载脂蛋白E基因多态性与阿托伐他汀调脂疗效的相关性
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摘要
目的：研究载脂蛋白E(ApoE)基因多态性对阿托伐他汀调脂疗效、以及对肝功能影响的相关性。为根据高脂血症患者基因型制定个体化给药方案提供依据。
方法：
1.研究对象及基因型分析选取某医院内科49例血脂异常患者[空腹血清检查总胆固醇(TC)>6.0mmol／L或低密度脂蛋白胆固醇(LDL-C)>3.36mmol／L或甘油三酯(TG)>1.78mmol／L或高密度脂蛋白(HDL-C)<0.82mmol／L]。抽取外周静脉血约1mL以提取基因组DNA；采用聚合酶链式反应-限制性内切酶片段长度多态性方法(PCR-RFLP)测定ApoE基因型,各基因型频率分布采用基因平衡估计,各等位基因例数取自然数。
2.阿托伐他汀疗效评价每人服用阿托伐他汀20mg,每晚一次；于治疗前及治疗后4周采集患者空腹静脉血,采用酶法测定血清总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白A(Apoa)以及血清碱性磷酸酶(ALP)、天门冬氨酸氨基转移酶(AST)、总胆红素(STB)、总胆汁酸(BA)、丙氨酸氨基转移酶(ALT)浓度,以给药后4周后TC、TG、LDL-C、HDL-C和Apoa的改变比例作为评价阿托伐他汀降脂疗效的标准,ALP、AST、STB、BA和ALT的改变比例作为评价阿托伐他汀肝功损害的标准；根据基因型分型结果将患者分组,分析不同等位基因与各生化指标水平变化的关系。
3.统计分析统计数据采用mean±SD表示,根据患者基因型分为E2、E3、E4三组。使用SPSS13.0统计软件分析：检测等位基因分布是否符合哈迪-温伯格(Hardy-Weinberg)平衡采用χ2检验；个体治疗前后各生化指标的比较采用配对t检验；不同基因型间生化指标的差异比较采用方差(ANOVA)分析。检测水准a=0.05。
结果：ApoE等位基因和基因型分布符合哈迪-温伯格(Hardy-Weinberg)平衡。
治疗前分析不同基因型的患者血脂水平无显著性差异(P>0.05)；患者每晚服用20mg阿托伐他汀4周后TC、TG、LDL-C水平有所下降,TC水平降低比例最大,TG降低比例最小。
治疗4周后分析不同基因型的患者血脂变化水平发现,在E2等位基因组的总胆固醇(TC)降低有统计学意义(P<0.05),而E3、E4组对血脂水平的降低作用不如E2组明显；各等位基因组间的指标变化程度经过统计分析没有发现显著性差异。
治疗前不同基因型的患者肝功水平无明显差异；患者每晚服用20mg阿托伐他汀4周后STB、BA和ALT水平有不同程度升高,ALT水平升高比例最大。
治疗4周后分析不同基因型的患者肝功变化水平发现,E3组等位基因组的STB(18±0.51%)与ALT(31±0.93%)改变较大；但各等位基因组间的肝功指标变化程度经过统计分析没有发现显著性差异。
结论：
1.阿托伐他汀降低E2携带者TC、LDL-C的作用优于E2非携带者；ApoE基因多态性对阿托伐他汀降脂疗效无显著影响。
2.阿托伐他汀对肝细胞有损害；ApoE基因多态性对阿托伐他汀发生肝功损伤无显著影响。
3.血脂异常患者每晚顿服20mg阿托伐他汀,4周后能获得良好的降脂疗效。
Objective:To study the relationship of ApoE restricted fragment length polymorphism and the therapeutic effect by atorvastatin, and the influence to hepatic function.The study provided an important foundation for the gene-directed rationalization and individualization of medication in the hyperlipidemic patients.
Methods:
Subjects and Genotyping A group of 49 Han Chinese hyperlipidemic patients[total cholesterol (TC)>6mmol·L-1 or triglycerides (TG)>1.78 mmol·L-1 or low-denstity lipoprotein cholesterol (LDL-C)>3.36 mmol·L-1 or high-denstity lipoprotein cholesterol (HDL-C)<0.82mmol·L-1] were recruited from hospitalized patients in a hospital. Venous blood(～1mL) was obtained from the patients and DNA was isolated from peripheral leucocytes. Genotyping of ApoE alleles were conducted by the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Genotype and allelic frequencies were calculated by gene counting.
Evaluation of efficacy of atorvastatin The hyperlipidemic patients were treated with 20mg atorvastatin daily for 4 weeks. The blood samples were obtained for lipids and hepatic function testing or DNA extraction before and after 4 weeks of treatment. The levels of serum TC, TG, LDL-C, HDL-C, Apoa and ALP, AST, STB, BA, ALT were measured by using Enzymatic in fasting condition. The effects measured at week 4 were the mean percentage change in TC, TG, LDL-C, HDL-C and Apoa from baseline; The hepatic dysfunction measured at week 4 were the mean percentage change in ALP, AST, STB, BA and ALT from baseline. We observed the effect of ApoE2, ApoE3 and ApoE4 genetic polymorphism on the lipid-lowering and hepatic function-changing efficacy by atorvastatin.
Statistical analysis The hyperlipidemic patients were divided into three groups according to the alleles, and allele frequencies were estimated from the observed numbers of each specific allele. SPSS 13.0 software was used for statistical analyses. Chi-square test was used to verify Hardy-Weinberg equilibrium. t test was used to compare the levels among before and after treatment. ANOVA was used to compare the differences in the lipid-lowering and change of hepatic function effects of atorvastatin. P-value<0.05 was considered statistically significant.
Results:The ApoE genetype and allelic frequency was consistent with Hardy-Weinberg equilibrium.
Baseline of lipid did not show significant difference in three groups; after oral intake of atorvastatin 20mg daily for 4 weeks, all the levels of TC, TG, LDL-C decreased than before treatment. The changed percentage of TC was the largest in the four levels; and the percentage of TG changed was the smallest.
After 4 weeks treatment, the group carrying E2 allele had more responsive(P<0.05) to atorvastatin than E3 and E4 alleles in total cholesterol(TC). Compared the changed value of lipids according to different alleles, we found that there were no significant differences about the change of TC, TG, LDL-C, HDL-C and Apoa. The ApoE locus did not account for any significant fraction of the variability in response.
At the same time, the levels of STB, BA and ALT increased after 4 weeks treatment in every groups. STB (18±0.51%) and ALT (31±0.93%) changed worse in the group carrying E3 allele, but we found that there were no significant differences between all groups.
Conclusion:
1.Patients carrying E2 allele was more prominent efficacy than non-carrying E2 allele; ApoE genetic polymorphism did not influence lipid-lowering efficacy of atorvastatin.
2. ApoE genetic polymorphism had no significant effect on adverse reactions of hepatic function.
3. Satisfactory lipid-lowering efficacy was obtained by hyperlipidemic patients with taking atorvastatin 20mg daily after 4 weeks.
方法：
1.研究对象及基因型分析选取某医院内科49例血脂异常患者[空腹血清检查总胆固醇(TC)>6.0mmol／L或低密度脂蛋白胆固醇(LDL-C)>3.36mmol／L或甘油三酯(TG)>1.78mmol／L或高密度脂蛋白(HDL-C)<0.82mmol／L]。抽取外周静脉血约1mL以提取基因组DNA；采用聚合酶链式反应-限制性内切酶片段长度多态性方法(PCR-RFLP)测定ApoE基因型,各基因型频率分布采用基因平衡估计,各等位基因例数取自然数。
2.阿托伐他汀疗效评价每人服用阿托伐他汀20mg,每晚一次；于治疗前及治疗后4周采集患者空腹静脉血,采用酶法测定血清总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白A(Apoa)以及血清碱性磷酸酶(ALP)、天门冬氨酸氨基转移酶(AST)、总胆红素(STB)、总胆汁酸(BA)、丙氨酸氨基转移酶(ALT)浓度,以给药后4周后TC、TG、LDL-C、HDL-C和Apoa的改变比例作为评价阿托伐他汀降脂疗效的标准,ALP、AST、STB、BA和ALT的改变比例作为评价阿托伐他汀肝功损害的标准；根据基因型分型结果将患者分组,分析不同等位基因与各生化指标水平变化的关系。
3.统计分析统计数据采用mean±SD表示,根据患者基因型分为E2、E3、E4三组。使用SPSS13.0统计软件分析：检测等位基因分布是否符合哈迪-温伯格(Hardy-Weinberg)平衡采用χ2检验；个体治疗前后各生化指标的比较采用配对t检验；不同基因型间生化指标的差异比较采用方差(ANOVA)分析。检测水准a=0.05。
结果：ApoE等位基因和基因型分布符合哈迪-温伯格(Hardy-Weinberg)平衡。
治疗前分析不同基因型的患者血脂水平无显著性差异(P>0.05)；患者每晚服用20mg阿托伐他汀4周后TC、TG、LDL-C水平有所下降,TC水平降低比例最大,TG降低比例最小。
治疗4周后分析不同基因型的患者血脂变化水平发现,在E2等位基因组的总胆固醇(TC)降低有统计学意义(P<0.05),而E3、E4组对血脂水平的降低作用不如E2组明显；各等位基因组间的指标变化程度经过统计分析没有发现显著性差异。
治疗前不同基因型的患者肝功水平无明显差异；患者每晚服用20mg阿托伐他汀4周后STB、BA和ALT水平有不同程度升高,ALT水平升高比例最大。
治疗4周后分析不同基因型的患者肝功变化水平发现,E3组等位基因组的STB(18±0.51%)与ALT(31±0.93%)改变较大；但各等位基因组间的肝功指标变化程度经过统计分析没有发现显著性差异。
结论：
1.阿托伐他汀降低E2携带者TC、LDL-C的作用优于E2非携带者；ApoE基因多态性对阿托伐他汀降脂疗效无显著影响。
2.阿托伐他汀对肝细胞有损害；ApoE基因多态性对阿托伐他汀发生肝功损伤无显著影响。
3.血脂异常患者每晚顿服20mg阿托伐他汀,4周后能获得良好的降脂疗效。
Objective:To study the relationship of ApoE restricted fragment length polymorphism and the therapeutic effect by atorvastatin, and the influence to hepatic function.The study provided an important foundation for the gene-directed rationalization and individualization of medication in the hyperlipidemic patients.
Methods:
Subjects and Genotyping A group of 49 Han Chinese hyperlipidemic patients[total cholesterol (TC)>6mmol·L-1 or triglycerides (TG)>1.78 mmol·L-1 or low-denstity lipoprotein cholesterol (LDL-C)>3.36 mmol·L-1 or high-denstity lipoprotein cholesterol (HDL-C)<0.82mmol·L-1] were recruited from hospitalized patients in a hospital. Venous blood(～1mL) was obtained from the patients and DNA was isolated from peripheral leucocytes. Genotyping of ApoE alleles were conducted by the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Genotype and allelic frequencies were calculated by gene counting.
Evaluation of efficacy of atorvastatin The hyperlipidemic patients were treated with 20mg atorvastatin daily for 4 weeks. The blood samples were obtained for lipids and hepatic function testing or DNA extraction before and after 4 weeks of treatment. The levels of serum TC, TG, LDL-C, HDL-C, Apoa and ALP, AST, STB, BA, ALT were measured by using Enzymatic in fasting condition. The effects measured at week 4 were the mean percentage change in TC, TG, LDL-C, HDL-C and Apoa from baseline; The hepatic dysfunction measured at week 4 were the mean percentage change in ALP, AST, STB, BA and ALT from baseline. We observed the effect of ApoE2, ApoE3 and ApoE4 genetic polymorphism on the lipid-lowering and hepatic function-changing efficacy by atorvastatin.
Statistical analysis The hyperlipidemic patients were divided into three groups according to the alleles, and allele frequencies were estimated from the observed numbers of each specific allele. SPSS 13.0 software was used for statistical analyses. Chi-square test was used to verify Hardy-Weinberg equilibrium. t test was used to compare the levels among before and after treatment. ANOVA was used to compare the differences in the lipid-lowering and change of hepatic function effects of atorvastatin. P-value<0.05 was considered statistically significant.
Results:The ApoE genetype and allelic frequency was consistent with Hardy-Weinberg equilibrium.
Baseline of lipid did not show significant difference in three groups; after oral intake of atorvastatin 20mg daily for 4 weeks, all the levels of TC, TG, LDL-C decreased than before treatment. The changed percentage of TC was the largest in the four levels; and the percentage of TG changed was the smallest.
After 4 weeks treatment, the group carrying E2 allele had more responsive(P<0.05) to atorvastatin than E3 and E4 alleles in total cholesterol(TC). Compared the changed value of lipids according to different alleles, we found that there were no significant differences about the change of TC, TG, LDL-C, HDL-C and Apoa. The ApoE locus did not account for any significant fraction of the variability in response.
At the same time, the levels of STB, BA and ALT increased after 4 weeks treatment in every groups. STB (18±0.51%) and ALT (31±0.93%) changed worse in the group carrying E3 allele, but we found that there were no significant differences between all groups.
Conclusion:
1.Patients carrying E2 allele was more prominent efficacy than non-carrying E2 allele; ApoE genetic polymorphism did not influence lipid-lowering efficacy of atorvastatin.
2. ApoE genetic polymorphism had no significant effect on adverse reactions of hepatic function.
3. Satisfactory lipid-lowering efficacy was obtained by hyperlipidemic patients with taking atorvastatin 20mg daily after 4 weeks.
引文
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