ABSTRACT
Background@#Isoniazid (INH) is metabolized by polymorphic N-acetyltransferase 2 (NAT2) enzyme, which noticeably alters INH plasma concentration. We aimed to determine the distribution of NAT2 genotype in Thai tuberculosis (TB) patients and correlate their genotype with plasma INH concentrations. @*Methods@#Blood samples from 55 newly diagnosed pulmonary tuberculosis participants from three hospitals were collected to classify the subject by NAT2 genotype performed by the Multiplex haplotype-specific polymerase chain reaction method. Patients were grouped into three acetylators (fast, intermediate, and slow). On day 14 of tuberculosis treatment, the second blood sample was taken to estimate the peak plasma concentration at 2 hours after oral administration. INH plasma concentration was analyzed by liquid chromatography‒tandem mass spectrometry/mass spectrometry method. @*Results@#The NAT2 genotype distribution of fast, intermediate, and slow acetylator was 10.9%, 36.4%, and 52.7%, from six, 20, and 29 patients, respectively. The median (interquartile range) of INH plasma concentration at 2 hours post drug administration for these three genotypes were 0.75 (0.69–0.86), 2.56 (2.12–3.97), and 4.25 (3.56–5.50) µg/mL from four, 14, and 12 cases, respectively. The INH plasma concentration at 2 hours after administration was significantly associated with body weight and NAT2 acetylator. @*Conclusion@#The INH plasma concentration was found lower in fast than intermediate and slow acetylators. Body weight and NAT2 acetylator influenced INH plasma concentrations at 2 hours after drug administration. Therefore, the NAT2 genotype should be known before starting TB treatment to maximize therapeutic outcomes.
ABSTRACT
Background@#Isoniazid (INH) is metabolized by polymorphic N-acetyltransferase 2 (NAT2) enzyme, which noticeably alters INH plasma concentration. We aimed to determine the distribution of NAT2 genotype in Thai tuberculosis (TB) patients and correlate their genotype with plasma INH concentrations. @*Methods@#Blood samples from 55 newly diagnosed pulmonary tuberculosis participants from three hospitals were collected to classify the subject by NAT2 genotype performed by the Multiplex haplotype-specific polymerase chain reaction method. Patients were grouped into three acetylators (fast, intermediate, and slow). On day 14 of tuberculosis treatment, the second blood sample was taken to estimate the peak plasma concentration at 2 hours after oral administration. INH plasma concentration was analyzed by liquid chromatography‒tandem mass spectrometry/mass spectrometry method. @*Results@#The NAT2 genotype distribution of fast, intermediate, and slow acetylator was 10.9%, 36.4%, and 52.7%, from six, 20, and 29 patients, respectively. The median (interquartile range) of INH plasma concentration at 2 hours post drug administration for these three genotypes were 0.75 (0.69–0.86), 2.56 (2.12–3.97), and 4.25 (3.56–5.50) µg/mL from four, 14, and 12 cases, respectively. The INH plasma concentration at 2 hours after administration was significantly associated with body weight and NAT2 acetylator. @*Conclusion@#The INH plasma concentration was found lower in fast than intermediate and slow acetylators. Body weight and NAT2 acetylator influenced INH plasma concentrations at 2 hours after drug administration. Therefore, the NAT2 genotype should be known before starting TB treatment to maximize therapeutic outcomes.
ABSTRACT
BACKGROUND AND PURPOSE: The prevalence of Huntington's disease (HD) among East Asians is less than one-tenth of that among Caucasians. Such a low prevalence may be attributable to a lack of carriers of specific predisposing haplogroups associated with the high instability of the Huntingtin gene (HTT). The aim of this study was to evaluate the association between specific HTT haplogroups and the occurrence of HD in a Thai population. METHODS: CAG-repeat sizes and HTT haplotypes were analyzed in 18 Thai HD patients and 215 control subjects. Twenty-two tagging single-nucleotide polymorphisms (tSNPs) were genotyped. RESULTS: Only 18 patients from 15 unrelated families were identified over the last 17 years. Pathological CAG-repeat alleles ranged from 39 to 48 repeats (43.5+/-3.0, mean+/-SD), and normal alleles ranged from 9 to 24 repeats (16.49+/-1.74). Only two of the chromosomes studied comprised intermediate alleles. Unlike the Caucasian data, all but 1 of the 22 tSNPs were not associated with the occurrence of HD. The predisposing haplogroups for Caucasian HD (haplogroups A1 and A2) are very rare in Thai patients (<4%). Both HD and normal chromosomes are commonly haplogroups A5 and C, in contrast to the case for Chinese and Japanese patients, in whom only haplogroup C was common in HD chromosomes. The frequency of CAG-repeat sizes of haplogroup A5 and C were also similarly distributed. CONCLUSIONS: HD chromosomes of Thai patients may arise randomly from each haplogroup, with a similar mutation rate. This rate is much lower than the CAG expansions from Caucasian HD haplogroups. These data suggest that the different mechanisms underlie CAG expansion in Thai and Caucasian patients.