Arylamine N-acetyltransferase 2 slow acetylator polymorphisms in unrelated Iranian individuals

Bakayev, Valery V.; Mohammadi, F; Bahadori, Moslem; Sheikholslami, Mariam; Javeri, Arash; Masjedi, Mohammad Reza; Velayati, Ali Akbar

doi:10.1007/s00228-004-0799-z

Cited by 25 publications

(19 citation statements)

References 26 publications

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“…T341C (rs1801280) was assayed by an allele-specific PCR protocol modified from Bakayev et al [63]. Since in compound heterozygotes the products obtained with this allele-specific PCR contain markers in a haploid form, the same assay was also used to determine the phase of specific variants with respect to position 341 by either digestion with restriction enzyme (Supplementary Fig.…”

Section: Methodsmentioning

confidence: 99%

Multiple Advantageous Amino Acid Variants in the NAT2 Gene in Human Populations

et al. 2008

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BackgroundGenetic variation at NAT2 has been long recognized as the cause of differential ability to metabolize a wide variety of drugs of therapeutic use. Here, we explore the pattern of genetic variation in 12 human populations that significantly extend the geographic range and resolution of previous surveys, to test the hypothesis that different dietary regimens and lifestyles may explain inter-population differences in NAT2 variation.Methodology/Principal FindingsThe entire coding region was resequenced in 98 subjects and six polymorphic positions were genotyped in 150 additional subjects. A single previously undescribed variant was found (34T>C; 12Y>H). Several aspects of the data do not fit the expectations of a neutral model, as assessed by coalescent simulations. Tajima's D is positive in all populations, indicating an excess of intermediate alleles. The level of between-population differentiation is low, and is mainly accounted for by the proportion of fast vs. slow acetylators. However, haplotype frequencies significantly differ across groups of populations with different subsistence.Conclusions/SignificanceData on the structure of haplotypes and their frequencies are compatible with a model in which slow-causing variants were present in widely dispersed populations before major shifts to pastoralism and/or agriculture. In this model, slow-causing mutations gained a selective advantage in populations shifting from hunting-gathering to pastoralism/agriculture. We suggest the diminished dietary availability of folates resulting from the nutritional shift, as the possible cause of the fitness increase associated to haplotypes carrying mutations that reduce enzymatic activity.

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Section: Methodsmentioning

confidence: 99%

Multiple Advantageous Amino Acid Variants in the NAT2 Gene in Human Populations

et al. 2008

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“…The higher prevalence of high compared to low plasma concentrations of INH and the increased rate of hepatitis patients may be due to acetylation status. The predominance of slow over rapid acetylators has been shown in Iranians [21,22]. …”

Section: Discussionmentioning

confidence: 99%

Isoniazid Blood Levels in Patients with Pulmonary Tuberculosis at a Tuberculosis Referral Center

Fahimi¹,

Kobarfard

Tabarsi

et al. 2010

Chemotherapy

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Background: Serum concentrations of isoniazid (INH) were evaluated in Iranian patients admitted to the Tuberculosis Ward of Masih Daneshvari Hospital, Tehran, Iran. Factors correlated to plasma INH levels were determined. Methods: Blood samples were obtained 2 h after ingestion of 5 mg/kg INH in 82 patients (1 sample/patient) on days 3–15 of treatment. The following variables were investigated: INH plasma level, duration of therapy, age, sex, weight, dose of INH administered and smoking status. Results: The average (±SD) age and weight of patients were 60.68 ± 18.53 years and 74.96 ± 7.15 kg, respectively. INH concentrations were low in 14.63% and high in 23.17% of the patients (INH reference range: 3–5 µg/ml). Plasma INH was statistically correlated with duration of INH administration (Kendall’s rank correlation, r = 0.66, p < 0.001) but not with other variables. Conclusion: Based on the result of this study, plasma INH concentrations were not within the therapeutic range for 37.80% of the patients on conventional therapy. Therefore therapeutic drug monitoring may be needed to optimize INH dosage, especially in patients with inadequate clinical response or toxicity to INH.

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“…Many genetic analyses of the NAT2 polymorphisms have focussed on the 341T>C (2*5), 590G>A (2*6) and 857G>A (2*7) SNPs [40][41][42][43]. More often than not, the 191G>A (2*14) SNP is simply not determined.…”

Section: Phenotype and Genotypementioning

confidence: 99%

“…These studies have also found that the maximum early bactericidal activity of INH is associated with a 2-h INH serum concentration of 2-3 µg/ml. It has also [54] South African Venda 0.385 0.219 0.052 0.109 [59] Tanzanian 0.338 0.205 0.034 0.115 [59] Zimbabwean 0.307 0.209 0.058 0.138 [59] South African colored 0.250 0.110 0.029 0.047 [62] South African Xhosa 0.200 0.150 0.017 0.025 [62] Spanish 0.470 0.180 0.010 nf [87] Iranian 0.33 0.019 0.06 nf [42] Egyptian 0.497 0.260 0.028 nd [41] Thai 0.038 0.326 0.204 nf [88] Chinese 0.011 0.206 0.174 nf [43] Non-Caste Dogon (Mali) 0.300 0.470 0.030 0.050 [60] Gabonese 0.410 0.220 0.020 0.090 [60] Guinea Bissau nd nd nd 0.192 [51] NAT2: N-acetyltransferase 2; nd: Not determined; nf: Not found.…”

Section: Nat2 In Different Populationsmentioning

confidence: 99%

NAT2 Polymorphisms and their Influence on the Pharmacology and Toxicity of Isoniazid in TB Patients

Werely

Donald

Helden

2007

Personalized Medicine

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Tuberculosis is a global pandemic that threatens to overwhelm healthcare budgets in many developing countries. Despite the availability of adequate effective treatment, many patients default on treatment, experience adverse side effects from antibiotics or fail to respond rapidly and recover. Isoniazid, one of the most important first-line tuberculosis drugs, is acetylated in the liver to a variable degree in different individuals giving rise to fast, intermediate and slow acetylator phenotypes. We present the view that the acetylation status of individuals plays an important contributory role in the tuberculosis pandemic. It is important to study the acetylation alleles, and to understand isoniazid metabolism and the manner in which it could affect patient compliance, isoniazid-toxicity and the emergence of drug-resistant strains of mycobacteria.

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Arylamine N-acetyltransferase 2 slow acetylator polymorphisms in unrelated Iranian individuals

Cited by 25 publications

References 26 publications

Multiple Advantageous Amino Acid Variants in the NAT2 Gene in Human Populations

Multiple Advantageous Amino Acid Variants in the NAT2 Gene in Human Populations

Isoniazid Blood Levels in Patients with Pulmonary Tuberculosis at a Tuberculosis Referral Center

NAT2 Polymorphisms and their Influence on the Pharmacology and Toxicity of Isoniazid in TB Patients

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