The Infruence Of UGT1A1 Gene Mutation On The Outcome Of HBV-related Acute-on-chronic Liver Failure

Objective:To investigate the infruence of UGT1A1 gene mutation on the outcome of HBV-related acute-on-chronic liver failure?ACLF?.Methods:UGT1A1 gene sequencing was performed in 246 patients with HBV-related acute-on-chronic liver failure?ACLF?diagnosed at Fujian Medical University Mengchao Hepatobiliary Hospital from May 2015 to October 2017.According to the UGT1A1 gene sequencing results,246 patients with HBV-related acute-on-chronic liver failure?ACLF?were divided into mutation group?n=195?and non-mutation group?n=51?,and the differences in clinical characteristics between these two groups were compared.T test was used to compare the Measurement data of normal distribution between these two group,Mann-Whitney U test for comparing the measurement data of skewed distribution,and Chi-square test for comparison between counting data sets.The jaundice and MELD scores at different times between groups were analyzed by using generalized linear mixed-effects models?GLMMs?.Chi-square test was used to analyze the difference in survival rates between groups.Result:?The prevalence of UGT1A1 gene mutation in patients with HBV-related ACLF:the mutation rate of UGT1A1 gene in this population was 79.27%?195/246?, male168cases/female 27cases.?The main mutation sites were TA-box,c.-3279 T?G,exon 1 c.211G?A,c.-3279 T?G sites mutation was the most common,among which43 cases were heterozygous mutation,the mutation rate was 17.48%,5 cases were homozygous mutation,the mutation rate was 2.03%.The second was c.211G?A,37patients had mutation,the mutation rate was 15.04%.The most common genotype was GG.?The base line of UGT1A1 gene mutation group and the non-mutated patients with HBV-related ACLF were basically similar,but the IBIL level of the mutant group was higher than that of the non-mutated group,and the difference between the two groups was statistically significant?t=-1.976,P=0.05?.?The effect of UGT1A1 gene mutation on the dynamic changes of bilirubin and MELD scores in patients with HBV-related ACLF:there were significant differences in TBIL,IBIL level and MELD scores with time between mutant group and non-mutation group (F_TBIL=24.915,P=0.000;F_IBIL=17.903,P=0.000;F_{MELD scores}=8.179,P=0.000).The decrease of TBIL,IBIL level of the first 7 times in the 12 times of course of disease of mutation group were significantly slower than those in non-mutation group(t_TBIL=—6.272,P<0.001;t_IBIL=—7.732,P<0.001).There was significant difference in the changes of MELD scores in the first 6 times between the two groups(t_{MELD scores}=—3.399,P=0.01<0.05)in 12 times of course of disease?P<0.05?.?The effect of UGT1A1 gene mutation on the survival rate of the patients with HBV-related ACLF:there was no significant difference between ACLFearly stage,ACLF mid-stage,ACLF later stage mutation group and non-mutation group?P?0.05?on the basis of chronic hepatitis B and liver cirrhosis.The chi-square test among the six groups was no statistically significant?P?0.05?.?The effect of UGT1A1 mutation sites on bilirubin,MELD scores and survival rate:compared with the changes of TBIL,IBIL level overtime for 12 times,the TBIL,IBIL level in the first 7 times of GS mutation group changed?the increase was faster,the decrease was slower?with time there was a significant difference between GS mutation group and and non-mutation group(t_TBIL=—4.752,P=0.000;t_IBIL=—3.904,P=0.000;t_{MELD scores}=—6.717,P=0.000).In the course of the disease,there were significant differences in MELD scores in the first,second,ninth times between the non-mutation group and GS mutation group?t1=2.107,P=0.035;t2=1.870,P=0.02;t9=-2.153,P=0.032?.The effect of the mutation site of CNSII group on the TBIL,IBIL level and MELD scores in 12 times of course of disease were compared with each other over time.The changes?the increase was faster,the decrease was slower?of TBIL,IBIL level in the first 7 times and the MELD scores in the first 9 times in the mutant group were significantly different from those in the non-mutation group(t _TBIL=—7.664,P=0.000;t_IBIL=—9.637,P=0.000;t_{MELD scores}=—6.717,P=0.000).The effect of mutation on bilirubin and MELD scores in GS group and CNSII group:compared with the change of TBIL,IBIL level in 12 times of course of disease,the TBIL,IBIL level of CNSII group changed with time in the first7 times?the increase was faster,the decrease was slower?than that in the GS group (t_TBIL=—4.131,P=0.000;t_IBIL=—5.859,P=0.000).MELD scores was analyzed by GLMMs between the GS and CNSII groups,and there was an interaction between the mutation sites and the time(F_{MELD scores}=6.759,P=0.000),although the MELD scores of the CNSII group was higher than that of the GS group(F_MELDscores=111.382,P=0.000),which was a significant difference between the CNSII group and the GS group,there was also significant difference in MELD scores with time (F_{MELD scores}=6.988,P=0.000).The effect of pathogenicity mutation on survival rate was not statistically different among the three groups:no significant difference was found among the three groups?Chi square test,P?0.05?.Conclusion:?UGT1A1 is highly polymorphic in patients with HBV-related ACLF in Fujian Han nationality.Promoter region TATA box,enhancer c.-3279T?G,exon 1region c.211G?A were common mutation sites.?The mutation of UGT1A1 gene had a certain effect on the outcome of the patients with ACLF,mainly in the metabolism of bilirubin:the bilirubin of the mutant group increased faster than that of the non-mutant group,and the regression was slower than that of the non-mutation group.?The mutation of UGT1A1 gene affected MELD score,but had no effect on survival rate of patients with HBV-related ACLF.