Polymorphisms of NAT2, CYP2E1, GST, and HLA related to drug-induced liver injury in indonesian tuberculosis patients

Abstract

Background: Gene polymorphisms have been associated with drug-induced liver injury (DILI). This study aimed to elucidate the association between polymorphisms of NAT2, CYP2E1, GSTT1, GSTM1, and HLA genes with isoniazid plasma concentration and DILI. Methods: This study was a prospective cohort study recruiting adult newly diagnosed tuberculosis (TB) patients who met the inclusion criteria from the Public Health Centers in Yogyakarta and Lampung. Defined single-nucleotide polymorphisms were rs1799929, rs1799930, rs1799931, rs1801280, and rs1041983 of NAT2; rs2031920, rs8192775, and rs2515641 of CYP2E1; rs1041981, rs1063355, and rs6906021 of HLA. GSTT1 and GSTM1 were defined as GSTT1, GSTM1, and GSTT1 deletion and GSTM1 deletion. The DNA was taken from the patient saliva. Data of anti-TB drug plasma concentration on the weeks 4–8 of treatment were retrieved from the patients' medical report. Statistical analysis was performed using Chi-square test, Student's t-test, and multinomial logistic regression. Results: Over the 207 patients, up to 1.9% of them experienced DILI. The percentage of slow acetylators of NAT2 was 69.5%. Patients with extensive acetylator phenotype did not experience DILI (odds ratio [OR]: 0.46; 95% confidence interval [CI]: 0.23–0.94). The G carriership of HLA rs1063355 could protect the patients from the DILI (OR: 0.39; 95% CI: 0.14–0.9). Furthermore, the C carriership of HLA rs1041981 can protect the patients from DILI (OR: 0.38; 95% CI: 0.15–0.50). The genotype of HLA-DQB*0302 significantly affects the isoniazid concentration. Conclusion: The NAT2 genotype was significantly associated with DILI. Furthermore, the absence of G carriership of HLA-DQA*0102 could protect the patients from DILI without being associated with an effect on the isoniazid concentration.

Keywords

• Antituberculosis
• CYP2E1
• drug-induced liver injury
• GST
• HLA
• Indonesia
• NAT2