The NAT2 tag SNP rs1495741 correlates with the susceptibility of antituberculosis drug-induced hepatotoxicity

Abstract

The present study demonstrated that the three genotypes according to rs1495741 were in good accordance with conventional NAT2 alleles-inferred phenotypes and the tag SNP could be used as a proxy to determine the susceptibility to ATDIH.

Relevance of NAT2 genotype to anti‐tuberculosis drug‐induced hepatotoxicity in a Chinese Han population

“…We confirmed the relationship between the tagging SNP rs1495741 genotypes and the risk of ATDH under the criteria of the International Consensus meeting. To date, a total of three studies have explored the relationship between the tagging SNP rs1495741 and ATDH, and our results were consistent with these studies, which were conducted in Taiwan, Bolivian and Argentinian and Singaporean patients, respectively. Taken together, the existing studies and the present study all identified a robust association between the tagging SNP rs1495741 in NAT2 and ATDH, which contributes to the potential clinical utility of the tagging SNP rs1495741 for ATDH prediction in anti‐TB treatment patients.…”

“…The tagging SNP rs1495741 genotype has been shown to be strongly related to NAT2 phenotypic activity in vitro in cryopreserved human hepatocytes or in vivo using caffeine urinary tests . Patients with the rs1495741 AA genotype have relatively lower NAT2 activity in INH metabolism, and serum clearance of INH is also significantly lower in patients with the AA genotype . NAT2 slow metabolizers acetylate not only INH, but also hydrazine and acetylhydrazine more slowly, resulting in the accumulation of hepatotoxic hydrazine and acetylhydrazine in the liver and the occurrence of ATDH .…”

“…Patients with the rs1495741 AA genotype have relatively lower NAT2 activity in INH metabolism, and serum clearance of INH is also significantly lower in patients with the AA genotype . NAT2 slow metabolizers acetylate not only INH, but also hydrazine and acetylhydrazine more slowly, resulting in the accumulation of hepatotoxic hydrazine and acetylhydrazine in the liver and the occurrence of ATDH . Pharmacogenetic testing has been increasingly used to predict individuals at serious risk of toxicity if a drug is prescribed .…”

“…Both the tagging SNP and the two SNPs were found to be independent variables in predicting ATDH and had the same strength as the seven SNPs of NAT2 in Bolivian and Argentinian TB patient populations . Significant differences between the tagging SNP rs1495741 genotypes and susceptibility to hepatotoxicity were also noted in Taiwanese TB patients . The tagging SNP rs1495741 could be used as a proxy to determine susceptibility to ATDH and the potential for the practical utility of this SNP needs to be evaluated in multiple world populations.…”

PharmGKB summary

“…Patients with this haplotype had significantly decreased acetylation and clearance of INH, as compared to the other haplotypes examined, and this is likely attributed to the presence of the ultra-slow NAT2*6 signature SNP [75]. Another study has correlated genotype AA of rs1495741 (NC_000008.10:g.18272881G>A, a tag SNP located about 14 kb downstream of NAT2 ) with increased risk of INH hepatotoxicity [69]. This association is indirect, as the A allele of rs1495741 is likely to be in linkage disequilibrium with a slow NAT2 variant [90].…”