Relationships Of CYP 450 Gene Polymorphisms With Anti-tuberculosis Drug-induced Liver Injury

Objective To explore the correlation between the single nucleotide polymorphism(SNP)of cytochrome P450(CYP)gene family and the occurrence and development of antituberculosis drug-induced liver injury(ATDILI).Methods The case-control method was adopted in the research.281 patients diagnosed tuberculosis were selected in Shenzhen third people's hospital from January to October in 2017.According to whether ATDILI occurred during treatment,the patients were divided into ATDILI group(101 cases)and non-ATDILI group(180 cases).The ATDILI group was divided into mild ATDILI group,moderate ATDILI group and severe ATDILI group.Four SNP in the CYP gene family were selected,namely CYP1A1 rs36090160?CYP1B1 rs2551189?CYP1B1 rs2567206,and CYP3A4 rs2740574.All peripheral blood samples of the patients were collected,the whole blood genome DNA was extracted and total 4 SNPs was genotyped by using Time of Fight Mass Spectrum(TOF-MS).All the SNPs were detected whether they were in Hardy-Weinberg equilibrium.The statistical analysis was performed on the frequencies of alleles in different populations of SNPs.The SNPs associated with ATDILI susceptibility were screened out and stratified according to the severity of ATDILI to evaluate each allele and genotype and the correlation between SNPs and ATDILI severity susceptibility.Further stratification was based on gender and age to evaluate the relationship between the above-mentioned SNPs and ATDILI susceptibility in different gender and age groups.Results(1)The SNP high-throughput typing technology platform for CYP gene family based on Time of Fight Mass Spectrum(TOF-MS)was established.(2)There are two alleles(C?T)and two genotypes(CC?CT)at the CYP1A1 rs36090160 locus.Genotype distribution in both groups is in a genetic equilibrium.The C allele frequency in ATDILI group(93.6%)was higher than the non-ATDILI group(87.5%),and the difference was statistically significant(OR=2.08,95%CI=1.09-3.95,P =0.023).(3)CYP1B1(rs2551189,rs2567206)SNP locus in both groups were in equilibrium.There are two alleles(C?G)and two genotypes(GG?CG)at the CYP1B1 rs2551189.The frequencies of C allele in ATDILI group(9.4%)were significantly higher than those in non-ATDILI group(2.5%),and the difference was statistically significant(OR=4.05,95%CI=1.80-9.13,P= 0.0003).There are two alleles(G?A)and three genotypes(GG?AG?AA)at the rs2567206 locus.The genotypes were in equilibrium between the two groups.The frequency of the two alleles was not statistically significant between the two groups(P>0.05).(4)There are two alleles(C?T)and two genotypes(TT?CT)at the rs2567206 locus.The genotypes were in equilibrium between the two groups.The frequency of the two alleles was not statistically significant between the two groups(P>0.05).(5)In the ATDILI group,the mean values of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)at the rs36090160 locus were significantly higher than those in the CT genotype population,and the difference was statistically significant(P=0.0088,P=0.0066).According to the severity of liver function,the frequency of CC genotype at rs36090160 was increasing in the non-ATDILI group(75%),mild ATDILI group(81.8%),and moderate to severe ATDILI group(97.1%).After the trend chi-square test(?2=8.59,P=0.003),the difference was statistically significant.There was no difference in ALT,AST levels between different genotypes at the rs2551189(P>0.05).(6)In the ATDILI group,the mean ESR of the CC genotype at rs36090160 locus was significantly higher than the CT genotype group,and the difference was statistically significant(P<0.05).In the ATDILI group,the average of high-sensitivity C-reactive protein in the CC genotype at the rs36090160 was significantly higher than that in the CT genotype,with no statistically significant difference(P>0.05).(7)According to gender stratification,in the male population,the frequency of C allele at the rs36090160 was significantly higher in the ATDILI group(95.5%)than that in the non-ATDILI group(86.1%),and the difference was statistically significant(OR=3.39,95%CI=1.28-9.00,P=0.010).In the female population,the C allele frequency at rs36090160 was not different between the two groups.(8)According to age stratification,in the population aged more than 60 years old,the frequency of C allele at the rs36090160 locus was significantly higher in the ATDILI group(93.3%)than that at the non-ATDILI group(87.7%)(OR =1.97,95% CI =1.00-3.87,P=0.0454).Among people over 60 years old,the frequency of C allele in rs36090160 was not different between the two groups.Conclusions(1)The SNP of CYP1A1 rs36090160 was associated with susceptibility to ATDILI and its severity,and the C allele was a susceptible allele.(2)The SNP of CYP1B1 rs2551189 was associated with susceptibility to ATDILI,and the C allele was a susceptible allele.(3)The SNP of CYP1A1 rs36090160 would affect the erythrocyte sedimentation rate of patients and had no effect on the patient's high-sensitivity C-reactive protein.(4)The rs36090160 locus SNP had a higher value in predicting the risk of ATDILI in males and people no more than the age of 60 years.