Association Study Of UGT1A4Genetic Polymorphism With The Serum Concentration And Clinical Effects Of Lamotrigine

Objective:Investigate the association between UGT1A470C>A、UGT142T>G genepolymorphisms and the serum concentrations of lamotrigine and clinical curativeeffect to provide the theory basis for the individual antiepileptic treatment.Methods:Collected106epileptic patients who took lamotrigine singlely and regularlymore than one month and daily doses greater than50mg from June2011to September2012,male40cases and female66cases.All patients were monitored in the firstclinical hospital and the third clinical hospital of jilin university.The span of age is14-77(32.07±12.88).Steady serum concentration were monitored from6ml venousblood drawed in the morning before the patients took lamogritine.Liquidchromatography-tandem mass spectrometry(LC-MS/MS) was used to measure theserum concentration of lamotrigine which was standardized by dosage and bodyweight. Genome DNA were extracted from blood cells.The genotypes of UGT1A470C>A and UGT1A4142T>G in all subjects were determined by directsequencing.At the same time,to track and observe the clinical efficacy of patients for ayear.Statistical analyses were performed by multivariate linear regression,T-test,nonparametric-test and chi-square test.Differences at P<0.05were consideredsignificant.Results：The genotype of UGT1A470C>A of the106cases of epilepsy patients areUGT1A470CC,none of the patients have mutations.Of the106cases of epilepsypatients,82are UGT1A4142TT,22are UGT1A4142TG and2are UGT1A4142GG.Their frequencies are respectively77.36％,20.75％,1.89％.UGT1A4142T>Gallele frequency distribution T is87.74％,G is12.26％.At the same time,1case ofpatients has point mutations: UGT1A430G>A (P10P),2cases of patients have deletion mutations: UGT1A4127A/-(127delA). Of the106cases of epilepsy patients,105are UGT1A430GG,1are UGT1A430GA.Their frequencies are respectively99.06％,0.94％.UGT1A430G>A allele frequency distribution G is99.53％,A is0.47％.The genetic polymorphisms of UGT1A4142T>G and UGT1A430G>A genes areconsistent with Hardy-weiberg equilibrium.The serum concentration of lamotrigine of106patients are between1.040ug/mlto13.850ug/ml. Age,body mass index and gender have no significant effects on theserum concentration of lamotrigine. Daily dose according to weight and the serumconcentration of lamotrigine were positively correlated (R2=0.359,P=0.000<0.05).Excluding patients carrying UGT1A430G>A and UGT1A4127delAmutations.The remaining103patients,81are UGT1A4142TT,20are UGT1A4142TG and2are UGT1A4142GG.According to the genotypes of UGT1A4,the103cases of patients are divided into two groups,one is group A(142TG+142GG)and theother is group B(142TT).The differences of gender,weight and age between group Aand group B are not statistically significant.The standardized serum concentration oflamotrigine of group A is2.325±0.5988ug.Kg/ml.mg,and that of the other group is4.503±1.4701ug.Kg/ml.mg. The difference was statisticallysignificant(t=-10.503,P=0.000<0.05).In group A,there are7cases with good curativeeffect and15cases with poor curative effect.In group B, there are65cases with goodcurative effect and16cases with poor curative effect.Compare the two groups withchi-square test(χ2=19.287，P=0.000<0.05), The difference was statistically significant.Because of the small number of cases,the relationship between UGT1A430G>A,UGT1A4127delA gene polymorphisms and the serum concentrations oflamotrigine do not make statistical analysis.Conclusion:1.Distribution characteristics of UGT1A4142T>G gene polymorphism inChinese population:the frequencies of TT,TG and GG are respectively77.36％、20.75％、1.89％.2.The research results show that UGT1A4142T>G might plan an importantrole in the metabolism of lamotrigine,and has certain effect to the serum concentrationof lamotrigine,as genotype TT is much more higher than genotype TG and genotypeGG. 3.Clinical curative effect of patients with UGT1A4142TT genotype aresignificantly better than patients with UGT1A4142TG and142GGgenotype.Clinicians can choose antiepileptic drugs and dosage according to thegenotype of patients.4.The serum concentration of lamotrigine in patients with UGT1A4127delAgenotype are extremely high,this genotype is easy to cause skin rashes and otheradverse reactions.