MMP2基因多态性与盐酸多奈哌齐治疗阿尔茨海默病的血药浓度和效果的关系

Relationship betweenmatrix metalloproteinase 2(MMP2)gene polymorphism and plasma concentration and efficacy of Donepezil hydrochloride in treatment of Alzheimer's disease(AD)

目的 探讨基质金属蛋白酶2(Matrix metalloproteinase 2,MMP2)基因单核苷酸多态性对盐酸多奈哌齐在阿尔茨海默病(Alzheimer′s disease, AD)中的血药浓度和治疗效果的影响。方法 选择2020年1月-2023年1月于徐州市东方人民医院老年精神科就诊治疗的97例AD患者为AD组,以同期进行体检的100名健康老年人为健康对照组。所有患者入院接受5 mg/d的盐酸多奈哌齐治疗,连续30 d,将盐酸多奈哌齐剂量增至10mg/d,连续150 d。治疗前后采用简明精神状况量表(Mini-mental state examination, MMSE)评估患者的认知功能,依据最后一次MMSE评分与第一次MMSE评分相比是否下降,分为应答组和未应答组。治疗6个月后采用高效液相色谱-串联质谱联用法测定两组血液中盐酸多奈哌齐血药浓度。采用实时定量PCR(Polymerase chain reaction, PCR)和限制性片段长度多态性分析检测血液中MMP2基因rs243865(C>T)、rs2285053(C>T)基因分型。结果 与健康对照组比较,AD组MMP2基因rs243865、rs2285053基因型分布,rs243865位点遗传模型差异无统计学意义(P>0.05),rs2285053位点显性模型差异有统计学意义(P<0.05)。经盐酸多奈哌齐治疗后,与未应答组比较,应答组MMP2基因rs243865基因型分布、遗传模型及隐性模型差异均无统计学意义(P>0.05),rs2285053基因型分布、相加模型、显性模型差异有统计学意义(P<0.05)。不同MMP2基因位点rs243865位点基因型AD患者的盐酸多奈哌齐血药浓度比较差异无统计学意义(P>0.05)。与rs2285053位点TT基因型AD患者比较,CC、CT基因型患者的盐酸多奈哌齐血药浓度增大,差异有统计学意义(P<0.05)。未应答组与应答组间盐酸多奈哌齐血药浓度差异无统计学意义(P>0.05)。结论 MMP2基因rs2285053位点变异与盐酸多奈哌齐治疗AD的血药浓度和疗效有关,对于临床治疗用药有一定指导价值。

Objective To investigate the effects of matrix metalloproteinase 2(MMP2)gene single nucleotide polymorphism on serum concentration and therapeutic efficacy of donepezil hydrochloride in Alzhei-mer's disease(AD).Methods 97 cases of AD patients treated in the hospital from January 2020 to Janu-ary 2023 were selected as AD group,and 100 healthy elderly people who underwent physical examination during the same period were selected as healthy control group.All patients were admitted to the hospital to receive 5 mg/d of donepezil hydrochloride for 1 month and then the dose of donepezil hydrochloride was increased to 10 mg/d for 150 days.Mini-mental state examination(MMSE)was used to evaluate the cog-nitive function of the patients before and after treatment.The patients were divided into response group and non-response group according to whether the last MMSE score was decreased compared with the first MMSE score.After 6 months of thetreatment,the concentration of donepezil hydrochloride in the blood of the 2 groups was determined by high performance liquid chromatography-tandem mass spectrometry.The genotypes of MMP2 gene rs243865(C>T),rs2285053(C>T)in blood were detected by real-time quantitative polymerase chain reaction(PCR)and restriction fragment length polymorphism analysis.Results Compared with the healthy control group,the genotype distribution of MMP2 gene rs243865 and rs2285053 in the AD group showed no statistically significant difference in the genetic model of rs243865 locus(P>0.05),while the dominant model of rs2285053 locus showed a statistically significant difference(P<0.05).Af-ter the treatment with donepezil hydrochloride,compared with the non responsive group,the response group showed no statistically significant differences in the distribution of MMP2 gene rs243865 genotype,genetic model and implicit model(P>0.05),while the distribution of rs2285053 genotype,additive mod-eland explicit model showed statistically significant differences(P<0.05).There was no statistically sig-nificant difference in the blood concentration of donepezil hydrochloride among AD patients with different MMP2 gene loci rs243865 genotype(P>0.05).Compared with the TT genotype AD patients at the rs2285053 locus,the blood concentration of donepezil hydrochloride was increased in CC and CT genotype patients,and the difference was statistically significant(P<0.05).There was no statistically significant difference in the blood concentration of donepezil hydrochloride between the non responsive group and the responsive group(P>0.05).Conclusion The variation of rs2285053 locus of MMP2 gene is related to the serum concentration and efficacy of donepezil hydrochloride in the treatment of AD,which has certain guiding value for clinical treatment.