Next Article in Journal
Association of Ventilatory Disorders with Respiratory Symptoms, Physical Activity, and Quality of Life in Subjects with Prior Tuberculosis: A National Database Study in Korea
Previous Article in Journal
Molecular Pathology of Cancer: The Past, the Present, and the Future
Previous Article in Special Issue
RNF8–CDH1 Co-Expression Predicts Clinical Benefit of Chemoradiotherapy in Triple-Negative Breast Cancer
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JPM
Volume 11
Issue 7
10.3390/jpm11070677
jpm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Association between CYP3A5 Polymorphism and Statin-Induced Adverse Events: A Systemic Review and Meta-Analysis

by
Jeong Yee
†,
Hamin Kim
†,
Yunhee Heo
,
Ha-Young Yoon
,
Gonjin Song
and
Hye-Sun Gwak
*
College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea
*
Author to whom correspondence should be addressed.
†
These authors equally contributed to the paper.
J. Pers. Med. 2021, 11(7), 677; https://doi.org/10.3390/jpm11070677
Submission received: 25 June 2021 / Revised: 11 July 2021 / Accepted: 17 July 2021 / Published: 19 July 2021
(This article belongs to the Special Issue Integrating Genomics into Basic and Clinical Research)
Browse Figures
Versions Notes

Abstract

:
Purpose: Cytochrome P450 (CYP) is involved in the metabolism of statins; CYP3A5 is the main enzyme responsible for lipophilic statin metabolism. However, the evidence of the association between CYP3A5*3 polymorphism and the risk of statin-induced adverse events remains unclear. Therefore, this study aimed to perform a systematic review and meta-analysis to investigate the relationship between the CYP3A5*3 polymorphism and the risk of statin-induced adverse events. Methods: The PubMed, Web of Science, and EMBASE databases were searched for qualified studies published until August 2020. Observational studies that included the association between statin-induced adverse events and the CYP3A5*3 polymorphism were reviewed. The odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated to assess the strength of the relationship. The Mantel–Haenszel method was used to provide the pooled ORs. Heterogeneity was estimated with I2 statistics and publication bias was determined by Begg’s and Egger’s test of the funnel plot. Data analysis was performed using Review Manager (version 5.4) and R Studio (version 3.6). Results: In total, data from 8 studies involving 1614 patients were included in this meta-analysis. The CYP3A5*3 polymorphism was found to be associated with the risk of statin-induced adverse events (*3/*3 vs. *1/*1 + *1/*3: OR = 1.40, 95% CI = 1.08–1.82). For myopathy, the pooled OR was 1.30 (95% CI: 0.96–1.75). The subgroup analysis of statin-induced myopathy revealed a trend, which did not achieve statistical significance. Conclusions: This meta-analysis demonstrated that the CYP3A5*3 polymorphism affected statin-induced adverse event risk. Therefore, CYP3A5 genotyping may be useful to predict statin toxicity.

1. Introduction

Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (Supplementary Materials Figure S1), are one of the most prescribed medications for both primary and secondary prevention of atherosclerotic cardiovascular events [1]. These drugs decrease cholesterol synthesis by competitively inhibiting HMG-CoA reductase, which catalyzes the conversion of HMG-CoA to mevalonate, a precursor of cholesterol [2].
The most common adverse events of statins include constipation, abdominal pain, nausea, dyspepsia, muscle pain, headache, and skin rash [3]. Although statins are generally safe and well-tolerated, some adverse events, especially muscle-related symptoms and liver toxicity, may cause statin intolerance. According to Mancini et al., almost 20–30% of patients have experienced statin intolerance [4]. As statin discontinuation can increase the risk of acute cardiovascular risk, statin adverse events and intolerance should be managed appropriately [5,6].
Advanced age, female sex, Asian ethnicity, pre-existing liver and kidney diseases, high-dose statin therapy, and drug interactions are known to be risk factors for statin intolerance [7]. In addition, recent studies have reported the pharmacogenetic features in relation to statin adverse events [8,9]. Most studies have focused on the association between the solute carrier organic anion transporter family 1B1 (SLCO1B1) gene and risk of statin-induced adverse events [10,11]. The Clinical Pharmacogenetics Implementation Consortium (CPIC) provided clinical recommendations for simvastatin-induced myopathy based on SLCO1B1 genotype [12]. Nevertheless, other genetic factors still remain to explain statin-induced adverse events.
As most statins are primarily metabolized by two members of the cytochrome P450 superfamily, CYP3A4 and CYP3A5 [13] (Supplementary Materials Figure S2), and CYP3A5*3 is one of the functionally important single-nucleotide polymorphisms (SNPs) with high allele frequency (5%, 22%, 28%, and 81% in European, American, Asian, and African populations, respectively) [14,15], it is reasonable to assume that CYP3A5*3 may influence the risk of statin-induced adverse events. Therefore, we conducted a systematic review and meta-analysis to assess the genetic association between the CYP3A5*3 polymorphism and the risk of statin-induced adverse events.

2. Methods and Materials

2.1. Literature Search Strategy and Inclusion Criteria

This meta-analysis was conducted according to the checklist outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [16]. Two reviewers independently searched for studies that had been published until August 11, 2020. An extensive search of electronic databases (PubMed, Web of Science, and EMBASE) was performed using the following search terms: (statin* OR (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor*) OR (hydroxymethylglutaryl coenzyme A reductase inhibitor*) OR (HMG-CoA reductase inhibitor*) OR atorvastatin OR cerivastatin OR crilvastatin OR fluvastatin OR lovastatin OR mevastatin OR pitavastatin OR pravastatin OR rosuvastatin OR simvastatin) AND (CYP3A5* OR (cytochrome p450 3A5) OR (cytochrome p450 3A5)) AND (polymorph* OR variant* OR mutation* OR genotyp* OR phenotyp* OR haplotyp* OR allele* OR SNP* OR pharmacogen*). There was no language limitation.
Studies were included if (i) they evaluated the association of the CYP3A5*3 polymorphism with statin-induced adverse events; (ii) they were based on observational design (cohort study, case-control, or cross-sectional study); and (iii) they provided sufficient information to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Studies were excluded if they were (i) not original articles (e.g., conference/meeting abstract, reviews, comments, letters, editorials, or protocols); (ii) in vitro or animal studies; or (iii) studies on healthy subjects. In case of overlapping data, only the most recent and comprehensive data were included in the meta-analysis.

2.2. Data Extraction and Study Quality Assessment

Two reviewers independently extracted data, and discrepancies were resolved by consensus. Extracted data included the following information: the name of the first author, publication year, country, study design, number of cases and controls, mean age, percentage of males, case definition, statins included in the analysis, and the genotyping method. Articles were assessed by two investigators based on the Newcastle–Ottawa Scale (NOS) evaluating studies in the three categories of selection, comparability, and outcome assessment [17]. The score range of NOS is from 0 to 9.

2.3. Statistical Analysis

The meta-analysis was performed using Review Manager (version 5.4; The Cochrane Collaboration, Copenhagen, Denmark). ORs and 95% CIs were used to identify the relationship between the CYP3A5*3 polymorphism and the risk of statin-induced adverse events. The Mantel–Haenszel method and Z-test were used to evaluate the significance of the pooled OR [18]. A P-value < 0.05 was considered statistically significant. The heterogeneity across studies was estimated by way of a chi-square test and an I2 statistic. Given the high heterogeneity (I2 > 75%), a random-effects model was applied [19].
Subgroup analysis was performed in patients with statin-induced myopathy. Both Begg’s rank correlation test and Egger’s regression test of the funnel plot were performed using R Studio software (version 3.6.0; R Foundation for Statistical Computing, Vienna, Austria) to detect publication bias [20,21]. To evaluate the robustness of the results, sensitivity analysis was conducted by sequentially omitting each study.

3. Results

Literature Search

A detailed flow chart of the study selection process is presented in Figure 1. A total of 458 studies were identified from searches of three databases. After removal of 144 duplicates, 314 records were initially identified, of which the titles and abstracts were screened for inclusion in this study. From this initial review, 47 studies were selected for full-text reviews and assessed for eligibility. Of these 47 studies, 39 were excluded for the following reasons: non-original articles (n = 3), pharmacokinetic studies (n = 3), studies evaluating efficacy only (n = 27), studies with healthy control groups (n = 1), studies on other genotypes (n = 3), studies unable to extract data (n = 1), and overlapping studies (n = 1). Ultimately, eight articles were selected for this systematic review [22,23,24,25,26,27,28,29].
The characteristics of the included studies are presented in Table 1. The studies were published from 2005 to 2018, and all studies were conducted on adults. Four of them were conducted in Asia, three in America, and one in Europe. There were two cohort studies and six case-control studies, with NOS scores ranging from 6 to 9.
Eight studies involving 1641 patients were evaluated to investigate the association between the CYP3A5*3 polymorphism and the risk of statin-induced adverse events. A statistically significant association was found between the CYP3A5*3 polymorphism and the risk of statin-induced adverse events (*3/*3 vs. *1/*1 + *1/*3: OR = 1.40, 95% CI = 1.08–1.82; I2 = 68%; Figure 2). In a subgroup analysis for statin-induced myopathy, the CYP3A5*3 polymorphism showed a similar trend; patients with the CYP3A5*3/*3 showed a higher risk of myopathy after statin treatment compared to the CYP3A5*3 allele carriers, although it did not achieve a statistical significance (*3/*3 vs. *1/*1 + *1/*3; OR = 1.30; 95% CI = 0.96–1.75; I2 = 64%; Figure 3). The results of Begg’s and Egger’s test did not reveal any publication bias for statin-induced adverse events (p = 0.4579 and p = 0.5325, respectively) and myopathy (p = 0.3476 and p = 0.2251, respectively) (Supplementary Materials Figure S3). The sensitivity analysis by omitting each study showed mostly similar results to that from the entire meta-analysis (OR range: 1.17–1.80). The result was stable except for excluding Shek et al. [27].

4. Discussion

In summary, our results showed that the CYP3A5*3 polymorphism increased the risk of statin-induced adverse events. Subgroup analysis showed that CYP3A5*3 tended to increase the risk of statin-induced myopathy without statistical significance, possibly because of insufficient power due to the small sample size. No significant publication bias was detected, and sensitivity analysis provided stable results except for excluding Shek et al. [27]. As the OR of CYP3A5*3 and statin-induced adverse event risk was high in the study of Shek et al. [27] and this study might largely influence the pooled data, the findings in the meta-analysis should be interpreted carefully.
Statins can induce a wide range of adverse events from mild gastrointestinal symptoms to autoimmune disorders; however, statin-induced adverse events are often dose dependent [30,31]. Most studies included in this meta-analysis investigated myopathy; the pooled estimate of the effects of CYP3A5*3 on myopathy was similar to the overall one, although it showed a marginally statistical significance. The failure to achieve statistical significance in the subgroup analysis with myopathy was attributable to two studies, which had opposite trends [24,28]. There are two studies investigating the association between CYP3A5*3 and liver injury. A study by Shek et al. [27] revealed that the CYP3A5*3 polymorphism increased the risk of hepatotoxicity (OR 9.63, 95% CI: 3.29–28.1), whereas a study by Fukunaga et al. [23] did not find significant differences (OR 1.28, 95% CI: 0.60–2.73).
Several studies investigated the effect of CYP3A inhibitors (e.g., amiodarone, itraconazole, ritonavir) on the adverse events of statins [32,33]. Similarly, grapefruit juice, which contains inhibitors of CYP3A, triggered statin-induced rhabdomyolysis [34]. The aforementioned studies suggest that the CYP3A enzyme played an important role in statin metabolisms. CYP3A5 is responsible for at least 50% of the total hepatic CYP3A content. As CYP3A5*3 is the most prevalent variant allele related to reduced enzyme activity by alternative splicing and protein truncation of the CYP3A5 protein [35], the CYP3A5 gene could be the leading genetic contributor to inter-individual differences in CYP3A-dependent drug clearance and responses.
Several meta-analyses have been performed to examine the association between CYP3A5*3 polymorphism and drug responses. A meta-analysis on the association between CYP3A5*3 and tacrolimus response in kidney transplant recipients revealed that CYP3A5*1 allele carriers had a higher risk of acute rejection and chronic nephrotoxicity than CYP3A5*3/*3 carriers. The plasma concentration divided by the daily dose per body weight was significantly lower among CYP3A5*1 allele carriers compared with CYP3A5*3/*3 carriers [36]. Similar results were found in other meta-analyses in renal transplant recipients treated with cyclosporine; CYP3A5*3 polymorphism was found to be associated with the cyclosporine dose-adjusted concentration. Patients carrying the CYP3A5*3/*3 genotype required a lower dose of cyclosporine to reach target levels than CYP3A5*1 allele carriers [37]
Lipophilic statins, such as atorvastatin, lovastatin, and simvastatin, are known to be metabolized primarily by CYP3A [23]. In line with our results, it was reported that CYP3A5*3/*3 was associated with decreased statin clearance, along with increased statin exposure and decreased clearance [38]. In addition, a study on the pharmacodynamic effects of CYP3A5*3 reported that CYP3A5*1 carriers had significantly less effective responses than those with CYP3A5*3/*3 during lipophilic statin therapy [39].
Studies by Liu [24] and Ramakumari [26] included not only lipophilic agents, but also hydrophilic agents. However, we included those studies because in the study by Liu, atorvastatin and simvastatin comprised more than 70% of the statins administered, while in the study by Ramakumari on patients with atorvastatin and rosuvastatin in a 40:60 ratio, it was found that the CYP3A5*3 polymorphism significantly increased statin-induced myopathy. With respect to the association between rosuvastatin and CYP3A5, the Genetic Effects On STATins (GEOSTAT-1) study reported a significantly enhanced response to rosuvastatin in patients with variant genotypes of CYP3A5 [40].
In addition to genetic factors, several factors can affect drug metabolism, such as age, sex, nutritional conditions, comorbidities, and concomitant medications [41]. Such non-genetic factors can cause phenoconversion, which is the mismatch between the genotype-based prediction of drug metabolism and true metabolizing capacity [42]. Therefore, the effects of genetic polymorphisms should be interpreted in line with the patients’ clinical features [43].
This study has some limitations. First, the number of studies was relatively small, making it difficult to achieve sufficient statistical power for subgroup analysis. Second, there was clinical heterogeneity, including the definition of adverse events. Third, we could not adjust the statin type, dose, or the concomitant medications, which could affect the occurrence of statin-induced adverse events. Despite those limitations, to our knowledge, this is the first meta-analysis to reveal an association between the CYP3A5*3 polymorphism and the risk of statin-induced adverse events.

5. Conclusions

This study showed that the CYP3A5*3 polymorphism increased the statin-induced adverse event risk. This finding suggests that CYP3A5 genotyping can help individualized statin therapy. Further studies are needed to evaluate the utility of CYP3A5 genotyping in statin therapy.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/jpm11070677/s1, Figure S1. Chemical structures of statins. The chemical structure for each drug was drawn with the PubChem Sketcher V2.4. (a) Atorvastatin. (b) Fluvastatin. (c) Lovastatin. (d) Pravastatin. (e) Rosuvastatin. (f) Simvastatin. Figure S2. CYP3A4/5 metabolic pathways of statins. Figure S3. Funnel plot of the association between CYP3A5*3 and statin-induced adverse events. (a) Statin adverse events. (b) Statin-induced myopathy.

Author Contributions

All the authors have made substantial contributions to the conception of the study. J.Y., H.K. and H.-S.G. contributed to designing the study. J.Y., H.K. and Y.H. contributed to acquisition and analysis of data. J.Y., H.K., H.-Y.Y., G.S. and H.-S.G. contributed to interpretation of data. J.Y., H.K., Y.H., H.-Y.Y. and G.S. contributed to drafting of the manuscript. J.Y. and H.-S.G. contributed to critical revision of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

No external funding was used.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

Jeong Yee, Hamin Kim, Yunhee Heo, Ha-Young Yoon, Gonjin Song, and Hye-Sun Gwak declare that they have no conflict of interest.

Abbreviations

CIconfidence interval
CKcreatine kinase
CPICClinical Pharmacogenetics Implementation Consortium
CYPcytochrome P450
GEOSTAT-1Ge-netic Effects On STATins
HMG-CoA3-hydroxy-3-methylglutaryl coenzyme A
NOSNewcastle–Ottawa Scale
ORodds ratio
PCRpolymerase chain reaction
RFLPre-striction fragment length polymorphism
SLCO1B1solute carrier organic anion transporter family 1B1
SNPsingle-nucleotide polymorphism

References

  1. Jellinger, P.S.; Smith, D.A.; Mehta, A.E.; Ganda, O.; Handelsman, Y.; Rodbard, H.W.; Shepherd, M.D.; Seibel, J.A. American Association of Clinical Endocrinologists’ Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis. Endocr. Pr. 2012, 18, 1–78. [Google Scholar] [CrossRef] [Green Version]
  2. Vaughan, C.J.; Gotto, A.M., Jr.; Basson, C.T. The evolving role of statins in the management of atherosclerosis. J. Am. Coll. Cardiol. 2000, 35, 1–10. [Google Scholar] [CrossRef] [Green Version]
  3. Tomlinson, B.; Chan, P.; Lan, W. How well tolerated are lipid-lowering drugs? Drugs Aging 2001, 18, 665–683. [Google Scholar] [CrossRef] [PubMed]
  4. Mancini, G.B.; Baker, S.; Bergeron, J.; Fitchett, D.; Frohlich, J.; Genest, J.; Gupta, M.; Hegele, R.A.; Ng, D.; Pearson, G.J.; et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Consensus Working Group Update (2016). Can. J. Cardiol. 2016, 32, S35–S65. [Google Scholar] [CrossRef] [PubMed]
  5. Serban, M.-C.; Colantonio, L.; Manthripragada, A.D.; Monda, K.L.; Bittner, V.A.; Banach, M.; Chen, L.; Huang, L.; Dent, R.; Kent, S.T.; et al. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction. J. Am. Coll. Cardiol. 2017, 69, 1386–1395. [Google Scholar] [CrossRef]
  6. Toth, P.P.; Patti, A.M.; Giglio, R.V.; Nikolic, D.; Castellino, G.; Rizzo, M.; Banach, M. Management of statin intolerance in 2018: Still more questions than answers. Am. J. Cardiovasc. Drugs 2018, 18, 157–173. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Fitchett, D.H.; Hegele, R.A.; Verma, S. Cardiology patient page. Statin intolerance. Circulation 2015, 131, e389–e391. [Google Scholar] [PubMed] [Green Version]
  8. Kitzmiller, J.P.; Mikulik, E.B.; Dauki, A.; Mukherjee, C.; A Luzum, J. Pharmacogenomics of statins: Understanding susceptibility to adverse effects. Pharm. Pers. Med. 2016, ume 9, 97–106. [Google Scholar] [CrossRef] [Green Version]
  9. Donnelly, L.A.; Doney, A.S.; Tavendale, R.; Lang, C.C.; Pearson, E.R.; Colhoun, H.M.; McCarthy, M.I.; Hattersley, A.T.; Morris, A.D.; Palmer, C.N. Common nonsynonymous substitutions in SLCO1B1 predispose to statin intolerance in routinely treated individuals with type 2 diabetes: A go-DARTS study. Clin. Pharmacol. Ther. 2011, 89, 210–216. [Google Scholar] [CrossRef] [Green Version]
  10. Carr, D.; O’Meara, H.; Jorgensen, A.L.; Campbell, J.; Hobbs, M.; McCann, G.; van Staa, T.; Pirmohamed, M. SLCO1B1 genetic variant associated with statin-induced myopathy: A proof-of-concept study using the clinical practice research datalink. Clin. Pharmacol. Ther. 2013, 94, 695–701. [Google Scholar] [CrossRef]
  11. Xiang, Q.; Chen, S.-Q.; Ma, L.-Y.; Hu, K.; Zhang, Z.; Mu, G.-Y.; Xie, Q.-F.; Zhang, X.-D.; Cui, Y.-M. Association between SLCO1B1 T521C polymorphism and risk of statin-induced myopathy: A meta-analysis. Pharm. J. 2018, 18, 721–729. [Google Scholar] [CrossRef] [PubMed]
  12. Ramsey, L.B.; Johnson, S.G.; E Caudle, K.; E Haidar, C.; Voora, D.; A Wilke, R.; Maxwell, W.D.; McLeod, H.L.; Krauss, R.M.; Roden, D.M.; et al. The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update. Clin. Pharmacol. Ther. 2014, 96, 423–428. [Google Scholar] [CrossRef] [PubMed]
  13. Prueksaritanont, T.; Ma, B.; Yu, N. The human hepatic metabolism of simvastatin hydroxy acid is mediated primarily by CYP3A, and not CYP2D6. Br. J. Clin. Pharmacol. 2003, 56, 120–124. [Google Scholar] [CrossRef] [Green Version]
  14. Ward, L.D.; Kellis, M. HaploReg: A resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012, 40, D930–D934. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Lamba, J.K.; Lin, Y.S.; Schuetz, E.G.; E Thummel, K. Genetic contribution to variable human CYP3A-mediated metabolism. Adv. Drug Deliv. Rev. 2002, 54, 1271–1294. [Google Scholar] [CrossRef]
  16. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G. The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann. Intern. Med. 2009, 6, 264–269. [Google Scholar] [CrossRef] [Green Version]
  17. Aromataris, E.; Munn, Z. Joanna Briggs Institute Reviewer’s Manual. The Joanna Briggs Institute. Available online: https://reviewersmanual.joannabriggs.org (accessed on 25 June 2021).
  18. Mantel, N.; Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 1959, 22, 719–748. [Google Scholar]
  19. DerSimonian, R.; Laird, N. Meta-analysis in clinical trials. Control Clin. Trials 1986, 7, 177–188. [Google Scholar] [CrossRef]
  20. Begg, C.B.; Mazumdar, M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994, 50, 1088–1099. [Google Scholar] [CrossRef]
  21. Egger, M.; Smith, G.D.; Schneider, M.; Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997, 315, 629–634. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Fiegenbaum, M.; da Silveira, F.R.; Van der Sand, C.R.; Van der Sand, L.C.; Ferreira, M.E.; Pires, R.C.; Hutz, M.H. The role of common variants of ABCB1, CYP3A4, and CYP3A5 genes in lipid-lowering efficacy and safety of simvastatin treatment. Clin. Pharmacol. Ther. 2005, 78, 551–558. [Google Scholar] [CrossRef] [PubMed]
  23. Fukunaga, K.; Nakagawa, H.; Ishikawa, T.; Kubo, M.; Mushiroda, T. ABCB1 polymorphism is associated with atorvastatin-induced liver injury in Japanese population. BMC Genet. 2016, 17, 1–6. [Google Scholar] [CrossRef] [Green Version]
  24. Liu, J.-E.; Liu, X.-Y.; Chen, S.; Zhang, Y.; Cai, L.-Y.; Yan, Z.; Lai, W.-H.; Ren, B.; Zhong, S.-L. SLCO1B1 521T > C polymorphism associated with rosuvastatin-induced myotoxicity in Chinese coronary artery disease patients: A nested case-control study. Eur. J. Clin. Pharmacol. 2017, 73, 1409–1416. [Google Scholar] [CrossRef]
  25. V Willrich, M.A.; Kaleta, E.J.; Bryant, S.C.; Spears, G.M.; Train, L.J.; Peterson, S.E.; Lennon, V.A.; Kopecky, S.L.; Baudhuin, L.M. Genetic variation in statin intolerance and a possible protective role for UGT1A1. Pharmacogenomics 2018, 19, 83–94. [Google Scholar] [CrossRef]
  26. Ramakumari, N.; Indumathi, B.; Katkam, S.K.; Kutala, V.K. Impact of pharmacogenetics on statin-induced myopathy in South-Indian subjects. Indian Heart J. 2018, 70, S120–S125. [Google Scholar] [CrossRef]
  27. Shek, A.B.; Kurbanov, R.D.; Alieva, R.B.; Abdullaeva, G.J.; Nagay, A.V.; Abdullaev, A.; Hoshimov, S.U.; Nizamov, U.I. Personalized rosuvastatin therapy in problem patients with partial statin intolerance. Arch. Med Sci. Atheroscler. Dis. 2018, 3, e83–e89. [Google Scholar] [CrossRef] [Green Version]
  28. Wilke, R.A.; Moore, J.H.; Burmester, J.K. Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damage. Pharm. Genom. 2005, 15, 415–421. [Google Scholar] [CrossRef]
  29. Zuccaro, P.; Mombelli, G.; Calabresi, L.; Baldassarre, D.; Palmi, I.; Sirtori, C.R. Tolerability of statins is not linked to CYP450 polymorphisms, but reduced CYP2D6 metabolism improves cholesteraemic response to simvastatin and fluvastatin. Pharmacol. Res. 2007, 55, 310–317. [Google Scholar] [CrossRef] [PubMed]
  30. Kiortsis, D.N.; Filippatos, T.D.; Mikhailidis, D.P.; Elisaf, M.S.; Liberopoulos, E.N. Statin-associated adverse effects beyond muscle and liver toxicity. Atherosclerosis 2007, 195, 7–16. [Google Scholar] [CrossRef] [PubMed]
  31. Golomb, B.A.; Evans, M.A. Statin adverse effects: A review of the literature and evidence for a mitochondrial mechanism. Am. J. Cardiovasc. Drugs 2008, 8, 373–418. [Google Scholar] [CrossRef] [PubMed]
  32. Turner, R.M.; Pirmohamed, M. Statin-related myotoxicity: A comprehensive review of pharmacokinetic, pharmacogenomic and muscle Components. J. Clin. Med. 2019, 9, 22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Chatzizisis, Y.S.; Koskinas, K.C.; Misirli, G.; Vaklavas, C.; Hatzitolios, A.; Giannoglou, G.D. Risk factors and drug interactions predisposing to statin-induced myopathy: Implications for risk assessment, prevention and treatment. Drug Saf. 2010, 33, 171–187. [Google Scholar] [CrossRef] [PubMed]
  34. Dreier, J.P.; Endres, M. Statin-associated rhabdomyolysis triggered by grapefruit consumption. Neurology 2004, 62, 670. [Google Scholar] [CrossRef] [PubMed]
  35. Kuehl, P.M.; Zhang, J.; Lin, Y.; Lamba, J.K.; Assem, M.; Schuetz, J.D.; Watkins, P.B.; Daly, A.; Wrighton, S.A.; Hall, S.D.; et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat. Genet. 2001, 27, 383–391. [Google Scholar] [CrossRef] [Green Version]
  36. Rojas, L.; Neumann, I.; Herrero, M.J.; Boso, V.; Reig, J.; Poveda, J.L.; Megías, J.; Bea, S.; Aliño, S.F. Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: A systematic review and meta-analysis of observational studies. Pharm. J. 2015, 15, 38–48. [Google Scholar] [CrossRef] [PubMed]
  37. Zhu, H.J.; Yuan, S.H.; Fang, Y.; Sun, X.Z.; Kong, H.; Ge, W.H. The effect of CYP3A5 polymorphism on dose-adjusted cyclosporine concentration in renal transplant recipients: A meta-analysis. Pharm. J. 2010, 11, 237–246. [Google Scholar] [CrossRef] [Green Version]
  38. Kim, K.A.; Park, P.W.; Lee, O.J.; Kang, D.K.; Park, J.Y. Effect of polymorphic CYP3A5 genotype on the single-dose simvastatin pharmacokinetics in healthy subjects. J. Clin. Pharmacol. 2007, 47, 87–93. [Google Scholar] [CrossRef]
  39. Kivistö, K.T.; Niemi, M.; Schaeffeler, E.; Pitkälä, K.; Tilvis, R.; Fromm, M.F.; Schwab, M.; Eichelbaum, M.; Strandberg, T. Lipid-lowering response to statins is affected by CYP3A5 polymorphism. Pharmacogenetics 2004, 14, 523–525. [Google Scholar] [CrossRef]
  40. Bailey, K.M.; Romaine, S.P.; Jackson, B.M.; Farrin, A.J.; Efthymiou, M.; Barth, J.H.; Copeland, J.; McCormack, T.; Whitehead, A.; Flather, M.D.; et al. Hepatic metabolism and transporter gene variants enhance response to rosuvastatin in patients with acute myocardial infarction: The GEOSTAT-1 Study. Circ. Cardiovasc. Genet. 2010, 3, 276–285. [Google Scholar] [CrossRef] [Green Version]
  41. Zanger, U.M.; Schwab, M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther. 2013, 138, 103–141. [Google Scholar] [CrossRef]
  42. Klomp, S.D.; Manson, M.L.; Guchelaar, H.J.; Swen, J.J. Phenoconversion of cytochrome P450 metabolism: A systematic review. J. Clin. Med. 2020, 9, 2890. [Google Scholar] [CrossRef] [PubMed]
  43. Shah, R.R.; Smith, R.L. Addressing phenoconversion: The Achilles’ heel of personalized medicine. Br. J. Clin. Pharmacol. 2015, 79, 222–240. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Jpm 11 00677 g001 550
Figure 1. Flow diagram of study selection.
Figure 1. Flow diagram of study selection.
Jpm 11 00677 g001
Jpm 11 00677 g002 550
Figure 2. Forest plots of the association between CYP3A5*3 and statin adverse events.
Figure 2. Forest plots of the association between CYP3A5*3 and statin adverse events.
Jpm 11 00677 g002
Jpm 11 00677 g003 550
Figure 3. Forest plots of the association between CYP3A5*3 and statin-induced myopathy.
Figure 3. Forest plots of the association between CYP3A5*3 and statin-induced myopathy.
Jpm 11 00677 g003
Table
Table 1. Characteristics of the studies included.
Table 1. Characteristics of the studies included.
StudyCountryStudy DesignCase/Control NumberMean Age of Case/ControlMale % of Case/ControlCase DefinitionStatins Included in the AnalysisGenotyping MethodNOS
Fiegenbaum et al. (2005)BrazilProspective cohort study15/9963.0/59.218.8/25.3MyopathySimvastatinPCR-RFLP9
Fukunaga et al. (2016)JapanCase-control study30/41461.0/66.0 a60.0/53.9Liver injuryAtorvastatinInvader Assay6
Liu et al. (2017)ChinaCase-control study148/25560.6/63.382.4/82.7MyopathyAtorvastatin, fluvastatin, pravastatin, rosuvastatin, simvastatinTaqMan9
Ramakumari et al. (2018)IndiaRetrospective cohort study38/16463.0 b64.9 bMyopathy symptoms with elevated CK levelAtorvastatin, rosuvastatinPCR7
Shek et al. (2017)UzbekistanCase-control study50/5059.3/61.742.0/56.0Elevated transaminase or CK levelSimvastatinPCR-RFLP6
Wilke et al. (2005)USACase-control study68/6958.1/63.179.4/50.7Myopathy symptoms with elevated CK levelAtorvastatinInvader Assay6
Willrich et al. (2018)USACase-control study57/5765.5/65.756.6/56.6Statin intoleranceAtorvastatin, lovastatin, simvastatinTaqMan9
Zuccaro et al. (2007)ItalyRetrospective cohort study50/5061.4/61.144.0/46.0MyopathyAtorvastatin, simvastatin.PCR-RFLP8
CK: creatine kinase; NOS: Newcastle–Ottawa Scale; PCR: polymerase chain reaction; RFLP: restriction fragment length polymorphism.a Expressed as the median b Data for all participants.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Yee, J.; Kim, H.; Heo, Y.; Yoon, H.-Y.; Song, G.; Gwak, H.-S. Association between CYP3A5 Polymorphism and Statin-Induced Adverse Events: A Systemic Review and Meta-Analysis. J. Pers. Med. 2021, 11, 677. https://doi.org/10.3390/jpm11070677

AMA Style

Yee J, Kim H, Heo Y, Yoon H-Y, Song G, Gwak H-S. Association between CYP3A5 Polymorphism and Statin-Induced Adverse Events: A Systemic Review and Meta-Analysis. Journal of Personalized Medicine. 2021; 11(7):677. https://doi.org/10.3390/jpm11070677

Chicago/Turabian Style

Yee, Jeong, Hamin Kim, Yunhee Heo, Ha-Young Yoon, Gonjin Song, and Hye-Sun Gwak. 2021. "Association between CYP3A5 Polymorphism and Statin-Induced Adverse Events: A Systemic Review and Meta-Analysis" Journal of Personalized Medicine 11, no. 7: 677. https://doi.org/10.3390/jpm11070677

APA Style

Yee, J., Kim, H., Heo, Y., Yoon, H. -Y., Song, G., & Gwak, H. -S. (2021). Association between CYP3A5 Polymorphism and Statin-Induced Adverse Events: A Systemic Review and Meta-Analysis. Journal of Personalized Medicine, 11(7), 677. https://doi.org/10.3390/jpm11070677

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop