Allele Frequency Distribution of UGT1A6 rs6759892 T>G Valproic Acid Metabolic Enzyme-Encoding Gene among Healthy Javanese Population in Indonesia
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Keywords

Javanese-Indonesian population
rs6759892 T>G
UGT1A6
valproic acid

Abstract

Background Polymorphisms in the gene that encodes the metabolic enzyme of valproic acid are one of the important factors associated with interindividual variability in the effective dose and concentration of the drug. UGT1A6 as the encoding gene of glucuronidase enzyme is responsible for valproic acid metabolism, and polymorphisms can therefore influence the drug effectiveness and plasma concentration. This study aimed to analyze the allele frequency distribution of UGT1A6 rs6759892 T>G gene that encodes the metabolic enzyme of VPA among healthy respondents of Javanese as the largest ethnic group in Indonesia.

Methods This study used stored biological specimens in the form of DNA isolates from 100 healthy adult respondents who met the inclusion criteria. Genotyping of UGT1A6 rs6759892 gene was performed using PCR-RFLP method with 5'-CTGACACGGCCATAGTTGGT-3' forward primer and 5'-CCAGCAGCTTGTCACCTACA-3' reverse primer.

Results The results showed that the frequencies of T allele and G allele of UGT1A6 rs6759892 among Javanese population in Indonesia were 0.86 and 0.14, respectively.

Conclusion The frequency of G allele in Javanese-Indonesian ethnic population is similar to that found in a study involving Chinese, Caucasian, and African populations. This study recommends further analysis regarding the influence of such SNP on the pharmacokinetic variability of VPA and its clinical response. Analysis of such correlation as a risk factor for cancer is also required as an effort to seek an early and effective preventive therapy.

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References

Löscher W, Klotz U, Zimprich F, Schmidt D. The clinical impact of pharmacogenetics on the treatment of epilepsy. Epilepsia 2009;50:1–23. https://doi.org/10.1111/j.1528-1167.2008.01716.x.

PERDOSSI. Pedoman Tatalaksana Epilepsi. 5th ed. Surabaya: Airlangga Unversity Press; 2014.

Zhu M-M, Li H-L, Shi L-H, Chen X-P, Luo J, Zhang Z-L. The pharmacogenomics of valproic acid. J Hum Genet 2017;62:1009–14. https://doi.org/10.1038/jhg.2017.91.

Luís PBM, Ruiter JP, Ofman R, Ijlst L, Moedas M, Diogo L, et al. Valproic acid utilizes the isoleucine breakdown pathway for its complete β-oxidation. Biochem Pharmacol 2011;82:1740–6. https://doi.org/10.1016/j.bcp.2011.07.103.

Blanco-Serrano B, Otero MJ, Santos-Buelga D, García-Sánchez MJ, Serrano J, Domínguez-Gil A. Population estimation of valproic acid clearance in adult patients using routine clinical pharmacokinetic data. Biopharm Drug Dispos 1999;20:233–40.

Gervasini G, Benítez J, Carrillo JA. Pharmacogenetic testing and therapeutic drug monitoring are complementary tools for optimal individualization of drug therapy. Eur J Clin Pharmacol 2010;66:755–74. https://doi.org/10.1007/s00228-010-0857-7.

Nagar S, Zalatoris JJ, Blanchard RL. Human UGT1A6 pharmacogenetics: identification of a novel SNP, characterization of allele frequencies and functional analysis of recombinant allozymes in human liver tissue and in cultured cells. Pharmacogenetics 2004;14:487–99.

Owens IS, Basu NK, Banerjee R. UDP-glucuronosyltransferases: gene structures of UGT1 and UGT2 families. Methods Enzymol 2005;400:1–22. https://doi.org/10.1016/S0076-6879(05)00001-7.

Balestrini S, Sisodiya SM. Pharmacogenomics in epilepsy. Neurosci Lett 2018;667:27–39. https://doi.org/10.1016/j.neulet.2017.01.014.

Hung C-C, Ho J-L, Chang W-L, Tai JJ, Hsieh T-J, Hsieh Y-W, et al. Association of genetic variants in six candidate genes with valproic acid therapy optimization. Pharmacogenomics 2011;12:1107–17. https://doi.org/10.2217/pgs.11.64.

Goey AK, Sissung TM, Peer CJ, Figg WD. Pharmacogenomics and histone deacetylase inhibitors. Pharmacogenomics 2016;17:1807–15. https://doi.org/10.2217/pgs-2016-0113.

Guillemette C. Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 2003;3:136–58. https://doi.org/10.1038/sj.tpj.6500171.

Guo Y, Hu C, He X, Qiu F, Zhao L. Effects of UGT1A6, UGT2B7, and CYP2C9 Genotypes on Plasma Concentrations of Valproic Acid in Chinese Children with Epilepsy. Drug Metab Pharmacokinet 2012;27:536–42. https://doi.org/10.2133/dmpk.DMPK-11-NT-144.

Oussalah A, Bosco P, Anello G, Spada R, Guéant-Rodriguez R-M, Chery C, et al. Exome-Wide Association Study Identifies New Low-Frequency and Rare UGT1A1 Coding Variants and UGT1A6 Coding Variants Influencing Serum Bilirubin in Elderly Subjects. Medicine (Baltimore) 2015;94. https://doi.org/10.1097/MD.0000000000000925.

Chatzistefanidis D, Georgiou I, Kyritsis AP, Markoula S. Functional impact and prevalence of polymorphisms involved in the hepatic glucuronidation of valproic acid. Pharmacogenomics 2012;13:1055–71. https://doi.org/10.2217/pgs.12.78.

Guo Y, Hu C, He X, Qiu F, Zhao L. Effects of UGT1A6, UGT2B7, and CYP2C9 Genotypes on Plasma Concentrations of Valproic Acid in Chinese Children with Epilepsy. Drug Metab Pharmacokinet 2012;27:536–42. https://doi.org/10.2133/dmpk.DMPK-11-NT-144.

Kua L-F, Ross S, Lee S-C, Mimura K, Kono K, Goh B-C, et al. UGT1A6 Polymorphisms Modulated Lung Cancer Risk in a Chinese Population. PLoS ONE 2012;7. https://doi.org/10.1371/journal.pone.0042873.

Chatzistefanidis D, Lazaros L, Giaka K, Nakou I, Tzoufi M, Georgiou I, et al. UGT1A6- and UGT2B7-related valproic acid pharmacogenomics according to age groups and total drug concentration levels. Pharmacogenomics 2016;17:827–35. https://doi.org/10.2217/pgs-2016-0014.

Jain P, Shastri S, Gulati S, Kaleekal T, Kabra M, Gupta N, et al. Prevalence of UGT1A6 polymorphisms in children with epilepsy on valproate monotherapy. Neurol India 2015;63:35. https://doi.org/10.4103/0028-3886.152631.

Justenhoven C, Obazee O, Winter S, Rabstein S, Lotz A, Harth V, et al. The UGT1A6_19_GG genotype is a breast cancer risk factor. Front Genet 2013;4. https://doi.org/10.3389/fgene.2013.00104.

MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk. Genetic polymorphisms in phase I and phase II enzymes and breast cancer risk associated with menopausal hormone therapy in postmenopausal women. Breast Cancer Res Treat 2010;119:463–74. https://doi.org/10.1007/s10549-009-0407-0.

Ningrum VD, Istikharah R, Firmansyah R. Allele Frequency of SLC22A1 Met420del Metformin Main Transporter Encoding Gene among Javanese-Indonesian Population. Open Access Maced J Med Sci 2019;7:378–83. https://doi.org/10.3889/oamjms.2019.087.

Ningrum* VDA, Ikawati Z, Ikhsan AHS and MR. Allele Frequencies of Two Main Metformin Transporter Genes: SLC22A1 rs628031 A>G and SLC47A1 rs2289669 G>A among the Javanese Population in Indonesia. Curr Pharmacogenomics Pers Med Former Curr Pharmacogenomics 2017. http://www.eurekaselect.com/153849/article (accessed September 3, 2018).

Court MH. Interindividual variability in hepatic drug glucuronidation: Studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system. Drug Metab Rev 2010;42:209–24. https://doi.org/10.3109/03602530903209288.

Krishnaswamy S, Hao Q, Al-Rohaimi A, Hesse LM, von Moltke LL, Greenblatt DJ, et al. UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: II. Functional impact of the three most common nonsynonymous UGT1A6 polymorphisms (S7A, T181A, and R184S). J Pharmacol Exp Ther 2005;313:1340–6. https://doi.org/10.1124/jpet.104.081968.

Hu DG, Meech R, McKinnon RA, Mackenzie PI. Transcriptional regulation of human UDP-glucuronosyltransferase genes. Drug Metab Rev 2014;46:421–58. https://doi.org/10.3109/03602532.2014.973037.

Anderson GD. Children Versus Adults: Pharmacokinetic and Adverse-Effect Differences. Epilepsia 2002;43:53–9. https://doi.org/10.1046/j.1528-1157.43.s.3.5.x.

Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, et al. Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics 2013;23:236. https://doi.org/10.1097/FPC.0b013e32835ea0b2

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