Association Of Genetic Polymorphisms With Acute Rejection And Nephrotoxicity In Renal Transplant Patients Taking Tacrolimus

OBJECTIVETo explore the relationship between polymorphisms of related genes(CYP3A4,CYP3A5,POR,MDR1,SLCO1B3,PXR,FOXP3)and the acute reaction and nephrotoxicity of tacrolimus in kidney transplant patients,and provide a theoretical basis for individualized medication in kidney transplant patients.METHOD1.The 200 cases of kidney transplantation in our hospital from May 2007 to April2019 who had been using Tac-based triple immunosuppressive regimen for the first time after kidney transplantation were used as the research objects,and the basic data,medication status and clinical data of the patients were collected Wait.The time period for collecting clinical information was selected as 7 days,15 days,1 month,3 months,6months,12 months,and 24 months after the patient's operation,including the patient's medication status(Tac dosage,trough concentration)and related inspections in each time period(Mainly the situation of acute rejection,renal function,etc.).2.All selected renal transplant recipients were genotyped for metabolic enzyme genes(CYP3A4,CYP3A5,POR),transporter genes(MDR1,SLCO1B3),and transcriptional regulatory genes(PXR,FOXP3)polymorphisms by high-throughput technology.3.All data were processed by SPSS software to analyze the correlation between patient genotypes and clinical efficacy and nephrotoxicity of tacrolimus in kidney transplant patients.RESULT1.200 kidney transplant patients were divided into AR group(n=46)and NAR group(n=154)according to the presence or absence of acute rejection.There was a significant gender difference between the two groups(P<0.05).There was no significant difference in general clinical data such as body weight and cadaveric kidney rate(P>0.05);according to the presence or absence of nephrotoxicity,200 patients were divided into nephrotoxicity group(n=32)and control group(n=168).There was no significant difference in general Linchuan data between the two groups(P>0.05);2.The frequency of CYP3A4*18B,CYP3A5*3,POR*28,ABCB1,MDR1(rs1128503?rs2032582?rs1045642),SLCO1B3,PXR(rs6785049?rs1523127?rs3842689),and FOXP3mutation in the renal transplant recipients was 26.50%,68.50%,38.25%,62.25%,53.50%,36.5%,73.75%,38.00%,75.00%,26.50%,19.75%,and their gene distribution conformed to Hardy-Weinberg law;3.The Tac C₀/D value of patients with CYP3A4*18B gene mutation type significantly decreased at 1 week,1month,3months,6 months,12 months,and 24 months after surgery(P<0.05);Tac C₀/D value of patients with CYP3A5*3 gene mutation type Significantly increased at 1 week,1 month,3 months,6 months,12 months,and 24 months after surgery(P<0.05);POR*28 gene mutation was associated with the decrease of Tac C₀and C₀/D values in CYP3A5 expression group(P<0.05);Tac C₀/D in patients with SLCO1B3 gene mutation The D value increased significantly at 1 week after surgery(P<0.05);MDR1 C1236T,G2677T/A,C3435T and PXR G7635A,C24381A,6-base deletion,FOXP3 C3279A mutation and Tac C₀and C₀/D values had no significant correlation(P>0.05);4.Logistic regression analysis with general clinical data as a covariate.The results of the study showed that male patients are more likely to develop nephrotoxicity,and male was a risk factor for nephrotoxicity caused by Tac;the relevant genotype of the patient was used as a covariate to perform Logistic regression analysis.The results found that CYP3A4*18B AA genotype and CYP3A5*3GG genotype were risk factors for postoperative Tac-induced nephrotoxicity,and no correlation between the remaining gene polymorphisms and Tac acute rejection and nephrotoxicity was found.CONCLUSIONCYP3A4*18B and CYP3A5*3 in drug metabolizing enzyme-related genes were significantly correlated with Tac C₀and C₀/D values in kidney transplant patients.POR*28gene mutation was related to decreased Tac C₀and C₀/D values in patients with CYP3A5expression group;While there was no significant correlation between MDR1 C1236T,G2677T/A,C3435T,SLCO1B3,PXR G7635A,C24381A,6-base deletion,FOXP3C3279A with Tac C₀and C₀/D values of kidney transplant patients.Otherwise,male was a risk factor for nephrotoxicity caused by Tac,CYP3A4*18B AA genotype and CYP3A5*3GG Genotype was a risk factor for renal toxicity caused by Tac after operation.