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Volume 39 Issue 3
May  2021
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LIU Yanhui, DONG Jing, LU Yan, LU Man, DING Yunhe, LI Wenyan. Effects of SLCO1B1 521 T>C and APOE gene polymorphisms on lipid-lowering efficacy and adverse reactions of atorvastatin[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(3): 245-248. doi: 10.12206/j.issn.1006-0111.202012013
Citation: LIU Yanhui, DONG Jing, LU Yan, LU Man, DING Yunhe, LI Wenyan. Effects of SLCO1B1 521 T>C and APOE gene polymorphisms on lipid-lowering efficacy and adverse reactions of atorvastatin[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(3): 245-248. doi: 10.12206/j.issn.1006-0111.202012013

Effects of SLCO1B1 521 T>C and APOE gene polymorphisms on lipid-lowering efficacy and adverse reactions of atorvastatin

doi: 10.12206/j.issn.1006-0111.202012013
  • Received Date: 2020-12-21
  • Rev Recd Date: 2021-03-01
  • Available Online: 2021-05-25
  • Publish Date: 2021-05-25
  •   Objective  To study the effect of SLCO1B1 521 T>C and APOE gene polymorphisms on the clinical efficacy and safety of atorvastatin in ischemic stroke patients with dyslipidemia.  Methods  210 cases of ischemic stroke with dyslipidemia were enrolled from April 2018 to December 2018 to determine SLCO1B1 521 T>C and APOE gene polymorphisms. Patients received atorvastatin 20 mg/d orally. TC, TG, HDL-C, LDL-C levels were measured to evaluate the efficacy 3 months pre-and post- treatment. TBil, ALT, AST, CK levels were assayed with following up adverse reactions to evaluate safety.  Results  SLCO1B1 521 T>C genotype distribution was TT79.05%, TC19.05%, CC1.90%. E2, E3, E4 allele frequencies of APOE genes were 14.28%, 67.62%, 18.10%. Each genotype conforms to the law of Hardy-Weinberg balance. After three months of medication, there were significant differences in TC, TG, LDL-C, HDL-C changes in patients with different APOE genotypes. No obvious abnormality was found in safety index. The incidence of myalgia in SLCO1B1521 T>C mutant group was significantly higher than that in the wild group (P<0.01).  Conclusion  Lipid regulation of atorvastatin was affected by APOE gene polymorphism. SLCO1B1521 T>C may be associated with myalgia, the adverse reaction of atorvastatin. The detection of SLCO1B1 and APOE genotyping is helpful for individualized treatment of blood lipids and provides basis for rational use of statins in patients for drug therapy management.
  • [1] 中国心血管病风险评估和管理指南编写联合委员会. 中国心血管病风险评估和管理指南[J]. 中国循环杂志, 2019, 34(1):4-28. doi:  10.3969/j.issn.1000-3614.2019.01.002
    [2] MORAN A, GU D F, ZHAO D, et al. Future cardiovascular disease in China: Markov model and risk factor scenario projections from the coronary heart disease policy model-China[J]. Circ Cardiovasc Qual Outcomes,2010,3(3):243-252. doi:  10.1161/CIRCOUTCOMES.109.910711
    [3] 脑卒中防治系列指导规范编审委员会. 中国缺血性脑卒中血脂管理指导规范[J]. 实用心脑肺血管病杂志, 2015, 23(4):117.
    [4] BAIGENT C, KEECH A, KEARNEY PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, 056 participants in 14 randomised trials of statins[J]. Lancet,2005,366:1267-1278. doi:  10.1016/S0140-6736(05)67394-1
    [5] 何瑞, 徐志猛, 王来, 等. 他汀相关肌肉症状的研究进展[J]. 药学进展, 2020, 44(4):303-312.
    [6] BAI X, ZHANG B, WANG P, et al. Effects of SLCO1B1 and GATM gene variants on rosuvastatin-induced myopathy are unrelated to high plasma exposure of rosuvastatin and its metabolites[J]. Acta Pharmacol Sin,2019,40(4):492-499. doi:  10.1038/s41401-018-0013-y
    [7] 王婧, 赵帅, 王建欣. 缺血性脑卒中患者SLCO1B1和APOE基因多态性对阿托伐他汀疗效和安全性的影响[J]. 中国医院药学杂志, 2020, 40(16):1749-1754.
    [8] CHOUINARD-WATKINS R, PLOURDE M. Fatty acid metabolism in carriers of apolipoprotein E epsilon 4 allele: is it contributing to higher risk of cognitive decline and coronary heart disease? Nutrients,2014,6(10):4452-4471. doi:  10.3390/nu6104452
    [9] ZHANG Y, WEI DD, YUAN R, et al. Effects of APOE gene polymorphismon the efficacy of the atorvastatin in the treatment of hyperlipidemia[J]. Natl Med J China(中华医学杂志),2017,97(4):291-294.
    [10] KIRAC D, BAYAM E, DAGDELEN M, et al. HMGCR and APOE mutations may cause different responses to lipid lowering statin therapy[J]. Cell Mol Biol (Noisy-le-grand),2017,63(10):43-48. doi:  10.14715/cmb/2017.63.10.6
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Effects of SLCO1B1 521 T>C and APOE gene polymorphisms on lipid-lowering efficacy and adverse reactions of atorvastatin

doi: 10.12206/j.issn.1006-0111.202012013

Abstract:   Objective  To study the effect of SLCO1B1 521 T>C and APOE gene polymorphisms on the clinical efficacy and safety of atorvastatin in ischemic stroke patients with dyslipidemia.  Methods  210 cases of ischemic stroke with dyslipidemia were enrolled from April 2018 to December 2018 to determine SLCO1B1 521 T>C and APOE gene polymorphisms. Patients received atorvastatin 20 mg/d orally. TC, TG, HDL-C, LDL-C levels were measured to evaluate the efficacy 3 months pre-and post- treatment. TBil, ALT, AST, CK levels were assayed with following up adverse reactions to evaluate safety.  Results  SLCO1B1 521 T>C genotype distribution was TT79.05%, TC19.05%, CC1.90%. E2, E3, E4 allele frequencies of APOE genes were 14.28%, 67.62%, 18.10%. Each genotype conforms to the law of Hardy-Weinberg balance. After three months of medication, there were significant differences in TC, TG, LDL-C, HDL-C changes in patients with different APOE genotypes. No obvious abnormality was found in safety index. The incidence of myalgia in SLCO1B1521 T>C mutant group was significantly higher than that in the wild group (P<0.01).  Conclusion  Lipid regulation of atorvastatin was affected by APOE gene polymorphism. SLCO1B1521 T>C may be associated with myalgia, the adverse reaction of atorvastatin. The detection of SLCO1B1 and APOE genotyping is helpful for individualized treatment of blood lipids and provides basis for rational use of statins in patients for drug therapy management.

LIU Yanhui, DONG Jing, LU Yan, LU Man, DING Yunhe, LI Wenyan. Effects of SLCO1B1 521 T>C and APOE gene polymorphisms on lipid-lowering efficacy and adverse reactions of atorvastatin[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(3): 245-248. doi: 10.12206/j.issn.1006-0111.202012013
Citation: LIU Yanhui, DONG Jing, LU Yan, LU Man, DING Yunhe, LI Wenyan. Effects of SLCO1B1 521 T>C and APOE gene polymorphisms on lipid-lowering efficacy and adverse reactions of atorvastatin[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(3): 245-248. doi: 10.12206/j.issn.1006-0111.202012013
  • 目前,脑卒中、冠心病等心血管病(cardiovascular disease, CVD)是造成我国居民死亡和疾病负担的首要病因[1]。有研究预测,2010−2030年间我国成年人血清胆固醇水平的升高将会造成心血管病事件增加920万例,预示未来中国成年人血脂异常及相关疾病负担将继续加重[2]。以低密度脂蛋白胆固醇(LDL-C)或总胆固醇(TC)升高为特点的血脂异常是缺血性脑卒中的重要危险因素,血清胆固醇水平升高与缺血性卒中的发生密切相关[3]。降低LDL-C水平,可显著减少其发病及死亡危险[4]。阿托伐他汀(atrovastatin)为亲水性羟甲基戊二酰辅酶A还原酶(HMG-CoA)抑制剂,临床用于降脂和调脂治疗,但其疗效和不良反应具有明显的个体差异性,考虑可能与患者的基因多态性有关。

    以往他汀药物基因多态性研究多以高血脂症患者为研究对象,而对心血管疾病极高危和高危人群研究较少,且用药后观察时间较短,一般不超过2个月。笔者研究缺血性脑卒中伴血脂异常患者的SLCO1B1、APOE基因多态性及阿托伐他汀用药3个月后疗效、不良反应的相关性,从遗传变异角度评价药物疗效的临床差异,以期为阿托伐他汀的临床长期用药提供参考。

  • 选取上海市浦东新区公利医院2018年4月至2018年12月收治的缺血性脑卒中伴血脂异常患者。纳入标准:①符合2016年修订的《中国血脂异常防治指南》血脂异常诊断标准;②入院前3个月内服用过他汀类及其他调脂类(如贝特类、烟酸类、依折麦布等)。排除标准:①肝、肾功能不全者;②严重感染、恶性肿瘤、甲状腺和血液系统等疾病患者;③患者未进行规律服药及复查,临床记录不完整的患者。入选患者共210例,男132例(62.86%),女78例(37.14%),平均年龄(67.29±12.49)岁。

  • 入选患者首次服药前空腹抽取外周静脉血2 ml置于eDTA抗凝管中,采用磁珠法提取全血DNA,提取好的基因组DNA在−20 ℃下储存;采用PCR技术扩增特定基因片段:PCR系统包括:2 μl基因组DNA,25 mmol/L脱氧核糖核苷三磷酸(dNTPs),1 μmol/L引物,25 mmol/L镁离子(Mg2+),5 U/μl PCR DNA聚合酶,总反应体积为5 μl。PCR反应参数为循环参数:95 ℃ 2 min,(95 ℃ 30 s,60 ℃ 30 s,72 ℃ 60 s)45个循环,72 ℃ 5 min,4 ℃保温。7 μl的纯化PCR产物进行单碱基延伸反应,反应参数为:94 ℃ 30 s,[94 ℃ 5 s,(52 ℃ 5 s,80 ℃ 5 s)该步骤5个循环]40个循环,72 ℃ 3 min,4 ℃ 保温。运用飞行时间质谱法进行包括SLCO1B1 521T>C(rs4149056)与APOE 526C>T(rs429358)、388T>C(rs7412)的基因分型检测。

  • 入选患者首次服用阿托伐他汀20 mg/d前及服药3个月后,空腹采集全血标本2 ml,全自动生化仪测定疗效指标血清TC、TG、HDL-C和LDL-C,以及安全性指标总胆红素(TBil)、谷丙转氨酶(ALT)、碱性磷酸酶(ALP)、肌酸激酶(CK)水平。收集患者服药期间患者肌痛的发生情况,包括肌钝痛、酸痛,四肢及远端压痛,运动时或之后即刻痛性痉挛等不良反应。其中,他汀类相关肌病(SAM)诊断标准为①肌痛:肌组织疼痛或无力,但CK水平无明显升高。②肌炎:肌组织有疼痛症状,CK水平轻-中度升高但小于正常值上限5倍。③横纹肌溶解:肌组织有明显疼痛症状,CK水平超过正常上限5倍及以上、褐色尿及肌红蛋白尿合并急性肾功能衰竭[5]。追踪纳入的210例患者长期服用阿托伐他汀期间不良反应的主诉情况,并排除重体力劳动和长期剧烈运动对患者的影响。

  • 采用SPSS 22.0统计软件对观察指标的结果进行分析,连续变量以($ \bar x$±s)表示,通过χ2检验验证SLCO1B1和APOE各基因型分布是否符合Hardy-Weinberg平衡,P>0.05代表该基因型已经在本群体中达到遗传平衡。计量资料符合正态分布采用($ \bar x$±s)表示,组间均数比较采用方差分析,以P<0.05为差异有统计学意义。

  • 采用直接计数法统计基因型,计算各位点等位基因频率。SLCO1B1 521 T>C在缺血性脑卒中伴血脂异常患者中,等位基因型频率为11.43%,SLCO1B1 521T>C基因型分布符合Hardy-Weinberg平衡定律(χ2=0.73,P=0.39),P>0.05表明本研究人群具有群体代表性。APOE基因型分布符合Hardy-Weinberg平衡定律(χ2=0.61,P=0.43),P>0.05表明本研究人群具有群体代表性,各基因型分布见表1

    基因型野生型
    纯合型(TT)
    突变
    杂合型(TC)
    突变
    纯合型(CC)
    等位基因
    (频率/%)
    TC
    SLCO1B1521 T>C166
    (79.05)
    40
    (19.05)
    4
    (1.90)
    372
    (88.57)
    48
    (11.43)
    APOE526 C>T169
    (80.47)
    38
    (18.10)
    3
    (1.43)
    376
    (89.52)
    44
    (10.48)
    388 T>C5
    (2.38)
    28
    (13.33)
    177
    (84.29)
    38
    (9.05)
    382
    (90.95)
  • APOE基因表型E3组(e3/e3、e2/e4)最高,占67.62%;E2组(e2/e2、e2/e3)占14.28%;E4组(e3/e4、e4/e4)占18.10%,详见表2

    基因分型等位基因数量(例)合计(例)频率(%)
    E2e2/e2(TT/TT)53014.28
    e2/e3(TT/CT)25
    E3e3/e3(TT/CC)13914267.62
    e2/e4(TC/TC)3
    E4e3/e4(CT/CC)353818.10
    e4/e4(CC/CC)3
    合计210210100
  • 用药后APOE不同基因型患者TG、TC、HDL-C、LDL-C变化率均有显著性差异(P<0.01),见表3。经组间比较,TC值降低幅度和HDL-C升高幅度E3优于E2、E4(P<0.01),TG和LDL-C值降低幅度E2、E3优于E4(P<0.01)。

    APOE分型血脂水平变化率(%)
    TCTGHDL−CLDL−C
    E2(n=30)−5.14±43.07−10.33±20.52−3.66±17.97−15.93±24.38
    E3(n=142)−22.06±10.95−10.54±6.0810.75±7.31−17.85±6.39
    E4(n=38)−7.30±13.125.86±24.18−0.38±15.50−5.85±16.27
    F15.361522.055029.888613.6252
    P<0.01<0.01<0.01<0.01
  • 两组患者TBil、ALT、ALP的变化率差异无统计学意义(P>0.05),(TC+CC)组较TT组能显著升高CK,有统计学意义(P<0.01),见表4

    组别安全性指标变化(%)
    TBilALTALPCK
    TT(n=166)30.06±25.8336.27±50.2223.68±42.328.39±32.28
    TC+CC(n=44)22.62±31.0120.36±45.2235.49±54.6328.62±29.66
    P>0.05>0.05>0.05<0.05
  • 纳入的210例患者中,共有10例患者表示出现不同程度的肌痛症状,其中,8例患者为SLCO1B1突变型(CT+CC),2例为SLCO1B1野生型(TT型),两组肌痛发生率有显著性差异(P<0.01),见表5

    基因位点基因型无肌痛肌痛
    SLCO1B1(n=210)TT(n=166)164 2
    TC+CC(n=44) 36 8
    合计20010
  • 阿托伐他汀,3-羟基-3-甲基-戊二酰(HMG)-CoA还原酶抑制剂,不仅被广泛用于治疗高胆固醇血症,在动脉粥样硬化性心血管疾病(ASCVD)一级和二级预防中亦能显著降低心血管事件风险。但在临床实践中,阿托伐他汀的降脂效果,以及药物不良反应个体差异较大,这可能与基因遗传学方面有关,而SLCO1B1和APOE则是2个重要基因。

    有机阴离子转运体OATP1B1是SLCO1B1基因编码蛋白,主要存在于人体肝脏的基底膜外侧,负责将多种内源性和外源性物质由血液转运至肝细胞内。阿托伐他汀需经OATP1B1主动摄取进入肝细胞,从而发挥降血脂的作用。目前发现SLCO1B1具有很高的遗传变异性,尤其是521T>C位点突变使OATP1B1转运功能下降,降低了肝细胞内药物浓度, 而升高体循环中的药物浓度,此时可能导致肌肉损伤等毒副作用。BAI等分析了758例服用阿托伐他汀后出现SAM的患者,发现SLCO1B1521 T>C突变与高他汀类相关肌病(SAM)风险显著相关(R=1.741,95%CI:1.180~2.568,P=0.005)[6]。王婧等[7]研究认为,SLCO1B1基因388A>G对阿托伐他汀降脂效果无显著影响。本研究发现,SLCO1B1基因521 T>C TC/CC组有18.18%患者出现肌痛症状,与TT组相比差异有统计学意义,这可能与患者体内阿托伐他汀药物浓度升高有关。因此,SLCO1B1基因521 T>C增大了患者发生肌病的风险,对于有SLCO1B1521 T>C等位基因突变的患者,建议临床使用时降低他汀类药物剂量或更换他汀类品种。

    APOE是一种蛋白质,在脂质体内平衡中起着关键作用,因为它调节血液和大脑中的胆固醇,甘油三酸酯和磷脂代谢。ApoE蛋白的产生受APOE基因的控制,针对该基因可识别3个不同的等位基因:ε2,ε3和ε4。APOE位于乳糜微粒、高密度脂蛋白(HDL)、中密度脂蛋白(IDL)和极低密度脂蛋白(VLDL)的表面。APOE基因调节该蛋白的表达,并具有3个不同的等位基因:ε2,ε3和ε4[8]。张宇等[9]报道,经阿托伐他汀治疗后,APOE基因型e3/e3患者的血脂水平及APOE基因表达的下调程度均高于e3/e4型患者。Kirac等[10]研究发现,经阿托伐他汀治疗后,对APOE基因e2携带者的降脂作用最强,e4突变型患者主要见于无效组中。本研究中,患者经阿托伐他汀治疗后,APOE E4等位基因携带者对阿托伐他汀降脂治疗不敏感,故此类型患者可采用非他汀类调脂药物治疗。

    综上所述,本研究发现APOE基因型影响阿托伐他汀降脂效果,而SLCO1B1521 T>C基因型与增加肌病的风险相关。药师在开展药物治疗管理时,可通过相应的基因多态性检测评估患者疗效和出现肌病的风险,合理选择降脂药物品种和剂量,提高临床用药的有效性和安全性,实现个体化用药。因本研究病例数有限,后续还需多中心、大样本、前瞻性研究等临床试验进一步验证。

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