. Moreover, the SLCO1B1 c.463C>A (p.Pro155Thr, rs11045819, P = 7.2 × 10−6) and c.1929A>C (p.Leu643Phe, rs34671512, P = 5.3 × 10−4) variants associated with decreased simvastatin acid AUC. Based on these results and the literature, we classified the volunteers into genotype‐predicted OATP1B1 and CYP3A4 phenotype groups. Compared with the normal OATP1B1 function group, simvastatin acid AUC was 273% larger in the poor (90% confidence interval (CI), 137%, 488%; P = 3.1 × 10−6), 40% larger in the decreased (90% CI, 8%, 83%; P = 0.036), and 67% smaller in the highly increased function group (90% CI, 46%, 80%; P = 2.4 × 10−4). Intermediate CYP3A4 metabolizers (i.e., heterozygous carriers of either CYP3A4*2 or CYP3A4*22 (rs35599367)), had 87% (90% CI, 39%, 152%, P = 6.4 × 10−4) larger simvastatin acid AUC than normal metabolizers. These data suggest that in addition to no function SLCO1B1 variants, increased function SLCO1B1 variants and reduced function CYP3A4 variants may affect the pharmacokinetics, efficacy, and safety of simvastatin. Care is warranted if simvastatin is prescribed to patients carrying decreased function SLCO1B1 or CYP3A4 alleles.

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Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4] Factors increasing simvastatin exposure, such as drug interactions or genetic variation, heighten the risk for adverse effects. 1,2,4,5 In simvastatin pharmacokinetics, marked interindividual variability exists. 6 Simvastatin is an inactive lactone prodrug, which converts to pharmacologically active simvastatin acid.…”

Section: Articlementioning

confidence: 99%

Genomewide Association Study of Simvastatin Pharmacokinetics

Mykkänen

Taskinen

Neuvonen

et al. 2022

Clin Pharma and Therapeutics

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“…Recently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) conducted a systematic review and published the guideline for statin-associated with musculoskeletal symptoms, including ABCG2 421 C>A [ 29 ]. According to the CPIC guideline, a rosuvastatin dose of ≤ 20 mg is recommended as the starting dose for individuals with ABCG2 poor function due to the high exposure.…”

Section: Discussionmentioning

confidence: 99%

The Association between ABCG2 421C>A (rs2231142) Polymorphism and Rosuvastatin Pharmacokinetics: A Systematic Review and Meta-Analysis

et al. 2022

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Although several studies have revealed the association between rosuvastatin pharmacokinetics and the ABCG2 421C>A (rs2231142) polymorphism, most studies were conducted with small sample sizes, making it challenging to apply the findings clinically. Therefore, the purpose of this study is to perform a meta-analysis of the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. We searched three electronic databases, EMBASE, PubMed, and Web of Science, using search terms related to ABCG2 gene polymorphisms and rosuvastatin. In addition, we reviewed studies published before 12 August 2021, to examine the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. To examine the magnitude of the association, the log geometric mean difference (lnGM) and 95% confidence intervals (CIs) were calculated and interpreted as the antilogarithm of a natural logarithm (elnGM). The meta-analysis was performed using Review Manager (version 5.4) and R Studio (version 4.0.2). Subgroup analysis was performed according to race and the types of mean values. Among the 318 identified studies, a total of 8 studies involving 423 patients is included in this meta-analysis. The A allele carriers of ABCG2 421C>A showed 1.5 times higher in both AUC0-∞ (lnGM = 0.43; 95% CI = 0.35‒0.50; p < 0.00001) and Cmax (lnGM = 0.42; 95% CI = 0.33‒0.51; p < 0.00001) than non-carriers, while there was no significant difference in Tmax and half-life. There was no significance in the pharmacokinetic parameters of the subgroups using either ethnicity or mean values. This meta-analysis demonstrates that subjects carrying the A allele of ABCG2 421C>A show significantly increased AUC0-∞ and Cmax values compared to subjects with the CC genotype. Therefore, information about ABCG2 genotypes might be useful for individualized rosuvastatin therapy.

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“…Our data could be implemented in diverse clinical guidelines for the pharmacogenetic analysis of the CYP2C9 gene before treatment with different drugs, such as non-steroidal/anti-inflammatory drugs, warfarin, phenytoin and statins [ 28 , 29 , 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

Frequency of CYP2C9 Promoter Variable Number Tandem Repeat Polymorphism in a Spanish Population: Linkage Disequilibrium with CYP2C9*3 Allele

Dorado

Santos-Díaz²,

Gutiérrez-Martı́n

et al. 2022

JPM

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Background: A promoter variable number tandem repeat polymorphism (pVNTR) of CYP2C9 is described with three types of fragments: short (pVNTR-S), medium (pVNTR-M) and long (pVNTR-L). The pVNTR-S allele reduces the CYP2C9 mRNA level in the human liver, and it was found to be in high linkage disequilibrium (LD) with the CYP2C9*3 allele in a White American population. The aim of the present study is to determine the presence and frequency of CYP2C9pVNTR in a Spanish population, as well as analyzing whether the pVNTR-S allele is in LD with the CYP2C9*3 allele in this population. Subjects and Methods: A total of 209 subjects from Spain participated in the study. The CYP2C9 promoter region was amplified and analyzed using capillary electrophoresis. Genotyping for CYP2C9*2 and *3 variants was performed using a fluorescence-based allele-specific TaqMan allelic discrimination assay. Results: The frequencies of CYP2C9pVNTR-L, M and S variant alleles are 0.10, 0.82 and 0.08, respectively. A high LD between CYP2C9pVNTR-S and CYP2C9*3 variant alleles is observed (D’ = 0.929, r2 = 0.884). Conclusion: The results from the present study show that both CYP2C9pVNTR and CYP2C9*3 are in a high LD, which could help to better understand the lower metabolic activity exhibited by CYP2C9*3 allele carriers. These data might be relevant for implementation in the diverse clinical guidelines for the pharmacogenetic analysis of the CYP2C9 gene before treatment with different drugs, such as non-steroidal anti-inflammatory drugs, warfarin, phenytoin and statins.

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The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin‐Associated Musculoskeletal Symptoms

Cited by 195 publications

References 50 publications

Genomewide Association Study of Simvastatin Pharmacokinetics

Genomewide Association Study of Simvastatin Pharmacokinetics

The Association between ABCG2 421C>A (rs2231142) Polymorphism and Rosuvastatin Pharmacokinetics: A Systematic Review and Meta-Analysis

Frequency of CYP2C9 Promoter Variable Number Tandem Repeat Polymorphism in a Spanish Population: Linkage Disequilibrium with CYP2C9*3 Allele

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