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Letters to the Editor |
1 Center of Molecular and Structural Biomedicine Institute for Biotechnology and Bioengineering, Universidade do Algarve, Gambelas, Portugal
2 Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at Göteborg University Göteborg, Sweden
3 Institutionen för Biovetenskaper och Näringslära Centrum för Bioteknik Karolinska Institutet Stockholm, Sweden
4 Malaria Research Laboratory Unit of Infectious Diseases Department of Medicine Karolinska University Hospital Karolinska Institute Stockholm, Sweden
5 National Institute of Malariology, Parasitology and Entomology Hanoi, Vietnam
aAddress correspondence to this author at: Malaria Research Unit, Karolinska University Hospital, M9, Plan 2, 17176KS, Stockholm, Sweden. Fax 46 8 51776740; e-mail jose.pedro.gil{at}ki.se.
To the Editor:
Vietnam ranks 13th among the 23 countries that must deal with 80% of global deaths from tuberculosis (1). The National Tuberculosis Control Program of Vietnam implemented the WHO DOTS (directly observed therapy, short course) strategy in 1989. The standard treatment regimen for previously untreated patients consists of 2 months of streptomycin, isoniazid (INH), rifampin, and pyrazinamide, followed by 6 months of INH and ethambutol (the 2SHRZ/6HE regimen).
INH, a central component of this chemotherapy, is extensively metabolized by the polymorphic N-acetyltransferase 2 (NAT2) enzyme. N-acetyltransferase 2 (arylamine N-acetyltransferase) (NAT2) gene polymorphisms are associated with individual phenotypes generally classified as INH rapid (homozygous or heterozygous) and slow acetylators. Among the described NAT2 alleles, NAT2*5, *6, *7, 12*, *14, *17, and *19 have been associated with the slow acetylator phenotype, and NAT2*4 and *13 are associated with fast acetylation. Under treatment with standard dosages, patients who are slow metabolizers may be at risk for INH side effects, which include peripheral neuropathy, hepatic toxicity, and psychotic symptoms. On the other hand, insufficient drug concentrations may be more frequent among fast metabolizers. The determination of the NAT2 gene allele pattern of a population can supply valuable baseline information for determining drug dosage and expected efficacy for specific groups.
Although Vietnam has exceptional DOTS coverage, with extensive use of INH, information on population-related NAT2 pharmacogenetics has been unavailable. Accordingly, we sequenced the full NAT2 gene in 72 unrelated adult Vietnamese volunteers [51 male and 21 female, average age: 29 (18–45) years], sampled at the National Institute of Malariology, Parasitology and Entomology, Hanoi, Vietnam. With the exception of 2 Thai individuals, all volunteers were self-identified as belonging to the Khin ethnic group, the prevalent population in Vietnam. All study participants gave written informed consent. All protocols were approved by the Ministry of Health Hanoi, Vietnam; the Swedish Medical Products Agency, Uppsala, Sweden; and the Ethics Committee of Göteborg University.
We used an ABI 6100 Nucleic Acid PrepStation (Applied Biosystems) to extract genomic DNA from peripheral blood samples. The NAT2 gene was analyzed through full sequencing with PCR amplification in ABI 7420 thermocyclers. The primers used were as follows: 5'-TCACACGAGGAAATCAAATG-3' (NAT2Fw) and 5'-GTGCTATCAGATATCCTCTCTACC-3' (NAT2Rev).
Our results show that 90% (65 of 72) of the investigated individuals harbored at least 1 NAT2 fast allele (Table 1
), suggesting a particularly low frequency of slow acetylators, even in an Asian population. This high prevalence of fast acetylator–associated alleles is essentially attributable to the exceptionally high frequency of the NAT2*13. Although this allele has been observed at frequencies 
5% in other populations, in our study we detected it at a prevalence of 31%, significantly different from previous studies on a sample of 264 Thai individuals (*13 <5.1%; P <0.0001) (2) (Table 1
). Notably, the NAT2*7 allele, consistently found in Asian populations, was not observed in our study. This finding also contrasts with the 20% prevalence in the Northeast Thai population, and the 6.3% prevalence among 64 individuals from the Cambodian Khmer population (6.3%)(2) (Table 1
).
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During analysis we found cases in which it was not possible to distinguish between haplotypes (Table 1
) because the presence of multiple heterozygous single-nucleotide polymorphisms prevented us from determining which alleles were in cis (same chromosome) or trans (different chromosomes). For example, when we have both the 282 C>T and 803 A>G in the heterozygote form, 2 possible haplotypes appear: NAT2*4/*12B (one chromosome 282C/803A + the other 282T/803G) and NAT2*12A/*13 (282C/803G + 282T/803A).
The observed 9.7% frequency of slow acetylators among the Vietnamese Khin predicts a low incidence of adverse effects caused by overexposure to INH, and potential drug-drug interactions associated with this drug (3). For this minority group of slow acetylators, a decrease in drug dosage would likely reduce the risk of adverse events without compromising the efficacy of the drug, because a dose of INH as low as 3 mg/kg has recently been shown to be sufficient for a successful therapy(4). On the other hand, a dose reduction below 6 mg/kg in fast acetylators can compromise INH efficacy. The observed high frequency of fast alleles may hypothetically affect the success of the standard INH dosing in the overall Vietnamese population, particularly in terms of early bactericidal activity(5).
Limited pharmacogenetic data are available to account for the diversity of the Southeast Asian populations. Future studies should be performed to identify particular population characteristics that might influence pivotal pharmacotherapy in these geographic regions.
Acknowledgments
Grant/funding support: This study was supported by the Swedish International Development Cooperation Agency (SIDA/SAREC). I.C. is the recipient of a scholarship from Fundação para a Ciência e Tecnologia, Portugal (Ref. SFRH/BD/2002/8887).
Financial disclosures: None declared.
References
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