Polymorphisms of NAT2, CYP2E1, GST, and HLA Related to Drug‑Induced Liver Injury in Indonesian Tuberculosis Patients

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. Defned 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 defned 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% confdence 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 signifcantly affects the isoniazid concentration. Conclusion: The NAT2 genotype was signifcantly 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, NAT

Exclusion of Acute Myocardial Infarction. The Value of Measuring Creatine Kinase Slope

Peer Reviewe

Prenatal exposure to serotonin reuptake inhibitors and congenital heart anomalies:An exploratory pharmacogenetics study

Aim: To explore the role of pharmacogenetics in determining the risk of congenital heart anomalies (CHA) with prenatal use of serotonin reuptake inhibitors.  Methods: We included 33 case-mother dyads and 2 mother-only (child deceased) cases of CHA in a case-only study. Ten genes important in determining fetal exposure to serotonin reuptake inhibitors were examined: CYP1A2, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC6A4, HTR1A, HTR1B, HTR2A and HTR3B.  Results: Among the exposed cases, polymorphisms that tended to be associated with an increased risk of CHA were SLC6A4 5-HTTLPR and 5-HTTVNTR, HTR1A rs1364043, HTR1B rs6296 and rs6298 and HTR3B rs1176744, but none reached statistical significance due to our limited sample sizes.  Conclusion: We identified several polymorphisms that might potentially affect the risk of CHA among exposed fetuses, which warrants further investigation