Genotype and allele frequencies of isoniazid-metabolizing enzymes NAT2 and GSTM1 in Latvian tuberculosis patients

Igumnova, Viktorija; Capligina, Valentina; Krams, Alvils; Cīrule, Andra; Elferts, Didzis; Pole, Ilva; Jansone, Inta; Bandere, Dace; Ranka, Renāte

doi:10.1016/j.jiac.2016.04.003

Cited by 6 publications

(4 citation statements)

References 32 publications

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“…Different ethnicities have shown different proportions of rapid, intermediate, and slow phenotypes. The frequency of slow acetylators varies in different countries, for example, in Latvia (51.8%), Senegal (49%), and Brazil (41%), 24–26 which is much higher than in our study population. Interestingly, several Asian countries reported slow acetylator phenotypes in lower frequencies, for example, China (15.2%) and South Korea (14.4%).…”

Section: Discussioncontrasting

confidence: 62%

Acetylator Status Among Newly Diagnosed and Recurrent Tuberculosis Patients from Kupang, Eastern Part of Indonesia

Sahiratmadja

Rini

Penggoam³

et al. 2021

PGPM

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Purpose N-acetyltransferase-2 enzyme in the liver, encoded by NAT2 gene, plays a central role in metabolizing tuberculosis (TB) drug isoniazid (INH). Low compliance of patients toward six-month TB therapy and internal host factors, ie comorbid diseases, immune status, and genetic profiles, are factors leading to treatment failure and recurrence of pulmonary TB infection. This study aimed to explore the NAT2 acetylator status among newly diagnosed and recurrent pulmonary TB patients in eastern part of Indonesia. Patients and Methods Archived DNA of TB patients (n=124) and healthy controls (n=124) were sequenced, and NAT2 acetylator status was determined, then categorized as fast, intermediate, or slow acetylators. Pulmonary TB patients who had no previous TB treatment history were designated as newly diagnosed pulmonary TB, whereas patients with a history of TB treatment were designated as recurrent pulmonary TB. The demographic, clinical, and microbiological data between pulmonary TB groups were compared, and acetylator status was described among groups. Results Male was more significantly prevalent in the recurrent pulmonary TB group (p=0.025), and anemia was more prevalent in new pulmonary TB (p=0.003). The acetylator status in pulmonary TB patients compared to healthy controls were rapid (33.9% vs 48.1%), intermediate (57.8% vs 33.0%), and slow acetylators (8.3% vs 18.9%), respectively. Interestingly, the rapid and intermediate acetylator were significantly more prevalent in pulmonary TB patients than in healthy controls (p=0.023, OR=2.58 (1.12–5.97). Furthermore, no differences were found in acetylator status between new and recurrent pulmonary (p=0.776). Conclusion Rapid and intermediate acetylators status predominated the pulmonary TB patients in Kupang, eastern part of Indonesia, postulating different genetic makeup in this area. As the pulmonary TB patients in Kupang exhibit more rapid acetylator phenotype, the acetylator status might be relevant to be checked before TB therapy for adjusting treatment dose to prevent drug resistances.

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Section: Discussioncontrasting

confidence: 62%

Acetylator Status Among Newly Diagnosed and Recurrent Tuberculosis Patients from Kupang, Eastern Part of Indonesia

Sahiratmadja

Rini

Penggoam³

et al. 2021

PGPM

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“…Meanwhile, slow acetylation genotypes are more likely to lead to ATLI. It has been reported that 52%‐72% of Caucasians have slow acetylating phenotypes, while 34%‐61% of Africans carry slow acetylated phenotypes . In America, the rate of slow acetylation types ranges from 23% to 75%, while Asians only have 9%‐32% of the slow acetylation phenotype .…”

Section: Discussionmentioning

confidence: 99%

The role of NAT2 polymorphism and methylation in anti‐tuberculosis drug‐induced liver injury in Mongolian tuberculosis patients

et al. 2019

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What is known and objective: Anti-tuberculosis drug-induced liver injury (ATLI) is one of the most significant adverse reactions for this line of therapy. N-acetyltransferase 2 (NAT2) is an important metabolic enzyme involved in drug metabolism and detoxification. Genetic polymorphism and DNA methylation have been proven to be key factors that affect the expression of NAT2. Therefore, the objective of the study was to investigate the relationship between NAT2 gene polymorphism and DNA methylation in the promoter region with ATLI risk in Mongolian tuberculosis patients. Methods:Our study is a case-control design. Chi-square test, Mann-Whitney U nonparametric test and Pearson test were all used to analyse existing relationships. The association between NAT2 gene acetylation phenotype and the total methylation of the NAT2 promoter region was analysed by means of binary logistic regression analysis. The general situation of the patients was evaluated by questionnaire, and the NAT2 genotyping of the three major polymorphism loci of gene coding was carried out by a gene sequencing technique. The methylation status of the NAT2 gene promoter region was detected by bisulphite sequencing and mass spectrometry.Result and discussion: Our study found that the detection rate of ATLI in Mongolian tuberculosis patients was 27.6%. There were no significant differences in demographic characteristics and living habits amongst the two groups, while significant differences were observed in the polymorphism of the NAT2 genes 481 (rs1799929) and 590 (rs1799930) and the acetylation phenotype. Moreover, the composition and distribution of the NAT2*4/4 and NAT2*4/5 genotypes were found in the two groups. The risk of ATLI in the slow acetylation type was 3.56 times higher than that of the fast acetylation type. Compared with the control group, the CpG5, CpG10, CpG11.12 and total methylation of the NAT2 promoter region in the ATLI group showed a hypermethylated pattern (P < .05). However, on performing binary logistic regression, neither the slow acetylation, intermediate acetylation nor rapid acetylation were found to be associated with ATLI (P > .05). It was found that the total methylation of NAT2 gene promoter region was an independent influencing factor of ATLI in Mongolian tuberculosis How to cite this article: Zhang D, Hao J, Hou R, Yu Y, Hu B, Wei L. The role of NAT2 polymorphism and methylation in anti-tuberculosis drug-induced liver injury in Mongolian tuberculosis patients. J Clin Pharm Ther. 2020;45:561-569.

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“…The PCR assays were performed under the following conditions: an initial denaturation at 98 °C 30 s; 40 cycles of denaturation at 98 °C for 10s, primer annealing at 65 °C for 30 s, and elongation at 72 °C for 30 s; and a final elongation step at 72 °C for 5 min. PCR products were purified using the ExoI and FastAP enzymes (Thermo Fisher Scientific, United States) and subsequently sequenced on both DNA strands using P100 and three additional internal primers (P90, 5′-ACACAAGGG TTTATTTTGTTCC-3'; NAT2_R_for, 5′ TAATTCTAGAGGCTG CCACATC-3'; NAT2_S_for, 5′-GAATACATACCTGCAGACGTC TC-3′) (Cascorbi et al, 1996;Igumnova et al, 2016). Sequencing was performed using the ABI PRISM BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems) according to the manufacturer's recommendations on an ABI Prism 3,100 Genetic Analyzer (Perkin-Elmer, United States).…”

Section: Nat2 Genotypingmentioning

confidence: 99%

“…The GSTM1 gene double deletion genotype (0/0) was detected based on the comparative duplex PCR assay as described previously (Igumnova et al, 2016). Briefly, the PCR master mix contained (per reaction) 1X Taq Buffer with (NH 4 ) 2 SO 4 , 2.5 mM MgCl 2 , 100 mM of each dNTPs, 0.2 mM of each primer Beta1 (5′-GGTTGGCCAATCTACTCCCAG G-3′), Beta2 (5′-GCTCACTCAGTGTGGCAAAG-3′), M1 (5′-CTG CCCTACTTGATTGATGGG-3′) and M2 (5′-CTGGATTGTAGC AGATCATGC-3′), 1.25 U of Taq DNA polymerase and 28 ng of DNA template.…”

Section: Gstm1 Genotypingmentioning

confidence: 99%

Effect of NAT2, GSTM1 and CYP2E1 genetic polymorphisms on plasma concentration of isoniazid and its metabolites in patients with tuberculosis, and the assessment of exposure-response relationships

Ulanova,

Kivrane,

Viksna

et al. 2024

Front. Pharmacol.

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Objectives: Isoniazid is a key drug in the chemotherapy of tuberculosis (TB), however, interindividual variability in pharmacokinetic parameters and drug plasma levels may affect drug responses including drug induced hepatotoxicity. The current study investigated the relationships between isoniazid exposure and isoniazid metabolism-related genetic factors in the context of occurrence of drug induced hepatotoxicity and TB treatment outcomes.Methods: Demographic characteristics and clinical information were collected in a prospective TB cohort study in Latvia (N = 34). Time to sputum culture conversion (tSCC) was used as a treatment response marker. Blood plasma concentrations of isoniazid (INH) and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) were determined at three time points (pre-dose (0 h), 2 h and 6 h after drug intake) using liquid chromatography-tandem mass spectrometry. Genetic variations of three key INH-metabolizing enzymes (NAT2, CYP2E1, and GSTM1) were investigated by application PCR- and Next-generation sequencing-based methods. Depending on variables, group comparisons were performed by Student’s t-test, one-way ANOVA, Mann-Whitney-Wilcoxon, and Kruskal-Wallis tests. Pearson correlation coefficient was calculated for the pairs of normally distributed variables; model with rank transformations were used for non-normally distributed variables. Time-to-event analysis was performed to analyze the tSCC data. The cumulative probability of tSCC was obtained using Kaplan-Meier estimators. Cox proportional hazards models were fitted to estimate hazard rate ratios of successful tSCC.Results: High TB treatment success rate (94.1%) was achieved despite the variability in INH exposure. Clinical and demographic factors were not associated with either tSCC, hepatotoxicity, or INH pharmacokinetics parameters. Correlations between plasma concentrations of INH and its metabolites were NAT2 phenotype-dependent, while GSTM1 genetic variants did not showed any effects. CYP2E1*6 (T > A) allelic variant was associated with INH pharmacokinetic parameters. Decreased level of AcINH was associated with hepatotoxicity, while decreased values of INA/INH and AcINH/INH were associated with month two sputum culture positivity.Conclusion: Our findings suggest that CYP2E1, but not GSTM1, significantly affects the INH pharmacokinetics along with NAT2. AcINH plasma level could serve as a biomarker for INH-related hepatotoxicity, and the inclusion of INH metabolite screening in TB therapeutic drug monitoring could be beneficial in clinical studies for determination of optimal dosing strategies.

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Genotype and allele frequencies of isoniazid-metabolizing enzymes NAT2 and GSTM1 in Latvian tuberculosis patients

Cited by 6 publications

References 32 publications

Acetylator Status Among Newly Diagnosed and Recurrent Tuberculosis Patients from Kupang, Eastern Part of Indonesia

Acetylator Status Among Newly Diagnosed and Recurrent Tuberculosis Patients from Kupang, Eastern Part of Indonesia

The role of NAT2 polymorphism and methylation in anti‐tuberculosis drug‐induced liver injury in Mongolian tuberculosis patients

Effect of NAT2, GSTM1 and CYP2E1 genetic polymorphisms on plasma concentration of isoniazid and its metabolites in patients with tuberculosis, and the assessment of exposure-response relationships

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