Türkiye Popülasyonunda UGT1A4 ve UGT1A6 Genetik Profillerinin Değerlendirilmesi

Amaç: Üridin difosfat glukuronosiltransferazlar (UGT'ler), konjugasyon faz II enzimlerinin bir süper ailesidir ve birçok endobiyotik veya ksenobiyotik substratın glukuronidasyonunu katalize etmekten sorumludur. Bu çalışmada, sağlıklı Türk popülasyonunda UGT1A4 c.142T>G, UGT1A6 c.541A>G ve UGT1A6 c.19T>G polimorfizmlerinin allel ve genotip frekanslarının belirlenmesi ve farklı popülasyon verileriyle karşılaştırılması amaçlanmıştır. Gereç ve Yöntem: UGT1A4 c.142T>G, UGT1A6 c.541A>G ve c.19T>G polimorfizmleri, polimeraz zincir reaksiyonu ve restriksiyon fragman uzunluğu polimorfizmi yöntemleri kullanılarak 114 sağlıklı Türk gönüllülerinin DNA örneklerinde belirlendi. Bulgular: Varyant allel frekansları UGT1A4 c.142T>G için % 12.7, UGT1A6 c.541A>G için % 39.9 ve UGT1A6 c.19T>G için % 44.7 idi. Belirlenen UGT1A4 ve UGT1A6 varyant allel frekanslarının, Avrupa popülasyonlarının çoğunluğuna benzer olduğu gözlendi. Ancak, Türk popülasyonundaki UGT1A6 frekanslarının, özellikle Tayland ve Doğu Asya popülasyonlarının frekanslarından önemli ölçüde farklıydı. Sonuç: Bu çalışma, Türk popülasyonunda UGT1A4 ve UGT1A6 polimorfizmlerinin sıklığını sunmaktadır. Bildiğimiz kadarıyla, sağlıklı bir Türk popülasyonunda UGT1A6 c.541A>G ve c.19T>G polimorfizmlerinin sıklığını araştıran ilk rapordur. Literatür taramasında Türk epilepsi hastalarında UGTA1A4*3 polimorfizmi ile ilgili bir çalışma bulundu, ancak sağlıklı bireyler ile ilgili veri bulunmadı. Dolayısıyla bu çalışmanın, sağlıklı Türk bireylerinde UGT1A4*3 polimorfizmini araştıran ilk rapor olduğu ifade edilebilir. Bu çalışma, Türk popülasyonunda UGT1A4 ve UGT1A6 ile gerçekleşen ilaç metabolizması hakkında klinik olarak faydalı bilgiler sağlayabilir.

Anahtar Kelimeler:

UGT1A4, UGT1A6, glukuronidasyon, polimorfizm, Türk popülasyonu

The Evaluation of Genetic Profiles of UGT1A4 and UGT1A6 in the Turkish Population

Aim: Uridine diphosphate glucuronosyltransferases (UGTs) are a superfamily of conjugation phase II enzymes and is responsible for catalyzing the glucuronidation of many endobiotic or xenobiotic substrates. The present study aimed to determine allele and genotype frequencies of UGT1A4 c.142T>G, UGT1A6 c.541A>G and UGT1A6 c.19T>G polymorphisms in the healthy Turkish population and also to compare them with different population data. Material and Method: UGT1A4 c.142T>G, UGT1A6 c.541A>G and c.19T>G polymorphisms were determined in DNA samples of 114 healthy Turkish volunteers using polymerase chain reaction and restriction fragment length polymorphism methods. Results: The frequencies of variant alleles were 12.7% for UGT1A4 c.142T>G, 39.9% for UGT1A6 c.541A>G and 44.7% for UGT1A6 c.19T>G. The frequencies of the UGT1A4 and UGT1A6 variant alleles determined were observed to be similar to those of the majority of European populations. However, the UGT1A6 frequencies in the Turk population differed significantly from those reported specifically for the Thai and East Asian populations. Conclusion: This study introduces the frequencies of UGT1A4 and UGT1A6 polymorphisms in the Turkish population. To our knowledge, this is the first report that investigated the frequencies of UGT1A6 c.541A>G and c.19T>G polymorphisms in a healthy Turkish population. A study of the UGTA1A4*3 polymorphism was found in Turkish epilepsy patients in the literature search, but not in healthy individuals. Therefore, it can be stated that this study is also the first report investigating the UGT1A4*3 polymorphism in the healthy Turkish individuals. This study could ensure clinically beneficial information about drug metabolism by UGT1A4 and UGT1A6 in Turkish population.

Keywords:

UGT1A4, UGT1A6, glucuronidation, polymorphism, Turkish population,

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Ge S,Tu Y, Hu M. Challenges and opportunities with predicting in vivo phase II metabolism via glucuronidation from in vitro Data. Curr Pharmacol Rep 2016;2(6):326-38.
Troberg J, Finel M. The polymorphic variant P24T of UDP-glucuronosyltransferase 1A4 and its unusual consequences. Drug Metab Dispos 2015;43(11):1769-72.
Mehboob H, Tahir IM, Iqbal T, Saleem S, Perveen S, Farooqi A. Effect of UDP-glucuronosyltransferase (UGT) 1A polymorphism (rs8330 and rs10929303) on glucuronidation status of acetaminophen. Dose Response 2017;15(3):1559325817723731.
Liu W, Ramírez J, Gamazon ER, et al. Genetic factors affecting gene transcription and catalytic activity of UDP-glucuronosyltransferases in human liver. Hum Mol Genet 2014; 23(20):5558-69.
López M, Dorado P, Ortega A, et al. Interethnic differences in UGT1A4 genetic polymorphisms between Mexican Mestizo and Spanish populations. Mol Biol Rep 2013;40(4):3187-92.
Reimers A, Sjursen W, Helde G, Brodtkorb E. Frequencies of UGT1A4*2 (P24T) and *3 (L48V) and their effects on serum concentrations of lamotrigine. Eur J Drug Metab Pharmacokinet 2016;41(2):149–55.
Meech R, Hu DG, McKinnon RA, et al. The UDP-glycosyltransferase (UGT) superfamily: new members, new functions, and novel paradigms. Physiol Rev 2019;99(2):1153-222.
Hanioka N, Iwabu H, Hanafusa H, Nakada S, Narimatsu S. Expression and inducibility of UDP-glucuronosyltransferase 1As in MCF-7 human breast carcinoma cells. Basic Clin Pharmacol Toxicol 2012;110(3):253-8.
Hakooz N, Alzubiedi S, Yousef AM, et al. UDP-glucuronosyltransferase 1A4 (UGT1A4) polymorphisms in a Jordanian population. Mol Biol Rep 2012;39(7):7763-8.
Gulcebi MI, Ozkaynakcı A, Goren MZ, Aker RG, Ozkara C, Onat FY. The relationship between UGT1A4 polymorphism and serum concentration of lamotrigine in patients with epilepsy. Epilepsy Res 2011;95(1-2):1-8.
Haslemo T, Loryan I, Ueda N, et al. UGT1A4*3 encodes significantly increased glucuronidation of olanzapine in patients on maintenance treatment and in recombinant systems. Clin Pharmacol Ther 2012;92(2):221-7.
Ghotbi R, Mannheimer B, Aklillu E, et al. Carriers of the UGT1A4 142T>G gene variant are predisposed to reduced olanzapine exposure-an impact similar to male gender or smoking in schizophrenic patients. Eur J Clin Pharmacol 2010;66(5):465-74.
Dadheech S, Raoa AV, Shaheen U, et al. Three most common nonsynonymous UGT1A6*2 polymorphisms (Thr181Ala, Arg184Ser and Ser7Ala) and therapeutic response to deferiprone in β-thalassemia major patients. Gene 2013;531(2):301–5.
van Oijen MG, Huybers S, Peters WH, et al. Polymorphisms in genes encoding acetylsalicylic acid metabolizing enzymes are unrelated to upper gastrointestinal health in cardiovascular patients on acetylsalicylic acid. Br J Clin Pharmacol 2005;60(6):623-8.
Palikhe NS, Kim SH, Nam YH, Ye YM, Park HS. Polymorphisms of aspirin-metabolizing enzymes CYP2C9, NAT2 and UGT1A6 in aspirin-intolerant urticaria. Allergy Asthma Immunol Res 2011;3(4):273-6.
Algharably EA, Hamamsy ME, Hassanein SM, et al. The Effect of UGT1A6 Polymorphism at Two Loci on the Clinical Response to Valproic Acid in Epileptic Children. Int J Pharm Sci Res 2016;7(10):3986-94.
Alkharfy KM, Jan BL, Afzal S, et al. Prevalence of UDP-glucuronosyltransferase polymorphisms (UGT1A6∗2, 1A7∗12, 1A8∗3, 1A9∗3, 2B7∗2, and 2B15∗2) in a Saudi population. Saudi Pharm J 2017;25(2):224–30.
1000 Genomes Project. https://www.internationalgenome.org/1000-genomes-browsers/ (accessed 16.09.2020).
Aphichartphunkawee S, Chinvarun Y, Kijsanayotin P. Association of genetic variants in UGT1A6 genes and non-genetic variant with valproic acid doses and plasma concentration in Thai epileptic patients. Thai J Pharm Sci 2014;38(2):98-105.
Saeki M, Saito Y, Jinno H, et al. Haplotype structures of the UGT1A gene complex in a Japanese population. Pharmacogenomics J 2006;6(1):63–75.
Yea SS, Lee SS, Kim WY, et al. Genetic variations and haplotypes of UDP-glucuronosyltransferase 1A locus in a Korean population. Ther Drug Monit 2008;30(1):23-34.
Suh HJ, Yoon SH, Yu KS, et al. The Genetic polymorphism UGT1A4*3 is associated with low posaconazole plasma concentrations in hematological malignancy patients receiving the oral suspension. Antimicrob Agents Chemother 2018;62(7):e02230-17.
Liu L, Zhao L, Wang Q, Qiu F, Wu X, Ma Y. Influence of valproic acid concentration and polymorphism of UGT1A4*3, UGT2B7 -161C > T and UGT2B7*2 on serum concentration of lamotrigine in Chinese epileptic children. Eur J Clin Pharmacol 2015;71(11):1341-7.
Chang Y, Yang LY, Zhang MC, Liu SY. Correlation of the UGT1A4 gene polymorphism with serum concentration and therapeutic efficacy of lamotrigine in Han Chinese of Northern China. Eur J Clin Pharmacol 2014;70(8):941-6.
Xing Y, Yang L, Wang L, et al. Systematic screening for polymorphisms within the UGT1A6 gene in three Chinese populations and function prediction through structural modeling. Pharmacogenomics 2009;10(5):741-52.
Chu XM, Zhang LF, Wang GJ, Zhang SN, Zhou JH, Hao HP. Influence of UDP-glucuronosyltransferase polymorphisms on valproic acid pharmacokinetics in Chinese epilepsy patients. Eur J Clin Pharmacol 2012;68(10):1395-401.
Shen X, Bi J, Liu Q, et al. Effects of UGT1A3, UGT1A6, and UGT2B7 genetic polymorphisms on plasma concentration of valproic acid in south Chinese epilepsy patients. Int J Clin Exp Pathol 2016;9(4):4513-22.
Jain P, Shastri S, Gulati S, et al. Prevalence of UGT1A6 polymorphisms in children with epilepsy on valproate monotherapy. Neurol India 2015;63(1):35-9.
Du Z, Jiao Y, Shi L. Association of UGT2B7 and UGT1A4 polymorphisms with serum concentration of antiepileptic drugs in children. Med Sci Monit 2016;22:4107-13.
Oussalah A, Bosco P, Anello G, 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(22):e925.
Kua LF, Ross S, Lee SC et al. UGT1A6 polymorphisms modulated lung cancer risk in a Chinese population. PLoS One 2012;7(8):e42873.
Zhang X, Ao G, Wang Y, et al. Genetic variants and haplotypes of the UGT1A9, 1A7 and 1A1 genes in Chinese Han. Genet Mol Biol 2012;35(2):428-34.
Uckun Z, Baskak B, Ozdemir H, Ozel-Kizil ET, Devrimci-Ozguven H, Suzen HS. Genotype and allele frequency of CYP3A4 -392A>G in Turkish patients with major depressive disorder. Turk J Pharm Sci 2018;15(2):200-6.