Research Of Genetic Polymorphism And Adverse Reactions After Methotrexate Chemotherapy

High-dose methotrexate is one of the important components of childhood acute lymphoblastic leukemia(ALL)chemotherapy.Clinical observations show that the adverse reactions caused by the improvement of cure rate are individualized.67 children with acute lymphoblastic leukemia(ALL)in Sichuan Provincial People’s Hospital were enrolled in the study.Peripheral venous blood was drawn from children.Rs1801133,rs1801131 in methylenetetrahydrofolate reductase(MTHFR);rs11045879,rs2306283,rs4149056 in organic anion transporter 1B1(SLCO1B1);rs1544105 in folate polyglutamic acid synthase(FPGS);rs11545078 in γ-glutamyl hydrolase(GGH);rs1979277 in serine hydroxymethyl transfer polymorphism of enzyme 1(SHMT1)and rs408626 in dihydrofolate reductase(DHFR)were detected by real-time quantitative PCR.To investigate the frequency of gene distribution in children with ALL in Sichuan,and observe the changes between the above genetic polymorphism and the changes in plasma concentration after chemotherapy.The correlation of the occurrence of the reaction provides a reference for the individualized use of clinical methotrexate.The results are as follows:1.There was a significant difference in the gastrointestinal reaction among the three groups of MTHFR rs1801133(P=0.004).And the wild group is different from the mutant group in the white blood cell count(P=0.041).There was a significant difference in the basophil count among the rs1801131 genotypes(P=0.021).And a significant difference was observed in the probability of gastrointestinal reactions during the follow-up study(P=0.012).And also a significant difference in the probability of partial damage(P=0.024).2.There was a significant difference in the incidence of rash between SLCO1B1 rs2306283(P=0.000).There was a significant difference in the rash response between the wild and VS mutation groups(P=0.001).(P=0.044),there was a significant difference in the Cr difference(P=0.036).Rs4149056 There were significant differences in genotype basophil counts(P=0.020),hemoglobin count differences(P=0.034),and Cr differences(P=0.018).Follow-up studies showed three genotypes.There was a significant difference in the probability of cardiovascular adverse events(P=0.022).Follow-up studies showed a significant difference in the probability of neurological adverse events in the SLCO1B1 rs11045879 genotype(P=0.007).3.GG group and AG group were observed a significant difference in the doseadjusted concentration(P=0.006)in GGH rs11545078,and so do Cr value(P=0.042).4.There was a significant difference in gastrointestinal reactions between the two groups(P=0.005)in SHMT1 rs1979277 G>A.5.DHFR rs408626 wild group and mutation group were significantly different in Nervous system damage(P = 0.041),there was a significant difference in hemoglobin cell count(P = 0.044).6.Regression analysis showed 72 h blood concentration≤ 0.1μmol / L(P = 0.002,OR = 0.032,95% CI [0.004-0.272])was a factor of gastrointestinal reactions,body mass index(BMI)was a risk factors for mucositis in children(P=0.013,OR=1.338,95% CI [1.063-1.684]);immunophenotyping was a factor of mucositis(P=0.051,OR=5.358,95% CI [0.995-28.852]).Conclusions:1.GGH rs11545078 G>A gene polymorphism may affect the plasma concentration of children after ALL receiving HD-MTX administration;2.MTHFR rs1801133 C>T,SHMT rs 11979277 G>A gene polymorphism can be used as a predictor of gastrointestinal reactions after MTX chemotherapy;SLCO1B1 rs 2306283 A>G gene polymorphism can be used as a predictor after MTX chemotherapy;DHFR408626 T>C gene polymorphism can be used as a predictor of neurological damage after MTX chemotherapy;MTHFR rs1801133 C>T,SLCO1B1 rs 4149056 T>C,DHFR408626 T>C gene polymorphism may influence blood index,SLCO1B1 rs 2306283,rs 4149056,GGH rs11545078 gene polymorphism is a factor of liver and kidney function index after MTX chemotherapy;MTHFR rs1801131 A>G,SLCO1B1 rs 11045879 C>T rs 4149056 T>C,may affect the long-term survival rate and survival status of children;3.72 of blood concentration level,BMI value,immune typing and BMI may affect the adverse reactions in children.4.Detection of genetic polymorphisms in ALL children can help children to develop individualized MTX regimens.