Prevalence of polymorphisms in N-acetyltransferase 2 gene among patients of Yakut ethnicity newly diagnosed with pulmonary tuberculosis

Cover Page
  • Authors: Krasnova N.M.1, Alekseeva E.A.2, Rudykh Z.A.3, Chertovskykh Y.V.2, Klimova T.M.1, Efremova E.N.4, Kravchenko A.F.4, Val N.S.4, Suvorova O.A.5, Suleymanov S.S.6, Vengerovsky A.I.7, Sychev D.A.5
  • Affiliations:
    1. M.K. Ammosov North-Eastern Federal University, Medical Institute
    2. Republican Hospital no. 3, Center for Personalized Medicine
    3. Republican Hospital no. 3, Center for Personalized Medicine, Yakutsk, Russia
    4. Phthisiatry Research-Practice Center
    5. Russian Medical Academy of Continuous Professional Education
    6. SAIKO Russian-Japanese Medical Center
    7. Siberian State Medical University
  • Issue: Vol 75, No 2 (2020)
  • Pages: 154-161
  • Section: PHTHISIOLOGY: CURRENT ISSUES
  • URL: https://vestnikramn.spr-journal.ru/jour/article/view/1217
  • DOI: https://doi.org/10.15690/vramn1217
  • Cite item
Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract


Background. Tuberculosis therapy can lead to considerably dissimilar outcomes among individual patients. Some patients benefit from anti-tuberculosis chemotherapy leading to a desired therapeutic effect, while other patients show insufficient or absent response, or develop adverse side effects. Individual response to isoniazid is affected by mutations in the gene encoding N-acetyltransferase 2 (NAT2). Wide variations were observed in distributions of polymorphic NAT2 alleles in human populations depending on race, ethnicity, or geographical origin. No data are available to date on prevalence of NAT2 gene polymorphic variants and acetylation types in Yakut (Sakha) patients with newly diagnosed pulmonary tuberculosis.

Aims: the frequencies of NAT2 polymorphic SNPs as well isoniazid acetylation phenotypes were evaluated in the patient’s cohort of Yakut ethnicity with newly diagnosed pulmonary tuberculosis (PTB). The comparison with, other ethnic groups of Asian origin was done.

Methods. Cross-sectional study was conducted among Yakut patient cohorts with newly identified pulmonary tuberculosis. Using real-time PCR the following SNPs were explored: NAT2*5 (rs1801280, Т341С), NAT2*6 (rs1799930, G590A), NAT2*7 (rs1799931, G857A), NAT2*11 (rs1799929, C481T), NAT2*12 (rs1208, A803G), NAT2*13 (rs1041983, C282T). Genetically determined metabolic rates were calculated using NATpred online tool.

Results. NAT2 SNPs were assessed, namely *5, *6, *7, *11, *12, and *13. The most frequent in Yakut patients were NAT2*6 and NAT2*13 SNPs (40.9% and 64.4%, respectively). Significant differences were detected in frequencies of NAT2 *5, *11, *12 polymorphisms; all studied NAT2 gene polymorphisms showed meaningful differences in genotype and minor allele prevalence rates after comparison between Yakut population and other Mongoloid ethnic groups (populations of China, Japan, Vietnam). High prevalence of intermediate acetylation type among ethnic Yakuts (58.3%) was established.

Conclusions. Certain distinct differences in allelic variants of NAT2 gene and acetylation type prevalence in patients of Yakut ethnic origin newly diagnosed with pulmonary tuberculosis let conclude that the existing genotyping and phenotyping data from studies among other Mongoloid populations cannot be implicitly extrapolated on Yakut people. Pharmacogenetic data on individual response to drugs in Yakut patients should be made use of in clinical practice, to develop personalized isoniazid administration algorithms, with a final goal to make treatment more effective and safe.


Full Text

Restricted Access

About the authors

Nataliya M. Krasnova

M.K. Ammosov North-Eastern Federal University, Medical Institute

Author for correspondence.
Email: krasnova14@mail.ru
ORCID iD: 0000-0002-4811-7801
SPIN-code: 8703-8169

Russian Federation, 58, Belinsky Street, Yakutsk, 677000

MD, PhD

Elizaveta A. Alekseeva

Republican Hospital no. 3, Center for Personalized Medicine

Email: elizavetaalal@mail.ru
ORCID iD: 0000-0001-6116-5720
SPIN-code: 8918-7035

Russian Federation, 677027, Sakha Republic (Yakutia), Yakutsk, Gorkogo str., 94

biologist

Zoya A. Rudykh

Republican Hospital no. 3, Center for Personalized Medicine, Yakutsk, Russia

Email: vitae003@rambler.ru
ORCID iD: 0000-0001-8212-0150
SPIN-code: 4930-4297

Russian Federation, 677027, Sakha Republic (Yakutia), Yakutsk, Gorkogo str., 94

clinical pharmacologist

Yana V. Chertovskykh

Republican Hospital no. 3, Center for Personalized Medicine

Email: yana_chertovski@mail.ru
ORCID iD: 0000-0003-0941-8633
SPIN-code: 8485-9530

Russian Federation, 677027, Sakha Republic (Yakutia), Yakutsk, Gorkogo str., 94

clinical pharmacologist, Head of the Center for Personalized Medicine

Tatiana M. Klimova

M.K. Ammosov North-Eastern Federal University, Medical Institute

Email: biomedykt@mail.ru
ORCID iD: 0000-0003-2746-0608
SPIN-code: 2635-0865

Russian Federation, 58, Belinsky Street, Yakutsk, 677000

MD, PhD, associate professor of the Department for pharmacology and pharmacy, Medical Institute

Efrosiniya N. Efremova

Phthisiatry Research-Practice Center

Email: efremovaen@tub.ykt.ru
ORCID iD: 0000-0001-6934-2971
SPIN-code: 3688-9742

Russian Federation, 677000, Sakha Republic (Yakutia), Yakutsk, Petra Alekseeva str., 93

TB clinician

Aleksandr F. Kravchenko

Phthisiatry Research-Practice Center

Email: kravchenkoaf@tub.ykt.ru
ORCID iD: 0000-0002-9210-3407
SPIN-code: 3188-6796

Russian Federation, 677000, Sakha Republic (Yakutia), Yakutsk, Petra Alekseeva str., 93

MD, PhD, Professor, Director 

Natalia S. Val

Phthisiatry Research-Practice Center

Email: yniit@mail.ru
ORCID iD: 0000-0003-2910-1895

Russian Federation, 677000, Sakha Republic (Yakutia), Yakutsk, Petra Alekseeva str., 93

MD, PhD, Deputy director for medical service

Olga A. Suvorova

Russian Medical Academy of Continuous Professional Education

Email: olga.a.suvorova@mail.ru
ORCID iD: 0000-0001-9661-7213

Russian Federation, 2/1, Barrikadnaya st., Moscow, 125993

Salavat Sh. Suleymanov

SAIKO Russian-Japanese Medical Center

Email: suleymanov-sh@mail.ru
ORCID iD: 0000-0002-3176-2716
SPIN-code: 9047-1399

Russian Federation, Khabarovsk

MD, PhD, Professor

Aleksandr I. Vengerovsky

Siberian State Medical University

Email: pharm-sibgmu@rambler.ru
ORCID iD: 0000-0001-5094-3742
SPIN-code: 8818-0543

Russian Federation, 2, Moscowski Trakt, Tomsk, 634050

MD, PhD, Professor

Dmitry A. Sychev

Russian Medical Academy of Continuous Professional Education

Email: dmitrysychevrmapo@gmail.com
ORCID iD: 0000-0002-4496-3680
SPIN-code: 4525-7556

Russian Federation, 2/1, Barrikadnaya st., Moscow, 125993

MD, PhD, Professor

References

  1. https://mednet.ru/. Эпидемическая ситуация по туберкулезу в России [доступ от 08.06.2019]. [https://mednet.ru/. Epidemicheskaya situatsiya po tuberkulezu v Rossii. (In Russ).] Доступно по: https://mednet.ru/images/materials/CMT/2018_god_tuberkulez_epidsituaciya.pdf. Ссылка активна на 15.01.2020.
  2. Jarrar YB, Balasmeh AA, Jarrar W. Sequence analysis of the N-acetyltransferase 2 gene (NAT2) among Jordanian volunteers. Libyan J Med. 2018;13(1):1408381. doi: 10.1080/19932820.2017.1408381.
  3. Khan S, Mandal RK, Elasbali AM, et al. Pharmacogenetic association between gene polymorphisms and isoniazid induced hepatotoxicity: trial sequence meta-analysis as evidence. Biosci Rep. 2019;39(1):BSR20180845. doi: 10.1042/BSR20180845.
  4. Fuselli S, Gilman RH, Chanock SJ, et al. Analysis of nucleotide diversity of NAT2 coding region reveals homogeneity across Native American populations and high intra-population diversity. Pharmacogenomics J. 2007;7(2):144–152. doi: 10.1038/sj.tpj.6500407.
  5. Hein DW. N-acetyltransferase single nucleotide polymorphisms: Emerging concepts serve as a paradigm for understanding complexities of personalized medicine. Expert Opin Drug Metab Toxicol. 2009;5(4):353–366. doi: 10.1517/17425250902877698.
  6. Walraven JM, Zang Yu, Trent JO, et al. Structure/function evaluations of single nucleotide polymorphisms in human N-acetyltransferase 2. Curr Drug Metab. 2008;9(6):471–486. doi: 10.2174/138920008784892065.
  7. Yadav D, Kumar R, Dixit RK, et al. Association of NAT2 gene polymorphism with antitubercular drug-induced hepatotoxicity in the Eastern Uttar Pradesh population. Cureus. 2019;11(4):e4425. doi: 10.7759/cureus.4425.
  8. Сналина Н.Е., Сычев Д.А. Генетические предикторы гепатотоксичности изониазида // Молекулярная медицина. ― 2018. ― Т.16. ― №2. ― С. 31–36. [Snalina NE, Sychev DA. Genetic predictors of isoniazid hepatotoxicity. Molecular medicine. 2018;16(2):31–36. (In Russ).] doi: 10.29296/24999490-2018-02-04.
  9. Zhu R, Kiser JJ, Seifart HI, et al. The pharmacogenetics of NAT2 enzyme maturation in perinatally HIV exposed infants receiving isoniazid. J Clin Pharmacol. 2012;52(4):511–519. doi: 10.1177/0091270011402826.
  10. Zabost A, Brzezińska S, Kozińska M, et al. Correlation of N-acetyltransferase 2 genotype with isoniazid acetylation in polish tuberculosis patients. Biomed Res Int. 2013;2013:853602. doi: 10.1155/2013/853602.
  11. Dursun R, Dursun HG, Zamani AG, et al. NAT2 gene polymorphisms in Turkish patients with psoriasis vulgaris. Biomed Res Int. 2018;3258708. doi: 10.1155/2018/3258708.
  12. Birch KE, Yakimov V, Bjorn-Mortensen K, et al. Study of correlation between the NAT2 phenotype and genotype status among Greenlandic Inuit. EXCLI J. 2018;17:1043–1053. doi: 10.17179/excli2018-1671.
  13. Sabbagh A, Darlu P, Crouau-Roy B, Poloni ES. Arylamine N-acetyltransferase 2 (NAT2) genetic diversity and traditional subsistence: a worldwide population survey. PLoS One. 2011;6(4):e18507. doi: 10.1371/journal.pone.0018507.
  14. Tang H, Quertermous T, Rodriguez B, et al. Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Amer J Human Genet. 2005;76(2):268–275. doi: 10.1086/427888.
  15. Kuznetsov IB, McDuffie M, Moslehi R. A web-server for inferring the human N-acetyltransferase-2 (NAT2) enzymatic phenotype from NAT2 genotype. Bioinformatics. 2009;25(9):1185–1186. doi: 10.1093/bioinformatics/btp121.
  16. Hein DW. N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk. Oncogene. 2006;25(11):1649–1658. doi: 10.1038/sj.onc.1209374.
  17. Kurose K, Sugiyama E, Saito Y. Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in eastern asians and europeans: implications in the clinical trials for novel drug development. Drug metabolism and pharmacokinetics. 2012;27(1):9–54. doi: 10.2133/dmpk.dmpk-11-rv-111.
  18. Hemanth Kumar AK, Ramesh K, Kannan T, et al. N-acetyltransferase gene polymorphisms & plasma isoniazid concentrations in patients with tuberculosis. Indian J Med Res. 2017;145(1):118–123. doi: 10.4103/ijmr.IJMR_2013_15.
  19. Shi J, Xie M, Wang J, et al. Susceptibility of N-acetyltransferase 2 slow acetylators to antituberculosis drug-induced liver injury: a meta-analysis. Pharmacogenomics. 2015;16(18):2083–2097. doi: 10.2217/pgs.15.144.
  20. Suvichapanich S, Fukunaga K, Zahroh H, et al. NAT2 ultra-slow acetylator and risk of anti-tuberculosis drug-induced liver injury: a genotype-based meta-analysis. Pharmacogenet Genomics. 2018;28(7):167–176. doi: 10.1097/FPC.0000000000000339.
  21. Wang PY, Xie SY, Hao Q, et al. NAT2 polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury: a meta-analysis. Int J Tuberc Lung Dis. 2012;16(5):589–595. doi: 10.5588/ijtld.11.0377.
  22. Zhang M, Wang S, Wilffert B, et al. The association between the NAT2 genetic polymorphisms and risk of DILI during anti-TB treatment: a systematic review and meta-analysis. Br J Clin Pharmacol. 2018;84(12):2747–2760. doi: 10.1111/bcp.13722.
  23. Donald PR, Sirgel FA, Venter A, et al. The influence of human N-acetyltransferase genotype on the early bactericidal activity of isoniazid. Clin Infect Dis. 2004;39(10):1425–1430. doi: 10.1086/424999.
  24. Weiner M, Burman W, Vernon A, et al. Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine. Am J Respir Crit Care Med. 2003;167(10):1341–1347. doi: 10.1164/rccm.200208-951OC.
  25. Golka K, Selinski S. NAT2 Genotype and isoniazid medication in children. EBio Med. 2016;11:11–12. doi: 10.1016/j.ebiom.2016.08.040.

Supplementary files

There are no supplementary files to display.

Statistics

Views

Abstract - 294

PDF (Russian) - 0

Cited-By


PlumX

Dimensions



Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies