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1 CYP2C9 genetic polymorphism is a potential predictive marker for the efficacy of rosuvastatin therapy Jiayao Lin1 MD, Yu Zhang1,*MD, Houguang Zhou1 MD,PhD, Xinqing Wang1 MD, Wenwen Wang1 MD 1 Department of Geriatrics, Huashan Hospital, Fudan University. Shanghai 200040, China. Short title: CYP2C9 polymorphism and the efficacy of rosuvastatin * Corresponding author: Yu Zhang, MD, Department of Geriatrics, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Rd, Shanghai 200040, China. Phone: 8621-52889999, Fax: 8621-6248919, Email: [email protected] 2 Abstract: Aims This study aimed to evaluate the associations of CYP2C9 genetic polymorphism with the efficacy and safety of rosuvastatin in Chinese patients with hyperlipidemia. Methods: A total of 218 patients with hyperlipidemia were selected and treated with 10 mg rosuvastatin per day for 12 weeks. Blood samples were collected prior to the treatment, and after 4, 8 and 12 weeks of treatment. Genotyping for CYP2C9 polymorphisms was performed using allele-specific real-time PCR. Results: 197 out of 218 patients featured a wild-type CYP2C9*1/*1 genotype, and 21 patients featured a CYP2C9*3 mutation genotype. No patients with CYP2C9*2 alleles were identified. 16 patients discontinued the medication due to adverse effects. After the 12 weeks of treatment, we observed significant reductions in total cholesterol (TC), triglycerides and low-density lipoprotein (LDL) levels compared to baseline (P < 0.05). Patients with the mutant genotype showed a higher TC-lowering and LDL-lowing effect compared to those with wild-type genotypes (TC: 45.05% vs. 38.96%, P=0.041; LDL: 44.97% vs. 39.28%, P=0.029). The frequency of adverse reactions in the studied patients did not differ by CYP2C9 genotypes (P > 0.05). Conclusions: This study suggests that the CYP2C9 polymorphism may be involved in the lipid-lowering efficacy of rosuvastatin in patients with hyperlipidemia. Key words: CYP2C9, polymorphism, rosuvastatin, hyperlipidemia, efficacy, tolerability 3 Introduction Statins are the most common drugs for the treatment of hyperlipidemia. Statins reduce the plasma level of total cholesterol ( TC ) , and can prevent atherosclerosis and other cardiovascular diseases by inhibiting the intracellular production of cholesterol and upregulating the expression of low-density lipoprotein (LDL) receptors in liver[1]. Compared to other statins (e.g. atorvastatin, simvastatin, and pravastatin), rosuvastatin delivers the greatest reduction in LDL cholesterol, and more than 80% of patients can reach their LDL cholesterol goal on the typical 10 mg dose of rosuvastatin[2]. However, there is well-known inter-individual variability in cholesterol-lowering during therapy with statins. In a large clinic trial, patients treated with simvastatin, 80 mg daily after 6 months of treatment, had a mean reduction rate of 46% in LDL.The top 5% of responders had a reduction ranged from 63-76%, whereas the bottom 5% responders with a reduction rate ranged from 23% to 20%[3]. Similarly, poor or diminishing responses have been observed in a minority of hyperlipidemia patients treated with lovastatin and rosuvastatin [4]. At present, inter-individual variability in response to rosuvastatin treatment in subjects with hypercholesterolemia has not been clearly established. Most statins, except pravastatin, primarily undergo phase I metabolism by the superfamily cytochrome p450 (CYP) in the liver[5]. The metabolism of rosuvastatin is principally mediated by the CYP2C9 enzyme, with some involvement of CYP3A4 and CYP2C8[6]. More than 30 single nucleotide polymorphisms (SNP) have been identified in the regulatory and coding regions of the CYP2C9 gene, and three alleles, CYP2C9 *1, *2 and *3, are present in most ethnic populations[7]. Using in vitro experiments, the allelic variants, CYP2C9*2 and CYP2C9*3, code for enzymes with approximately 10–40% and 5–15% of the activity of the 4 wild-type form CYP2C9*1, respectively[8]. This polymorphism divides the populations into two phenotypes: extensive metabolizers (EM) and poor metabolizers (PM), leading to individual and racial differences in drug metabolism [9]. In this study, we hypothesized that CYP2C9 gene polymorphism may also play an important role in metabolism of rosuvastatin, thus affecting drug efficacy and safety indirectly. CYP2C9 EM may not reach therapeutic concentrations at customary doses due to a faster drug metabolism, leading to therapeutic failure with rosuvastatin. In contrast, PM may show increased concentrations of metabolized drugs at conventional doses, increasing the risk of ADRs such as liver and kidney toxicity. In the present study, we recruited 72 Han Chinese patients with hyperlipidemia to assess the relationships between CYP2C9 polymorphism and the efficacy and toxicity of rosuvastatin. Materials and Methods Study Subjects We recruited 218 subjects with primary hyperlipidemia and mixed dyslipidemia from the outpatient clinic of the Huashan Hospital, Fudan University from January 2012 to December 2013. There are two primary eligibility criteria, as follows: (1) TC ≥ 5.18 mmol/L, and (or) LDL ≥ 3.37 mmol/L treated with a lipid-lowering diet; (2) Without previously using statin and fibrate drugs together. This study was reviewed and approved by the Fudan University Institutional Review Board. Treatment with rosuvastatin and biochemistry testing All subjects were on a lipid-lowering diet for at least eight weeks prior to entry into the study. 5 After an overnight fast, 2 mL blood samples were collected from each patient prior to rosuvastatin treatment for CYP2C9 genotyping and baseline biochemical examination. Then all patients were treated with a single lipid-lowering therapy of rosuvastatin (Crestor, AstraZeneca UK limited) at 10 mg per night for 12 weeks. Blood samples were collected and all biochemistry tests were conducted at 4 weeks, 8 weeks and 12 weeks treatment. The biochemistry tests for lipid profiles included TC, triglycerides (TG), high-density lipoprotein (HDL), LDL, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine phosphokinase (CPK) and serum creatinine (Scr), and were performed using the HITACHI 7600-020 automatic biochemistry analyzer in the Chemical Pathology laboratory of Huashan Hospital, Fudan University. Efficacy evaluations were as follows: (1) The changes of plasma TC and LDL after treatment; and (2) The proportion of patients who achieved treatment targets (e.g. LDL < 2.59 mmol/L, according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines) [10]. CYP2C9 genotyping Genomic DNA was isolated from whole peripheral blood samples by Tiangen RelaxGene Blood Kit (Tiangen Inc, Beijing, China). Genotyping for polymorphisms of CYP2C9 was performed by a PCR based restriction fragment length polymorphism (RFLP) approach using an AB7500 Real-time PCR (Applied Biosystems, Foster City, CA) as previously described [11]. Statistical analysis 6 Statistical analysis was conducted using the package SPSS 17.0 (SPSS Inc, Chicago, IL, USA) for Windows, and a two tailed p-value less than 0.05 was considered statistically significant. Each polymorphism was tested for deviation from Hardy-Weinberg equilibrium by comparing the observed and expected genotype frequencies using the ᵡ2 test with one degree of freedom. Quantitative data were presented as mean ± standard deviation (SD). Non-numeric data were presented as frequency. The effects of the rosuvastatin on the concentration of lipid profiles were assessed by one-way analysis of variance (ANOVA) with post hoc Bonferroni correction for multiple comparisons. In order to evaluate genetic polymorphisms and lipid lowering response to rosuvastatin, independent samples t-test was performed. Associations between serum lipid profile, adverse drug reactions, gender, baseline characteristics of the patients and CYP2C9 polymorphisms were evaluated using Fisher’s exact test of probabilities. Results Characteristics of study participants A total of 218 patients who met the selection criteria were included in this study. The median age was 58.2 years (range, 36-82 years). The patients consisted of 142 men (65.1%) and 76 women (34.9%). There were 114 (52.3%) patients with hypertension, 61 (28.0%) patients with coronary heart disease, 83 (38.1%) patients with type 2 diabetes, 47 (21.6%) patients with hyperuricemia and gout, and 94 (43.1%) patients with fatty liver. 122 of 218 patients (46.0%) had a history of smoking. Frequency distributions of CYP2C9 genotypes 7 All 218 patients could be genotyped unambiguously for the most common CYP2C9 alleles of CYP2C9*1, CYP2C9*2, and CYP2C9*3. Of the 218 patients, 197 (127 male and 70 female) had a wild-type CYP2C9*1/*1 genotype, whereas 21 (9.6%) had at least one mutated CYP2C9*3 allele. There were 18 (8.3%) subjects (13 male and 5 female) with the heterozygous CYP2C9*1/*3 genotype. and 3 (1.3%) subjects (2 male and 1 female) with the homozygous CYP2C9*3/*3 genotype. However, The CYP2C9*2 mutated allele was not observed in the studied subjects. All the genotype distributions were in Hardy-Weinberg equilibrium (P > 0.05). No statistical differences in the distribution of genotypes and phenotype were ascertained by gender (P > 0.05) (Table 1). Association between CYP2C9 genotypes and characteristics of patients We classified 218 patients into two groups based on CYP2C9 mutant allele (*3). Among them, 197 patients featured the wild-type genotype (CYP2C9*1/*1), and 21 patients carried at least one mutant genotype (CYP2C9*3/*3 or *1/ *3). There was no significant difference in baseline lipid profiles (ALT, Scr, CPK, LDL and TC) among wild-type and mutant genotypes. No significant differences were observed in sex, BMI, Comorbidity diseases such as hypertension,hypertension, fatty liver, hyperuricemia, smoking status,and baseline hepatic and renal function between wild-type groups and mutant genotypes groups. Intolerability and Efficacy of rosuvastatin therapy for patients with hypercholesterolemia Of 218 patients, 202 patients were treated with rosuvastatin (10 mg per day) for 12 weeks. other sixteen patients (10 male, 6 female) did not complete the study due to elevated transaminases, elevated CPK or irresistible gastrointestinal disorders. Nine of them left the study at 4 weeks, six patients quit between 5-8 weeks, and one patient quit between 9-12 weeks (Table 2). The median duration of their treatment was 34 days (range, 4-84 days). The 8 frequency of adverse reactions is 7.34%. The common ADRs included gastrointestinal reactions (three patients had abdominal distension and one patient had constipation). There are seven patients with abnormal liver function with no clinical symptoms during follow-up. There were five patients with elevated CPK, but lacking muscular soreness symptoms. After discontinuation and symptomatic treatment, the gastrointestinal reactions and elevated transaminases and CPK values returned to normal within one week in six patients and within two weeks in the other ten patients. No serious adverse events such as myopathy/muscle dissolution or drug-induced liver injury were observed in this clinical trial. Before treatment, the TC,TG, LDL and HDL level of 202 patients complete 12 weeks of treatment were 6.79±0.95 mmol/L, 3.32±1.31 mmol/L, 3.98±0.69 mmol/L and 1.17±0.25 mmol/L respectively. After the 4-weeks treatment, the levels of TC, TG, and LDL were significantly decreased, and HDL was significantly increased compared with their baseline levels (p < 0.05) (Table 3). The serum TC and LDL concentrations decreased by 27.37% and 22.93%, respectively, compared with the baseline levels. The target lipid levels, defined according to the NCEP ATP III guidelines, were achieved in 30.69% (62 cases) of patients in this study. After the 8-week treatment, serum TC and LDL concentrations decreased by 35.32% and 33.17%, respectively, compared to baseline levels (p < 0.01), and the target levels were achieved in 56.93% (115 case) of patients. Following the 12-week treatment, serum TC and LDL concentrations reduced by 39.16% and 41.49%, respectively, compared to baseline levels (p < 0.01), and the target levels were achieved in 75.74% (153 cases) of patients (Table 3). 9 The relationship between CYP2C9 genotype and lipid-lowering efficacy and Intolerability of the rosuvastatin After the 12-week treatment, the reduction of the serum TC levels was 2.70 ± 0.31 mmol/L (38.96%) and 3.14 ± 0.25 mmol/L (45.05%) in patients with the CYP2C9 wild-type and mutant genotype, respectively, and the difference on the reduction of TC between the two groups reached statistical significance (P = 0.041). The reduction of the serum LDL levels after the 12-week treatment was 1.52 ± 0.38 mmol/L (39.28%) and 1.79 ± 0.32 mmol/L (44.97%) in patients with the CYP2C9 wild-type and mutant genotype, respectively. The reduction of LDL between the two groups are also significantly different (P = 0.029). Furthermore, we compared the proportion of patients who achieved ATP III guidelines targets (LDL < 2.59 mmol/L). No significant difference on the compliance rate of LDL was observed between wild-type genotype and mutant genotype patients [74.59% (138/185) vs. 88.23% (15/17), P = 0.337] (Table 4). Regarding the intolerability evaluations, sixteen of 218 (7.34%) patients terminated their involvement in the study due to ADRs. Among these 16 patients, 12 patients are CYP2C9 wild-type and 4 patients with CYP2C9*3. The adverse reaction rate of mutant genotype patients was higher than that of wild genotype patients (19.05% vs. 6.09%). However,No significant difference on the frequency of adverse reactions was observed among wild genotype and mutant genotype patients (P = 0.085; Table 4). Discussion In this study, rosuvastatin was tolerated by 202 patients at the dosage of 10 mg/d. Only 16 patients discontinued the medication due to adverse effects (7.34%). No patient had hepatotoxicity and myolysis. We showed that rosuvastatin had a time-dependent effect on 10 lipid-lowering response, after 4-week, 8-week and 12-week treatment with rosuvastatin (10 mg/day). There was a significant reduction in TC、TG、LDL levels and increase in HDL-C levels compared to the baseline after treatment. We also showed that subjects with the CYP2C9 mutant genotype showed a higher TC-lowering and LDL-lowing effect compared to those with the wild-type genotype. There is inter-individual variability in the lipid-lowering efficacy of the rosuvastatin. Some patients with rosuvastatin at a low dose of 5 mg/d can be in compliance with lipid-lowering and even occurred adverse reactions, while some subjects with rosuvastatin at a high dose of 20-40mg/d cannot be in compliance with lipid-lowering and thus leading withdrawal and dressing of the drug ultimately. In this study, we also observed the variation in the lipid-lowering response. Of the 202 patients completed the treatment, 153 patients (75.74%) achieved the 2002 ATP III guidelines LDL-C goal, and 24.26% of patients did not achieve the LDL-C target goal of 100mg/dl, which is needed to increase and adjust dosage. Individual differences in drug metabolism are primarily due to CYP450 genetic variations [9]. At least thirty CYP2C9 polymorphisms have been reported. CYP2C9*1 was the most common allele (wild type) followed by the CYP2C9*3 allele (15%), the others alleles are absent in East Asian populations[12-14]. In our study, CYP2C9 mutation alleles were only found in 21 of 218 Chinese hyperlipidemia patients, including 18 subjects with the heterozygotes mutation (CYP2C9*1/*3) and 3 subjects with the homozygote mutation genotype (CYP2C9*3/*3). No subjects with CYP2C9*2 alleles were identified. The frequency of mutant alleles and genotypes of this polymorphism was similar to the results reported previously in a Japanese population [15] and in a Chinese healthy population [16]. 11 In vitro, the CYP2C9*2 and CYP2C9*3 variants, code for enzymes with approximately 10–40% and 5–15% of the activity of the wild-type CYP2C9*1, respectively [8].The decreased CYP2C9 activity may cause slow metabolism, and thus, a higher plasma concentration of rosuvastatin, which increases the risk of ADRs at conventional doses. The impact of the CYP2C9 polymorphisms on drug metabolism was first investigated and has been extensively studied in warfarin therapy[17-20]. Currently, a limited number of studies have been conducted to investigate the relation between CYP2C9 gene polymorphisms and lipid-lowering response to stains. Kirchheiner et al. [21, 22] reported that the pharmacokinetics of fluvastatin (e.g. AUC) differed significantly in CYP2C9 genotype in 24 patients after taking 40 mg of fluvastatin daily for 14 days (P < 0.00001). Subjects carrying the CYP2C9*3/*3 genotype had a three-fold increase of the AUC of fluvastatin compared to subjects with the wild-type CYP2C9*1/*1 genotype. In our study, after treatment with 10 mg rosuvastatin for 12 weeks, we found that subjects with the mutant CYP2C9*1/*1 genotype showed a higher TC-lowering and LDL-lowing effect compared to patients with the wild-type t genotype. The percentage reduction in TC and LDL showed a statistically significant difference between patients with wild-type and mutant CYP2C9 genotypes. Patients with wild-type CYP2C9 also showed a slightly lower compliance rate of LDL target achievement compared to patients with mutant CYP2C9, however, this finding did not reach statistical significance. These results suggested that the pharmacokinetics of rosuvastatin may be influenced, to some extent, by CYP2C9 polymorphisms. These results also support our hypothesis that patients with CYP2C9 mutations may show increased concentrations of metabolized drugs, increasing the risk of adverse drug reactions. In contrast, patients with CYP2C9 wild type may not reach therapeutic concentrations at conventional 12 doses, leading to therapeutic failure with rosuvastatin As the limitations of the current study, we acknowledged that the major drawback was the relatively small sample size. Further studies that utilize larger sample sizes are needed to assess the possible link between CYP2C9 genetic variants and the activity of CYP2C9 in vitro. Nevertheless, we observed significant reductions in TC, TG and LDL levels and increase in HDL-C levels after the treatment of 10 mg/d rosuvastatin for 12 weeks. Patients with the mutant CYP2C9 genotypes showed a higher TC-lowering and LDL-lowing effect compared to those with wild-type genotypes. Our study suggested that the CYP2C9 polymorphism may be involved in the lipid-lowering efficacy of rosuvastatin in patients with hyperlipidemia. Acknowledgments This work was supported by the research funding from Huashan Hospital, Fudan University and the research funding from Shanghai Medical Association geriatrics specialist branch. 13 References 1. Gotto A.M., Jr. Lipid lowering, regression, and coronary events. A review of the Interdisciplinary Council on Lipids and Cardiovascular Risk Intervention, Seventh Council meeting. Circulation. 1995;92(3):646-656. 2. Olsson A.G., McTaggart F., Raza A. Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor. Cardiovasc Drug Rev. 2002;20(4):303-328. 3. Thompson G.R., O'Nill., Seed M. Why some patients respond poorly to statins and how this might be remedied. Europ Heart J. 2002;23(3):200. 4. Rubinstein A., Weintraub M. Escape phenomenon of low-density lipoprotein cholesterol during lovastatin treatment. Am J Cardiol. 1995;76(3):184-186. 5. Ingelman-Sundberg M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol Sci. 2004;25(4):193-200. 6. Bottorff M., Hansten P. Long-term safety of hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors: the role of metabolism-monograph for physicians. Arch Intern Med. 2000;160(15):2273-2280. 7. Wiwanitkit V. Pharmacogenomic effect of cytochrome P450 2C9 polymorphisms in different populations. Clin Appl Thromb Hemost. 2006;12(2):219-222. 8. Scordo M.G., Caputi A.P., D'Arrigo C., Fava G., et al. Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population. 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Pharmacol Rev. 2011;63(1):157-181. 15 Table 1 Frequency of alleles and genotypes for CYP2C9 by gender in 218 patients Total patients By gender Genotypes/phenotypes (%) Male Female P value Allele frequency CYP2C9*1 412 (94.5%) CYP2C9*3 24 (5.5%) CYP2C9*2 0 CYP2C9*1/ *1 197(90.3%) 127 70 CYP2C9*1/ *3 18 (8.3%) 13 5 CYP2C9*3/ *3 3 (1.3%) 2 1 EM (*1/ *1) 197 (90.3%) 127 70 PM(*1/ *3 and*3/ *3) 21 (9.6%) 15 6 Genotypes 0.341 Phenotype 0.525 16 Table 2 Study outcomes of patients with hyperlipidemia after treatment of 10 mg/d rosuvastatin for 12 weeks Elevated transaminases (n) Elevated CPK (n) GI Disorders (n) Discontinue treatment patients (n) Remaining patient (n) Baseline 0 0 0 0 218 1-4 weeks 3 2 4 9 209 5-8 weeks 4 2 0 6 203 9-12 weeks 0 1 0 1 202 17 Table 3 Comparison of lipid profiles in hypercholesterolemia patients before and after treatment with rosuvastatin (mmol/L, X ± s) Lipid Baseline profile * After 4-week After 8-week After 12-week treatment treatment treatment TC 6.79±0.95 4.92±0.81* 4.34±0.63** 4.12±0.48** TG 3.32±1.31 3.02±0.91* 2.64±0.80* 2.33±0.62* LDL 3.98±0.69 3.07±0.43* 2.65±0.40** 2.31±0.37** HDL 1.17±0.25 1.19±0.23* 1.21±0.25* 1.32±0.31** P < 0.05, ** P < 0.01, compared to the baseline. 18 Table 4 Association of the CYP2C9 polymorphism with the lipid-lowering efficacy and intolerability of the rosuvastatin Patients with Patients with wild-type mutant CYP2C9 CYP2C9 Baseline 6.93 ± 0.35 6.97 ± 0.21 12-week treatment 4.23 ± 0.37 3.83 ± 0.32 Changes 2.70 ± 0.31 3.14 ± 0.25 Baseline 3.87 ± 0.46 3.98 ± 0.37 12-week treatment 2.35 ± 0.43 2.19 ± 0.39 Changes 1.52 ± 0.38 1.79 ± 0.32 0.029 a 74.59% 88.23% 0.337 b 6.09 (12/197) 19.05 (4/21) 0.085b Lipid levels P value TC (mmol/L) Efficacy 0.041 a LDL (mmol/L) Compliance rate of LDL(%) Frequency of adverse Intolerability reactions (%) a Changes from the baseline were assessed by independent samples t-test. were analyzed by Fisher’s exact test of probabilities. b Frequencies