NAT2 and CYP1B1 genetic polymorphisms in patients with genital endometriosis depending on tolerability of melatonin

BACKGROUND: Genital endometriosis is one of the most pressing problems of modern gynecology. Melatonin is a promising drug with a potentially curative effect on endometriosis. AIM: The aim of this study was to conduct a comparative analysis of the genetic polymorphism of some genes encoding enzymes involved in melatonin metabolism. MATERIALS AND METHODS: The genetic polymorphism in the NAT2 and CYP1B1 genes encoding enzymes involved in melatonin metabolism in patients with different tolerance to this drug was analyzed by PCR-RFLP analysis. RESULTS: In patients with genital endometriosis, the presence of a wild-type allele (N) of the NAT2 gene was associated with poor tolerance of melatonin. The NAT2 (N / N) rapid acetylator phenotype combined with the low catalytic activity of CYP1B1 (C / C) occurred more frequently in endometriosis patients having poor melatonin tolerability compared to the group of patients who tolerated the therapy well. CONCLUSIONS: For patients with genital endometriosis with the wild-type (N) allele of the NAT2 gene, melatonin administration is inappropriate due to numerous side effects during the drug use.

Drug Resistance and Distribution of NAT2 Variants in Newly Diagnosed and Recurrent Vietnamese Pulmonary Tuberculosis Patients

Drug resistant TB is currently a global challenge causing high risk of death and expanding the disease. This study explores the prevalence of drug resistance in newly diagnosed and recurrent TB patients and identifies the association between NAT2 gene polymorphism distribution and acetylator phenotype of NAT2 gene and the two study groups. The study results show that the newly diagnosed TB had l lower male ratio and younger age in comparison to the recurrent TB. Newly diagnosed group was more sensitive to first line TB drugs. However, both groups had significant resistance ratio in relation to INH and SM. Finally, the allele and acetylator phenotype frequency of NAT2 showed the significant association with TB status. The study concludes that the newly diagnosed and recurrent TB patients expressed differently in their profiles concerning patient’s background, drug resistance and NAT2 allele distribution. Keywords Drug resistance, INH, NAT2 polymorphism, newly diagnosed TB, recurrent TB1. References [1] WHO, Global Tuberculossi report, https://www.who.int/tb/publications/global_report/en/, 2018 (accessed 16 April 2019).[2] Hoàng Thị Phượng, Nghiên cứu đặc điểm lâm sàng, cận lâm sàng, tính kháng thuốc của vi khuẩn ở bệnh nhân lao phổi mới kết hợp bệnh đái tháo đường, Luận văn tiến sĩ Y học, trường Đại học Y Hà Nội, 2009.[3] S. Guaoua, I. Ratbi, F.Z. Laarabi, S.A. Elalaoui, IC. Jaouad, A. Barkat, A. Sefiani, Distribution of allelic and genotypic frequencies of NAT2 and CYP2E1 variants in Moroccan population, BMC Genet. 15 (2014) 156.[4] A. Toure, M. Cabral, A. Niang, C. Diop, A. Garat, L. Humbert, M. Fall, A. Diouf, F. Broly, M. Lhermitte, D. Allorge, Prevention of isoniazid toxicity by NAT2 genotyping in Senegalese tuberculosis patients, Toxicol Rep. 3 (2016) 826-831.[5] M. Majumder, N. Sikdar, S. Ghosh, B. Roy, Polymorphisms at XPD and XRCC1 DNA repair loci and increased risk of oral leukoplakia and cancer among NAT2 slow acetylators, Int J Cancer. 120(10) (2007) 2148-2156.[6] S. Morita, M. Yano, T. Tsujinaka, Y. Akiyama, M. Taniguchi, K. Kaneko, H. Miki, T. Fujii, K. Yoshino, H. Kusuoka, M. Monden, Genetic polymorphisms of drug-metabolizing enzymes and susceptibility to head-and-neck squamous-cell carcinoma, Int J Cancer. 80(5) (1999) 685-688.[7] Hoàng Hà, Nghiên cứu một số đặc điểm lâm sàng, cận lâm sàng, sinh học của vi khuẩn ở bệnh nhân lao phổi điều trị lại, Luận án tiến sỹ Y học, Trường Đại học Y Hà Nội, 2009.[8] S. Wattanapokayakit, T. Mushiroda, H. Yanai, N. Wichukchinda, C. Chuchottawon, S. Nedsuwan, A. Rojanawiwat, S. Denjanta, T. Kantima, J. Wongyai, W. Suwankesawong, W. Rungapiromnan, R. Kidkeukarun, W. Bamrungram, A. Chaiwong, S. Suvichapanich, S. Mahasirimongkol, K. Tokunaga, NAT2 slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients, Int J Tuberc Lung Dis. 20(10) (2016) 1364-1369.[9] Đinh Ngọc Sỹ, Chiến lược quản lý bệnh lao đa kháng thuốc tại Việt Nam, Tạp chí khoa học Hội Phổi Pháp - Việt. 2(3) (2011) 40-42.[10] Nguyễn Thu Hà, Trần Văn Sáng, Đinh Ngọc Sỹ, Lâm sàng, cận lâm sàng và tính kháng thuốc của vi khuẩn lao ở bệnh nhân lao phổi tái phát, JFran Viet Pneu. 2(3) (2011) 63-67.[11] D. Tu, L. Zhang, J. Su, Resistance and efficacy of treatment in relapse pulmonary tuberculosis, Zhonghua Jie He He Hu Xi Za Zhi. 23 (11) (2000) 666-668

NAT2 and oral clefts: evaluation of genetic risk and the relative importance of embryo and maternal genotypes

Non-syndromic cleft lip with or without cleft palate (NSCLP) is a congenital malformation that shows the characteristics of a multifactorial pathology. In order to describe the genetic predisposition to this disorder, NAT genes were analyzed with special interest since they codify for N-acetyltransferases, the enzymes responsible for the biotransformation of arylamines, hydrazine drugs and a great number of toxins and carcinogens present in diet, cigarette smoke and the environment. The allelic transmission of NAT2 that determines the slow acetylator phenotype in 174 trios (case-mother/father) from ECLAMC (Latin American Collaborative Study of Congenital Malformations) maternities in Argentina was evaluated. The *4, *5B, *6, and *7 variants by PCR-RFLP were analyzed. A higher risk for the 5B*5B* genotypes (OR=2. 24; p=0.050) was found, at the expense of the cases from Patagonia, without the influence of the maternal genotype.

Polimorfisme Gen N-Asetiltransferase 2 (NAT2) dan Implementasi Farmakogenomik dalam pengobatan Tuberkulosis

AbstrakTuberkulosis (TB) masih menjadi masalah kesehatan utama di Indonesia. Enzim N-asetil- transferase 2 (NAT2) telah diketahui memainkan peranan penting dalam proses metabolism obat anti tuberkulosis, terutama Isoniazid. Polimorfisme NAT2 dilaporkan memiliki asosiasi dengan resiko toksisitas obat dan perkembangan berbagai penyakit. Anti-TuberculosisDrug- induced liver injury (AT-DILI) merupakan efek samping yang biasanya terjadi pada pen- gobatan tuberkulosis. Beberapa penelitian menunjukkan bahwa pasien dengan fenotipe aset- ilator NAT2 lambat sangat rentan terhadap perkembangan AT-DILI. Penelitian kami sebe- lumnya menunjukkan bahwa frekuensi asetilator NAT2 lambat di Indonesia cukup tinggi, pada etnis Jawa-sunda sebesar 33% dan pada etnis Melayu 38%. Oleh karena itu, kesadaran masyarakat terhadap kerentanan AT-DILI harus di tingkatkan. Penelitian kami terbaru menunjukkan bahwa NAT2*6A, yang merupakan alel asetilator lambat, memiliki asosiasi yang signifikan terhadap AT-DILI (p=7.7×10−4, odds ratio (OR)=4.75 (1.8–12.55)). Selain itu, pasien dengan fenotipe asetilator lambat menunjukkan risiko AT-DILI lebih tinggi dibandingkan pasien dengan fenotipe cepat atau intermediet (p = 1,7 × 10-4, OR = 3,45 (1,79-6,67)). Farmakogenomik merupakan suatu studi variasi ekspresi gen individu terkait kerentanan terhadap penyakit dan respon terhadap obat baik pada individu itu sendiri mau- pun pada populasi. Penelitian dan penerapan farmakogenomik dapat membantu menentukan pengobatan yang terbaik untuk pasien dan memiliki peluang keberhasilan yang lebih tinggi. Oleh karena itu, kita perlu mendorong pengembangan penelitian farmakogenomik, mengusulkan kolaborasi baik secara nasional maupun internasional dan membuat masyarakat Indonesia menyadari betapa pentingnya penerapan farmakogenomik dalam kehidupan mereka.Kata kunci: NAT2, Asetilator lambat, AT-DILI, Farmakogenomik AbstractTuberculosis (TB) is still remains as a major health problem in Indonesia. The enzyme N- Acetyltransferase 2 (NAT2) has been known to play an important role in metabolizing anti- tuberculosis drugs, especially isoniazid. Polymorphisms of NAT2 are reportedly associated with the risk of drug toxicities and development of various diseases. Anti-Tuberculosis Drug-induced liver injury (AT-DILI) is the most common adverse drug reaction in the treatment of tuberculosis (TB). Several studies showed that a patient with slow acetylator phenotype has a high susceptibility to AT-DILI. Our research on the Indonesian population, in Javanese and Sundanese dan Malay ethnics showed 33% and 38% NAT2 slow acetylator phenotype, respectively. Therefore, Indonesia populations have to be aware with the development of AT-DILI. Our recent study showed thatNAT2*6A as a slow acetylator allele was signifi- cantly associated with AT-DILI (P=7.7×10−4, odds ratio (OR)=4.75 (1.8–12.55)). Addi- tionally, patients with slow acetylator phenotype showed higher risk of AT-DILI than pa- tients with the rapid acetylator or intermediate acetylator phenotypes (P=1.7×10−4,OR=3.45 (1.79–6.67)). Pharmacogenomics is a study of the variation of in- dividual gene expression related to susceptibility to disease and response to drugs both in the individual itself and population. Pharmacogenomics research and implementation can help to select the best therapeutic option for patients suffering from certain diseases that are both cost effective and having higher chance of success. Therefore, we need to foster phar- macogenomics research development, propose collaboration both nationally and interna- tionally and make the Indonesia society realize how important pharmacogenomics imple- mentation is in their life.Keywords: NAT2, Slow acetylator, AT-DILI, Pharmacogenomics

High frequency of NAT2 slow acetylator alleles in the Malay population of Indonesia: an awareness to the anti-tuberculosis drug induced liver injury and cancer

Background: Arylamine N-acetyltransferase 2 (NAT2) polymorphism was previously reported to have association with the risk of drug toxicities and the development of various diseases. Previous research on the Indonesian population, especially Javanese and Sundanese, showed that there were 33% NAT2 slow acetylator phenotype. The aim of this study was to map the NAT2 variation in the Malay ethnic to gain a deeper insight into NAT2 haplotypic composition in this ethnic.Methods: 50 healthy samples from the Indonesian Malay ethnic were obtained. They were interviewed about their ethnic backgrounds for the last three generations. DNA was extracted from peripheral blood and NAT2 genotyping was done using the PCR direct Sequencing. Data were compiled according to the genotype and allele frequencies estimated from the observed numbers of each specific allele. Haplotype reconstruction was performed using PHASE v2.1.1 software.Results: We found 7 haplotypes consisting of 6 SNPs and 14 NAT2 genotype variations in Indonesian Malay population. The most frequent allele was NAT2*6A (38%) which was classified as a slow acetylator allele. According to bimodal distribution, the predicted phenotype of the Malay population was composed of 62% rapid acetylator and 38% slow acetylator. According to trimodal distribution, the predicted phenotypes for rapid, intermediate and slow acetylators were 10%, 52% and 38% respectively.Conclusion: Our result indicates the presence of the allelic distribution and revealed the most frequent acetylator status and phenotype for the Indonesian Malay population. The result of this study will be helpful for future epidemiological or clinical studies and for understanding the genetic basis of acetylation polymorphism in Indonesia.