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The association between the SLCO1B1, apolipoprotein E, and CYP2C9 genes and lipid response to fluvastatin: a meta-analysis

Xiang, Qian; Zhang, Xiaodan; Ma, Lingyue; Hu, Kun; Zhang, Zhuo; Mu, Guangyan; Xie, Qiufen; Chen, Shuqing; Cui, Yimin

doi: 10.1097/FPC.0000000000000356
ORIGINAL ARTICLE

Objective The aim of this study was to determine the impact of the SLCO1B1, apolipoprotein E (ApoE), and CYP2C9 genotypes on the lipid-lowering efficacy of fluvastatin.

Methods We performed electronic searches on the PubMed, Embase, and Cochrane Library databases to identify studies published through October 2017. Studies that reported the effect estimates with 95% confidence intervals (CIs) of total cholesterol (TC), triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein were included so that the different genotype categories could be compared. Weighted mean difference (WMD) was used to summarize the effect estimates.

Results Six studies, involving a total of 1171 individuals, were included in the final analysis. We noted that the patient carrier SLCO1B1 521TT was associated with greater change in TC (WMD: −2.98; 95% CI: −5.12 to −0.84; P=0.006) and LDL (WMD: −5.58; 95% CI: −10.64 to −0.52; P=0.031) compared with 521TC or CC. Furthermore, the patient carrier ApoE*2/*3 showed more change in high-density lipoprotein compared with ApoE*3/*3 (WMD: 18.76; 95% CI: 8.97–28.55; P<0.001) and ApoE*3/*4 or *4/*4 (WMD: 22.51; 95% CI: 0.98–44.04; P=0.040). Finally, the CYP2C9 genotypes showed no correlation with the effects of fluvastatin on TC, triglyceride, and LDL.

Conclusion The findings of this study suggested that the SLCO1B1 and ApoE polymorphisms could influence the lipid-lowering effect of fluvastatin, whereas the CYP2C9 genotypes were not associated with the therapeutic effects of fluvastatin.

Department of Pharmacy, Peking University First Hospital, Beijing, China

Correspondence to Yimin Cui, PhD, MD, Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing 100034, China Tel/fax: +86 106 611 0802; e-mail: bdyyyljd@126.com

Received April 21, 2018

Accepted September 24, 2018

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Introduction

Cardiovascular disease (CVD) is a major cause of mortality, and the guidelines preventing the composite endpoints for CVD have already been illustrated 1–3. High low-density lipoprotein (LDL) levels are associated with an increased risk of CVD in middle-aged and elderly individuals; however, patients who receive lipid-lowering strategies show a reduction in the incidence of CVD 4,5. LDL oxidative modification, which involves a variety of enzymatic and nonenzymatic pathways, has been suggested as a potential mechanism for this process 6,7. A previous study showed that lifestyle interventions, although determined by self-control, could contribute toward a more favorable lipid profile 8. Statin (3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors) treatments have also been shown to lower LDL and increase high-density lipoprotein (HDL) levels in patients. Therefore, they could be used as primary or secondary methods of prevention in CVD progression. Alternatively, numerous genes have been investigated with respect to CVD progression and lipid-lowering 9–11.

The impact of the SLCO1B1 genotype on the pharmacokinetic effect of statins has been detailed in several studies 12–15; however, its role in lipid-lowering response and cholesterol synthesis has only been reported in a few studies 16,17. Furthermore, three common alleles of apolipoprotein E (ApoE) appear to play an important role in the lipid-lowering response; the locus on which these alleles appear is suggested to be the most highly ranked locus in regulating LDL 18–20. In addition, CYP2C9 is one of the most abundant CYP450 enzymes in the human liver, which metabolizes nearly 15% of pharmaceutical drugs. Fluvastatin is also primarily metabolized by CYP2C9 21. Several studies have suggested the influence of the SLCO1B1, ApoE, and CYP2C9 polymorphisms on the lipid-lowering effect of fluvastatin; however, these effects were inconsistent and thus need to be demonstrated thoroughly 19,22–26. Clarification of any potential effect of the SLCO1B1, ApoE, and CYP2C9 genotypes on the lipid-lowering effect of fluvastatin is particularly important as it has not yet been reported. Therefore, we attempted a comprehensive examination of available studies to determine the association between the SLCO1B1, ApoE, and CYP2C9 polymorphisms and total cholesterol (TC), triglyceride (TG), LDL, and HDL levels in patients treated with fluvastatin.

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Methods

Data sources, search strategies, and selection criteria

This review was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement issued in 2009 27. We evaluated the association between the SLCO1B1, ApoE, and CYP2C9 polymorphisms and TC, TG, LDL, and HDL levels in patients who received fluvastatin treatment, all of which were treated as inclusion criteria for this study. No restrictions were imposed on publication language and status. We systematically searched the PubMed, Embase, and Cochrane Library databases for articles published through October 2017 using the following search terms: (pharmacogenomics OR genetic polymorphism) OR (SLCO1B1 OR ApoE OR CYP2C9) AND (fluvastatin). Manual searches of the reference lists from relevant studies were also performed to identify other potential articles. Study topic, study design, individual status, exposure, and reported outcomes were also used to identify any included studies.

We performed the literature search and study selection independently using a standardized approach, and any inconsistencies were resolved by discussing with each other. A study was included if it fulfilled the following criteria: (a) all included patients received fluvastatin; (b) the study reported different categories of the SLCO1B1, ApoE, and CYP2C9 genotypes; (c) the study reported about at least one of the following lipids: TC, TG, LDL, and/or HDL; and (d) the lipid profiles included the baseline, after treatment, and percentage change in TC, TG, LDL, and/or HDL.

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Data collection and quality assessment

Data collection and quality assessment was performed independently by two authors. Inconsistencies were adjudicated by a third author referring to the original studies independently. The abstracted data items included the first author’s name, publication year, country, sample size, mean age, percentage of male participants, BMI, genetic types, and investigated outcomes. For studies that reported several lipid profiles, we selected the variables adjusted maximally for potential confounders. Study quality assessment was evaluated using the Newcastle–Ottawa Scale, which is quite comprehensive and has been partially validated in evaluating the quality of observational studies 28. This method is based on the selection (four items), comparability (one item), and outcome (three items) of the study groups, with a score scale ranging from 0 to 9.

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Statistical analysis

We evaluated the influence of the SLCO1B1, ApoE, and CYP2C9 polymorphisms (Supplementary Table 1, Supplemental digital content 1, http://links.lww.com/FPC/B329) on the percentage change in TC, TG, LDL, and HDL levels on the basis of the mean, SD, and sample size in each category of the SLCO1B1, ApoE, and CYP2C9 genotypes in each individual study. Weighted mean difference (WMD) and corresponding 95% confidence intervals (CIs) were used to calculate the summarized results using the random-effects model 29,30. Heterogeneity among the studies included was evaluated using the I 2 and Q statistic. I 2 more than 50% or P value less than 0.10 were considered to represent significant heterogeneity. P value less than 0.05 was considered to be statistically significant for the summary results. All statistical analyses were carried out using the STATA software, version 10.0 (Stata Corporation, College Station, Texas, USA).

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Results

Literature search

The initial electronic searches produced 221 potential articles, of which 193 were excluded after filtering for duplicates and irrelevant topics. A total of 28 potentially eligible studies were evaluated after the full text was read. After detailed evaluations, six studies were selected for the final pooled analysis 19,22–26. No additional eligible studies were found after manually searching the reference lists of the relevant studies. The results of the study selection are presented in Fig. 1 and the baseline characteristics of the studies included are summarized in Table 1.

Fig. 1

Fig. 1

Table 1

Table 1

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Study characteristics

Six studies, involving a total of 1171 individuals, were included in the final analysis and each investigated gene was reported in two studies. The studies were published between 2000 and 2014, and 26–420 participants were included in each study. Two of the included studies were carried out in Germany 22,26, one in France 23, one in Italy 19, one in the USA 24, and one in the Czech Republic 25. The mean age of the patients included ranged from 42.7 to 75.3 years, and the percentage of male participants ranged from 21.9 to 84.6%. Study quality was assessed using the Newcastle–Ottawa Scale. We observed that one study scored 8 22, three studies scored 7 23,24,26, and two studies scored 6 19,25.

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SLCO1B1

The summarized results of the impact of SLCO1B1 on the lipid-lowering efficacy of fluvastatin are shown in Fig. 2. Overall, patient carrier 388AA was not associated with the percentage change in TC (WMD: 1.82; 95% CI: −0.48 to 4.12; P=0.121; with no evidence of heterogeneity) and LDL (WMD: −0.59; 95% CI: −8.65 to 7.47; P=0.886; with significant heterogeneity) compared with 388AG or GG. However, patient carrier 521TT was associated with a lower percentage change in TC (WMD: −2.98; 95% CI: −5.12 to −0.84; P=0.006, with no evidence of heterogeneity) and LDL (WMD: −5.58; 95% CI: −10.64 to −0.52; P=0.031, with significant heterogeneity) compared with 521TC or CC.

Fig. 2

Fig. 2

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Apolipoprotein E

The summarized results of the impact of ApoE on the lipid-lowering efficacy of fluvastatin are shown in Fig. 3. We noted that ApoE*2/*3 was associated with a greater percentage change in HDL compared with ApoE*3/*3 (WMD: 18.76; 95% CI: 8.97–28.55; P<0.001; with no evidence of heterogeneity) and ApoE*3/*4 or *4/*4 (WMD: 22.51; 95% CI: 0.98–44.04; P=0.040; with significant heterogeneity). We also noted that ApoE*2/*3 had no significant effect on the LDL levels in patients treated with fluvastatin compared with ApoE*3/*3 (WMD: −4.30; 95% CI: −22.42 to 13.83; P=0.642; with significant heterogeneity) and ApoE*3/*4 or *4/*4 (WMD: −7.79; 95% CI: −21.12 to 5.53; P=0.252; with potentially significant heterogeneity). Moreover, patient carrier ApoE*2/*3 was not associated with TC levels compared with ApoE*3/*3 (WMD: −2.19; 95% CI: −19.84 to 15.46; P=0.808; with significant heterogeneity) and ApoE*3/*4 or *4/*4 (WMD: −1.47; 95% CI: −10.27 to 7.32; P=0.743; with no evidence of heterogeneity). Finally, ApoE*2/*3 did not affect TG levels compared with ApoE*3/*3 (WMD: −20.60; 95% CI: −58.98 to 17.78; P=0.293; with significant heterogeneity) and ApoE*3/*4 or *4/*4 (WMD: −21.02; 95% CI: −62.47 to 20.43; P=0.320; with significant heterogeneity).

Fig. 3

Fig. 3

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CYP2C9

The summarized results of the impact of CYP2C9 on the lipid-lowering efficacy of fluvastatin are shown in Fig. 4. Overall, we noted that neither patient carriers CYP2C9*1/*1 nor *1/*2 were not associated with LDL (WMD: 4.13; 95% CI: −8.52 to 16.78; P=0.522; with no evidence of heterogeneity), TC (WMD: 1.94; 95% CI: −6.29 to 10.16; P=0.644; with no evidence of heterogeneity), and TG (WMD: −1.88; 95% CI: −25.96 to 22.21; P=0.879; with no evidence of heterogeneity) levels compared with CYP2C9*1/*3 or *2/*3.

Fig. 4

Fig. 4

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Discussion

Our current study was based on available published studies and it explored all possible correlations between SLCO1B1, ApoE, and CYP2C9 polymorphisms and the outcomes of the TC, TG, LDL, and HDL levels. This quantitative study included 1171 individuals from 6 studies distributed across a broad range of baseline characteristics. The results of this study indicated that patient carrier SLCO1B1 521TT significantly affected the percentage change in TC and LDL levels, and that ApoE*2/*3 correlated significantly with changes in HDL levels compared with their corresponding control groups. No significant associations between the CYP2C9 genotypes and TC, TG, and LDL levels were observed. These results added to the accumulating evidence on fluvastatin’s lipid-lowering efficacy with respect to the patient carrier SLCO1B1, ApoE, and CYP2C9 polymorphisms.

Differences in lipid profiles were observed in patient carriers, specifically with respect to the genotypes, from our analysis and the results of previous studies 19,22–26. Meyer zu Schwabedissen et al. 22 carried out a cohort study that evaluated the influence of SLCO1B1 on the therapeutic efficacy of statins in 214 dyslipidemia patients during the 5-year follow-up. They pointed out that patient carrier 521TT induced a small change in LDL levels, without showing any other significant effects. Furthermore, Couvert et al. 23 observed that 521TT correlated with TC levels 2 months after follow-up in elderly hypercholesterolemic patients who received fluvastatin treatments.

Couvert et al. 23 also reported that another variant, c.463C>A (Pro155Thr) of SLCO1B1, was significantly and independently associated with a superior response to fluvastatin therapy, showing an absolute gain of 10% (−41 vs. −31.5%) in LDL-C reduction in homozygous Thr/Thr individuals when compared to the homozygous wild-type Pro/Pro individuals. Interestingly, a previous studies has already shown that the K m value for OATP1B1-mediated transport of fluvastatin (fluvastatin’s affinity for the OATP1B1 transporter) was 1.4–3.5 μmol/l 31,32.

The summarized results indicated that the ApoE genotypes affected the HDL levels, but did not correlate with LDL, TC, and TG levels. Zuccaro et al. 19 indicated that the ApoE*2/*3 genotype was significantly linked to increased HDL levels after fluvastatin treatments. The reason for this could be that the effect of the heterozygote patient carrier *2/*3 on HDL increases because of the higher incidence of hypertriglyceridemia. Furthermore, the patients who received fluvastatin treatments showed reduced LDL and TG levels and increased HDL levels. Ballantyne et al. 24 observed that the ApoE*4 allele showed a lower reduction in LDL levels in patients treated with fluvastatin. However, CVD progression remained similar among these groups. The reason for this could be that patient carrier ApoE*2/*3 did not affect LDL, TC, and TG levels.

No significant differences were observed between CYP2C9 and LDL, TC, and TG levels. All the included studies reported results consistent with our study. Buzková et al. 25 observed that the CYP2C9*1 or CYP2C9*3 alleles were associated with a trend of lower LDL and TC levels. They showed that the patient carriers CYP2C9*1/*3 and CYP2C9*1/*1 reduced LDL levels by 40.0 and 22.4%, respectively. Furthermore, the reduction in TC levels was 28.6% in patient carrier CYP2C9*1/*3 and 20.2% in CYP2C9*1/*1. No significant differences or trends were observed in combination comparisons of *1/*1 or *1/*2 and *1/*3 or *2/*3. A study by Kirchheiner et al. 26 involving 26 patients evaluated the pharmacokinetics and cholesterol-lowering effects of CYP2C9 polymorphisms. They indicated that TC and LDL concentrations reduced significantly during the 14-day treatment period; however, the CYP2C9 genotypes did not correlate with the pharmacokinetics and cholesterol-lowering effects. The authors explained that the potential reason for this could be the differences in the baseline lipid profiles among the genotype groups as the results were not stratified by baseline lipid profiles. Furthermore, the sample size of the study carried out by Kirchheiner et al. 26 was designed for pharmacokinetic effects, and not feasible in evaluating the pharmacodynamic effects of fluvastatin.

Finally, the limitations of this meta-analysis need to be mentioned. The results of the lipid-lowering effects in patients who received fluvastatin treatment were not adjusted for multiple variables, which may have affected the lipid profiles. Furthermore, the sensitivity or stratified results on the basis of important factors were not determined in this study because the summarized results for each polymorphism were available in two studies. Moreover, publication bias is an inevitable problem that affects any meta-analysis based on published studies. Finally, this meta-analysis was based only on pooled data and individual data were not used. Therefore, a more detailed analysis could not be provided.

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Conclusion

The summarized results indicated that the patient carrier, SLCO1B1 521TT, correlated with a significant reduction in TC and LDL levels. Furthermore, ApoE*2/*3 was associated with a percentage change in HDL levels. Finally, the CYP2C9 genotype showed no effect on the percentage change in the lipid profiles. Although these results are variable and calculated using two studies for each polymorphism, our findings are potentially more robust than those of any individual study. Future studies should focus on the pharmacodynamic effect of fluvastatin on composite events with respect to the SLCO1B1, ApoE, and CYP2C9 genotypes.

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Acknowledgements

This study was supported by grants from the National Key Technologies R&D Program (no. 2016YFC0904900), the National Natural Science Foundation of China (no. 81573504 and no. 81673509), the Beijing Natural Science Foundation (no. 7171012), and the National Science and Technology Major Projects for ‘Major New Drugs Innovation and Development’ (no. 2017ZX09304028 and no. 2017ZX09101001).

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

apolipoprotein E; CYP2C9; fluvastatin; meta-analysis; polymorphisms; SLCO1B1

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