Association between NAT2 polymorphisms and anti-tuberculosis drug-induced liver injury in Myanmar patients in Thailand

Abstract

The aims of this study were to determine the N-acetyl transferase 2 (NAT2) genetic distribution of Myanmar tuberculosis (TB) patients and evaluate the association of NAT2 polymorphisms and antituberculosis drug-induced liver injury (AT-DILI) in Myanmar patients. A case-control study was conducted in adult Myanmar TB patients at Samut Sakorn Hospital. Fifty-four patients who completed anti-TB treatment without liver injury (controls) and five patients with AT-DILI during their anti-TB treatment (cases) were enrolled. Patients’ baseline characteristics, anti-TB doses, and liver enzyme levels were collected from the hospital’s record. Blood samples were collected and four NAT2 SNPs, rs1041983, rs1799929, rs1799930, and rs1799931, were genotyped using allele-specific polymerase chain reaction (AS-PCR). In this study, all patients received the standard anti-TB regimen with anti-TB doses in World Health Organization (WHO) recommended dose range. Baseline characteristics of cases and controls were not different. NAT2 rs1041983 was highly found in all patients (56%), while cases had higher NAT2 rs1799929 frequency than control (50% vs 10%). The most common allele was NAT2*6A, and the most common genotype was NAT2*4/*7B. Forty-seven percent (n=28) were slow acetylators, while 44% (n=26) were intermediate acetylators. The phenotype distribution in this study is in concordance with Thai and Indonesian studies. There was no association of non-genetic factors and AT-DILI. NAT2 rs1799929 (CT and TT genotypes) showed higher risk to get liver injury than CC genotypes (OR= 19.2865, 95% C.I =1.751-212.417, p = 0.016 and OR = 22.50, 95% C.I = 1.001– 505.846, p = 0.005, respectively). However, there was no association between NAT2 genotype and phenotype and AT-DILI. When stratified patients according to their liver enzyme levels to normal and elevated levels, CT genotype of NAT2 rs1799929 was highly found in patients with elevated AST levels (OR=4.625, 95% C.I=1.078-19.840, p = 0.039). In addition, the highest AST and ALT levels were found in slow acetylators with NAT2*5B/*5B. Multiple linear regression analysis showed that NAT2 SNPs rs1799929, isoniazid dose, and age significantly associated with AST levels (B=49.334, p < 0.001, B=22.241, p=0.007 and B=1.991, p=0.025 respectively). These factors can describe 35% of AST level variation. Furthermore, NAT2 phenotype, isoniazid dose, and age also explained 22% of AST level variation (B=23.781, p=0.038, B=22.003, p=0.016 and B=2.581, p=0.008 respectively). In addition, NAT2 SNPs rs1799929 also exhibited 22% of ALT level variation (B=85.944, p < 0.001). To summarize, this study demonstrated a strong influence of NAT2 rs1799929 on AT-DILI and elevated liver enzymes in Myanmar patients receiving anti-TB treatment. As the NAT2 phenotype distribution of Myanmar patients is similar to the Thai population, this study supports the use of Thai TB guidelines in anti-TB adverse drug reaction monitoring for Myanmar TB patients in Thailand.