Slow N-acetyltransferase 2 genotype contributes to anti-tuberculosis drug-induced hepatotoxicity: a meta-analysis

Abstract

Pathogenesis and genetic factors influencing predisposition to antituberculosis drug-induced hepatotoxicity (ATDH) are not clear. Polymorphism at the genetic locus of a drug and xenobiotic compound metabolizing enzyme, N-acetyltransferase type 2 (NAT2), is reported to be associated with the excess generation of toxic reactive metabolites. To date, many case-control studies have been carried out to investigate the relationship between the NAT2 polymorphisms and ATDH, but the results have been inconsistent. To investigate this inconsistency, a meta-analysis was performed. Databases including PubMed, Web of Science, EMBASE and CNKI were searched to find relevant studies. A total of 26 case-control studies, involving 1,198 cases and 2,921 controls were included. Overall, we found significant association between slow acetylator genotype of NAT2 and ATDH (OR = 3.10, 95% CI: 2.47-3.88, P < 10(-5)). Significant results were also found in East Asians, South Asians, Brazilians and Middle Eastern when stratified by ethnicity. However, no significant associations were found for Caucasians. This meta-analysis demonstrated that the slow acetylator genotype of NAT2 is a risk factor associated with increased ATDH susceptibility, but these associations vary in different ethnic populations.

N-Acetyltransferase 2: ultra-slow acetylators enter the stage

“…NAT2 polymorphisms were initially discovered as risk factor for drug-induced liver injury (DILI) in tuberculosis patients receiving isoniazid therapy (Hughes et al 1954). Studies on anti-tuberculosis drug-induced hepatotoxicity (ATDH) are mostly conducted in East Asian and South American populations where tuberculosis is a major health concern (Daly 2013;Du et al 2013). A recent meta-analysis indicated that ultra-slow acetylators are at highest risk of ATDH (Selinski et al 2014) though results have to be interpreted with care due to the absence of NAT2*5B in East Asians.…”

High frequency of NAT2 slow acetylator alleles in the Malay population of Indonesia: an awareness to the anti-tuberculosis drug induced liver injury and cancer

“…A meta-analysis study showed that the SA genotype of NAT2 was significantly associated with increased risk of antituberculosis drug hepatotoxicity in East Asians, South Asians, Brazilians and Middle Eastern when stratified by ethnicity. 12 Another meta-analysis study reported significant association between slow acetylator and prostate cancer in Asians. 13 Many studies showed that NAT2 slow acetylator alleles are associated with several disease risks.…”

“…http://mji.ui.ac.id A previous reported study revealed that NAT2*6A is an important genetic marker for the risk of hepatotoxicity due to anti-tuberculosis treatment in Chinese, Japanese, Korean 12 and Indonesian Javanese and Sundanese. 5 A meta-analysis of 26 case-control studies also reported that the NAT2 SA genotype was a risk factor of antituberculosis drug induced liver injury (AT-DILI), but the associations are diverse in different ethnic populations.…”

“…Significant results were found in East Asians, South Asians, Brazilians and Middle Eastern, but not in Caucasians. 12 It was expected that subjects with NAT2 SA may have a decreased activity of NAT2 which affects the acetylation of both isoniazid and hydrazine; therefore they are more susceptible to AT-DILI.…”

Association between TXNRD1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in a prospective study

“…Non-genetic factors include female sex, race, and environmental factors such as alcohol intake (Pande et al, 1996;Lee et al, 2002;Marra et al, 2007;de Castro et al, 2010). The genetic factors are involved in drug metabolism, transport, and immune and antioxidant responses, and include N-acetyltransferase 2 (NAT2), BTB and CNC homology 1 (BACH1), tumor necrosis factor-a (TNF) and adenosine triphosphate binding cassette B1 (ABCB1) (Yimer et al, 2011;Kim et al, 2012;Nanashima et al, 2012;Du et al, 2013).…”