Abstract:

Objective　To investigate the influence of the gene polymorphism and expression level of recombinant phosphodiesterase 9A (PDE9A) on the lipid-regulating efficacy of atorvastatin in patients with coronary heart disease (CHD). Methods　It was a retrospective cohort study. A total of 186 patients with CHD who were admitted to Xianyang First People's Hospital and Yan'an University Xianyang Hospital from May 2022 to May 2023 were selected. Among them, there were 115 males and 71 females, with an age of (47.85±6.42) years old and a body mass index (BMI) of (22.27±2.53) kg/m². All the patients received 3-month atorvastatin treatment (oral administration, starting dose of 10 mg per time, once a day, and the lipid levels were rechecked every 4 weeks for individualized adjustment, with the maximum dose of 80 mg per time). Another 100 healthy individuals who underwent physical examinations during the same period were selected as the control group. Among them, there were 52 males and 48 females, with an age of (47.62±6.34) years old and a BMI of (22.15±2.60) kg/m². The expression level of PDE9A was compared between the control group and the CHD group. Based on the PDE9A genotype distribution of the CHD patients, they were divided into 3 groups: CC type (58 cases), CT type (86 cases), and TT type (42 cases). The frequency distribution of PDE9A alleles and genotypes were determined in the 186 CHD patients. The levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in the CHD patients with different genotypes were measured before and after treatment, and their change rates were calculated [lipid change rate = (lipid level before treatment - lipid level after treatment) / lipid level before treatment × 100%]. Statistical analysis was conducted using the independent sample t-test, one-way analysis of variance, LSD test, Kruskal-Wallis H test, and χ² test. Results　The expression level of PDE9A in the CHD patients was significantly upregulated compared with that in the control group [(1.06±0.08) vs. (0.87±0.13)], with a statistically significant difference (t=15.276, P<0.001). There were no statistically significant differences in the levels of gender, age, BMI, fasting blood glucose, systolic blood pressure, diastolic blood pressure, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and serum creatinine (Scr) among the three genotypes of the CHD patients (all P>0.05). The distribution of each genotype at the rs2250870 locus of the PDE9A gene in 186 CHD patients conformed to the Hardy-Weinberg genetic equilibrium law (χ²=0.870, P>0.05). Before treatment, there was no statistically significant difference in the blood lipid levels among the three groups of CHD patients (all P>0.05); compared with those before treatment, the levels of TC, TG, and LDL-C in the three groups decreased after treatment, while the level of HDL-C increased (all P<0.05); after treatment, there was no statistically significant difference in the TG level among the three groups (P>0.05), but the levels of TC and LDL-C of CC type were lower than those of CT and TT types, the level of HDL-C was higher than those of CT and TT types, and the level of LDL-C of CT type was lower than that of TT type (all P<0.05). The change rates of TC, LDL-C, and HDL-C levels of CC type were higher than those of CT and TT types, with statistically significant differences (H=3.568, 16.984, and 11.718, all P<0.05); there was no statistically significant difference in the change rate of TG level among the three groups (P>0.05). Conclusions　The polymorphism of the PDE9A gene is correlated with the lipid-regulating efficacy of atorvastatin. Different genotypes at the rs2250870 locus have differential effects on the efficacy of atorvastatin. The reductions in TC and LDL-C and the increase in HDL-C in patients with the CC genotype after treatment are greater than those in patients with the CT and TT genotypes. This locus may affect the drug response through the dominant inheritance pattern.

Key words:

Coronary heart disease, Atorvastatin, PDE9A, Gene polymorphism, Low density lipoprotein cholesterol

摘要：

目的　研究磷酸二酯酶9A（recombinant phosphodiesterase 9A，PDE9A）基因多态性及其表达水平对阿托伐他汀调脂的冠心病（coronary heart disease，CHD）患者疗效影响。方法　回顾性队列研究。选取2022年5月至2023年5月咸阳市第一人民医院及延安大学咸阳医院收治的186例CHD患者，其中男115例，女71例，年龄（47.85±6.42）岁，体重指数（BMI）（22.27±2.53）kg/m²，均接受3个月阿托伐他汀治疗（口服，起始剂量为10 mg/次，每日一次，每4周复查血脂进行个体化调整，最大剂量为80 mg/次）；另选取同期100例体检健康者作为对照组，其中男52例，女48例，年龄（47.62±6.34）岁，BMI（22.15±2.60）kg/m²。比较对照组与CHD组PDE9A表达水平；CHD患者依据PDE9A基因型分为3组，CC（58例）、CT（86例）与TT（42例）。测定186例CHD患者PDE9A等位基因与基因型频率分布；检测不同基因型CHD患者治疗前后总胆固醇（total cholesterol，TC）、甘油三酯（triglyceride，TG）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（high-density lipoprotein cholesterol，HDL-C）水平及变化率［血脂变化率=（治疗前血脂水平-治疗后血脂水平）/治疗前血脂水平×100%］。采用独立样本t检验、单因素方差分析、LSD检验、Kruskal-Wallis H检验、χ²检验进行统计学分析。结果　CHD患者PDE9A表达水平较对照组上调［（1.06±0.08）比（0.87±0.13）］，差异有统计学意义（t=15.276，P<0.001）。3种基因型CHD患者性别、年龄、BMI、空腹血糖、收缩压、舒张压、丙氨酸氨基转移酶（alanine aminotransferase，ALT）、天门冬氨酸氨基转移酶（aspartate aminotransferase，AST）、血尿素氮（blood urea nitrogen，BUN）、血肌酐（serum creatinine，Scr）水平对比，差异均无统计学意义（均P>0.05）。PDE9A基因rs2250870位点各基因型在186例CHD患者中的分布符合Hardy-Weinberg遗传平衡定律（χ²=0.870，P>0.05）。治疗前，3组CHD患者血脂水平对比，差异均无统计学意义（均P>0.05）；与治疗前相比，3组患者治疗后TC、TG、LDL-C水平降低，HDL-C水平升高（均P<0.05）；治疗后，3组患者TG水平对比差异无统计学意义（P>0.05），但CC型TC、LDL-C水平低于CT、TT型，HDL-C水平高于CT、TT型，CT型LDL-C水平低于TT型（均P<0.05）。CC型TC、LDL-C、HDL-C水平变化率高于CT、TT型，差异均有统计学意义（H=3.568、16.984、11.718，均P<0.05）；3组TG水平变化率对比，差异无统计学意义（P>0.05）。结论　PDE9A基因多态性与阿托伐他汀调脂疗效存在相关性，rs2250870位点不同基因型对阿托伐他汀疗效有差异化影响，CC型患者治疗后TC、LDL-C下降幅度及HDL-C升高幅度大于CT、TT型，该位点可能通过显性遗传模式影响药物反应。

关键词:

冠心病, 阿托伐他汀, PDE9A, 基因多态性, 低密度脂蛋白胆固醇