Interethnic Variations of UGT1A1 and UGT1A7 Polymorphisms in the Jordanian Population

Author(s): Sara Abudahab*, Nancy Hakooz, Yazun Jarrar, Mohammad Al Shahhab, Ahmad Saleh, Malek Zihlif, Rana Dajani.

Journal Name: Current Drug Metabolism

Volume 20 , Issue 5 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Glucuronidation is one of the most important phase II metabolic pathways. It is catalyzed by a family of UDP-glucuronosyltransferase enzymes (UGTs). UGT1A1 and UGT1A7 catalyze the glucuronidation of a diverse range of medications, environmental chemicals and endogenous compounds. Polymorphisms in the UGT1A gene could potentially be significant for the pharmacological, toxicological and physiological effects of the enzymes.

Objective: The UGT1A gene is polymorphic among ethnic groups and the aim of this study was to investigate the different UGT1A1 and UGT1A7 polymorphisms in Circassians, Chechens and Jordanian-Arabs.

Methods: A total of 168 healthy Jordanian-Arabs, 56 Circassians and 54 Chechens were included in this study. Genotyping of 20 different Single-nucleotide polymorphism (SNPs) was done by using polymerase chain reaction- DNA sequencing.

Results: We found that Circassians and Chechens have significantly higher allele frequencies of UGT1A7*2, UGT1A7*3 and UGT1A7*4 than the Jordanian-Arab population, but all three populations have similar frequencies of UGT1A1*28. Therefore, Circassians and Chechens are expected to have significantly lower levels of the UGT1A7 enzyme with almost 90% of these populations having genes that encode low or intermediate enzyme activity.

Conclusion: This inter-ethnic variation in the UGT1A alleles frequencies may affect drug response and susceptibility to cancers among different subethnic groups in Jordan. Our results can also provide useful information for the Jordanian population and for future genotyping of Circassian and Chechen populations in general.

Keywords: UDP-glucuronosyltransferase, polymorphisms, drug metabolism, glucuronidation, personalized medicine, interethnic variations Circassians, Chechens.

[1]
Wells, P.G.; Mackenzie, P.I.; Chowdhury, J.R.; Guillemette, C.; Gregory, P.A.; Ishii, Y.; Hansen, A.J.; Kessler, F.K.; Kim, P.M.; Chowdhury, N.R.; Ritter, J.K. Glucuronidation and the UDP-Glucuronosyltransferases in Health and Disease. Drug Metab. Dispos., 2004, 32(3), 281-290.
[2]
Conney, A.H.; Bubns, J.J. Factors Influencing Drug Metabolism. In:Advances in Pharmacology; Garattini, S.; Shore, P.A., Eds.; Academic Press Inc., 1962, Vol. 1, pp. 31-58.
[3]
Gibson, G.G.; Paul, S. Introduction to Drug Metabolism, 3rd ed; Nelson Thornes Publishers, 2001.
[4]
Wijnen, P.A.; Bekers, O.; Drent, M. Relationship between Drug-Induced Interstitial Lung Diseases and Cytochrome P450 Polymorphisms. Curr. Opin. Pulm. Med., 2010, 16(5), 496-502.
[5]
J., Belle D.; Singh, H. Genetic Factors in Drug Metabolism. Am. Fam. Physician, 2008, 77(11), 1553-1560.
[6]
Owens, I.S.; Ritter, J.K. The novel bilirubin/phenol UDP-glucuronosyltransferase UGT1 gene locus: Implications for multiple nonhemolytic familial hyperbilirubinemia phenotypes. Pharmacogenetics, 1992, 2(3), 93-108.
[7]
Ehmer, U.; Vogel, A.; Schütte, J.K.; Krone, B.; Manns, M.; Strassburg, C.C. Variation of hepatic glucuronidation: Novel functional polymorphisms of the UDP-glucuronosyltransferase UGT1A4. Hepatology, 2004, 39(4), 970-977.
[8]
Bosma, P.J.; Chowdhury, J.R.; Bakker, C.; Gantla, S.; de Boer, A.; Oostra, B.A.; Lindhout, D.; Tytgat, G.N.; Jansen, P.L.; Oude Elferink, R.P. The Genetic Basis of the Reduced Expression of Bilirubin UDP-Glucuronosyltransferase 1 in Gilbert’s Syndrome. N. Engl. J. Med., 1995, 333(18), 1171-1175.
[9]
Strassburg, C.P. Pharmacogenetics of Gilbert’s Syndrome. Pharmacogenomics, 2008, 9(6), 703-715.
[10]
Beutler, E.; Gelbart, T.; Demina, A. Racial Variability in the UDP-Glucuronosyltransferase 1 (UGT1A1) Promoter: A Balanced Polymorphism for Regulation of Bilirubin Metabolism? Proc. Natl. Acad. Sci. USA, 1998, 95(14), 8170-8174.
[11]
Padmanabhan, S. Handbook of Pharmacogenomics and Stratified Medicine, 1st ed; Sandosh Padmanabhan, 2014.
[12]
Richmond, W. The Circassian Genocide, 1st ed; Rutgers University Press, 2013.
[13]
Dweik, B. Linguistic and Cultural Maintenance Among the Chechens of Jordan. Lang. Cult. Curriculum, 2000, 13(2), 184-195.
[14]
Shami, S. Displacement, Historical Memory, and Identity: The Circassians in Jordan. Cent. Migr. Stud. Spec. issues, 1994, 11(4), 189-201.
[15]
Zhemukhov, S.N. Circassian World: Responses to the New Challenges. PONARS Eurasia, 2018, 1
[16]
Kailani, W. In: Chechens in the Middle East: Between Original and Host Cultures, Proceedings of the Caspian Studies Program, John F. Kennedy School of Government, Harvard University, September 18 2002.
[17]
Fathallah, R.M.T.; Dajani, R. Comparison of Population Based Cancer Incidence Rates among Circassians, Chechans and Arabs in Jordan (1996-2005). Asian Pac. J. Cancer Prev., 2013, 14(10), 6035-6040.
[18]
Dajani, R.; Khader, Y.S.; Fatahallah, R.; El-Khateeb, M.; Shiyab, A.H.; Hakooz, N. Diabetes Mellitus in Genetically Isolated Populations in Jordan: Prevalence, Awareness, Glycemic Control, and Associated Factors. J. Diabetes Complications, 2012, 26(3), 175-180.
[19]
Dajani, R.; Li, J.; Wei, Z.; March, M.E.; Xia, Q.; Khader, Y.; Hakooz, N.; Fatahallah, R.; El-Khateeb, M.; Arafat, A.; Saleh, T.; Dajani, A.R.; Al-Abbadi, Z.; Abdul Qader, M.; Shiyab, A.H.; Bateiha, A.; Ajlouni, K.; Hakonarson, H. Genome-Wide Association Study Identifies Novel Type II Diabetes Risk Loci in Jordan Subpopulations. PeerJ, 2017, 5, 3618.
[20]
Dajani, R.; Li, J.; Wei, Z.; Glessner, J.T.; Chang, X.; Cardinale, C.J.; Pellegrino, R.; Wang, T.; Hakooz, N.; Khader, Y.; Sheshani, A.; Zandaki, D.; Hakonarson, H. CNV Analysis Associates AKNAD1 with Type-2 Diabetes in Jordan Subpopulations. Sci. Rep., 2015, 5, 13391.
[21]
Al-Eitan, L.N.; Nassar, A.M.; Dajani, R.B.; Almomani, B.A.; Saadeh, N.A. Diabetes Mellitus in Two Genetically Distinct Populations in Jordan: A Comparison between Arabs and Circassians/Chechens Living with Diabetes. Saudi Med. J., 2017, 38(2), 163-169.
[22]
Dajani, R.; Khader, Y.S.; Hakooz, N.; Fatahalla, R.; Quadan, F. Metabolic Syndrome between Two Ethnic Minority Groups (Circassians and Chechens) and the Original Inhabitants of Jordan. Endocrine, 2013, 43(1), 112-119.
[23]
Maeda, H.; Hazama, S.; Shavkat, A.; Okamoto, K.; Oba, K.; Sakamoto, J.; Takahashi, K.; Oka, M.; Nakamura, D.; Tsunedomi, R.; Okayama, N.; Mishima, H.; Kobayashi, M. Differences in UGT1A1, UGT1A7, and UGT1A9 Polymorphisms between Uzbek and Japanese Populations. Mol. Diagn. Ther., 2014, 18(3), 333-342.
[24]
Lu, P.H.; Chen, M.B.; Wu, X.Y.; Gu, J.H.; Liu, Y.; Gu, R. Genetic Polymorphisms of UGT1A7 and Cancer Risk: Evidence From 21 Case–Control Studies. Cancer Invest., 2011, 29(10), 645-654.
[25]
Zhang, X.; Ao, G.; Wang, Y.; Yan, W.; Wang, M.; Chen, E.; Yang, F.; Yang, J. Genetic Variants and Haplotypes of the UGT1A9, 1A7 and 1A1 Genes in Chinese Han. Genet. Mol. Biol., 2012, 35(2), 428-434.
[26]
Verlaan, M.; Drenth, J.P.H.; Truninger, K.; Koudova, M.; Schulz, H.U.; Bargetzi, M.; Künzli, B.; Friess, H.; Cerny, M.; Kage, A.; Landt, O.; teMorsche, R.H.; Rosendahl, J.; Luck, W.; Nickel, R.; Halangk, J.; Becker, M.; Macek, M., Jr; Jansen, J.B.; Witt, H. Polymorphisms of UDP-Glucuronosyltransferase 1A7 Are Not Involved in Pancreatic Diseases. J. Med. Genet., 2005, 42(10), 62.
[27]
Yan, W.; Wang, Y.W.; Yang, F.F.; Wang, M.; Zhang, X.Q.; Dong, J.; Chen, E.; Yang, J. Differences in Frequencies of UGT1A9, 1A7, and 1A1 Genetic Polymorphisms in Chinese Tibetan versus Han Chinese Populations. Genet. Mol. Res., 2013, 12(4), 6454-6461.
[28]
Fu, Z.; Shrubsole, M.J.; Li, G.; Smalley, W.E.; Hein, D.W.; Chen, Z.; Shyr, Y.; Cai, Q.; Ness, R.M.; Zheng, W. Using Gene-Environment Interaction Analyses to Clarify the Role of Well-Done Meat and Heterocyclic Amine Exposure in the Etiology of Colorectal Polyps. Am. J. Clin. Nutr., 2012, 96(5), 1119-1128.
[29]
Dajani, R.; Fathallah, R.; Arafat, A. AbdulQader, M.E.; Hakooz, N.; Al-Motassem, Y.; El-Khateeb, M. Prevalence of MTHFR C677T Single Nucleotide Polymorphism in Genetically Isolated Populations in Jordan. Biochem. Genet., 2013, 51(9–10), 780-788.
[30]
Dajani, R.; Arafat, A.; Hakooz, N.; Al-Abbadi, Z.; Yousef, A.M.; El Khateeb, M.; Quadan, F. Polymorphisms in Factor II and Factor V Thrombophilia Genes among Circassians in Jordan. J. Thromb. Thrombolysis, 2013, 35(1), 83-89.
[31]
Charan, J.; Biswas, T. How to Calculate Sample Size for Different Study Designs in Medical Research? Indian J. Psychol. Med., 2013, 35(2), 121-126.
[32]
Wang, Y.; Yi, C.; Wang, Y.; Li, H.; Li, B.; Wang, D.; Du, J.; Liu, L.; Wang, X. Distribution of Uridine Diphosphate Glucuronosyltransferase 1A Polymorphisms and Their Role in Irinotecan-Induced Toxicity in Patients with Cancer. Oncol. Lett., 2017, 14(5), 5743-5752.
[33]
Barrett, J.C.; Fry, B.; Maller, J.; Daly, M.J. Haploview: Analysis and Visualization of LD and Haplotype Maps. Bioinformatics, 2005, 21(2), 263-265.
[34]
Liu, X.; Cheng, D.; Kuang, Q.; Liu, G.; Xu, W. Association of UGT1A1*28 Polymorphisms with Irinotecan-Induced Toxicities in Colorectal Cancer: A Meta-Analysis in Caucasians. Pharmacogenomics J., 2014, 14(2), 120-129.
[35]
Culley, C.L.; Kiang, T.K.L.; Gilchrist, S.E.; Ensom, M.H.H. Effect of the UGT1A1*28 Allele on Unconjugated Hyperbilirubinemia in HIV-Positive Patients Receiving Atazanavir: A Systematic Review. Ann. Pharmacother., 2013, 47(4), 561-572.
[36]
Wenning, L.A.; Petry, A.S.; Kost, J.T.; Jin, B.; Breidinger, S.A.; DeLepeleire, I.; Carlini, E.J.; Young, S.; Rushmore, T.; Wagner, F.; Lunde, N.M.; Bieberdorf, F.; Greenberg, H.; Stone, J.A.; Wagner, J.A.; Iwamoto, M. Pharmacokinetics of Raltegravir in Individuals with UGT1A1 Polymorphisms. Clin. Pharmacol. Ther., 2009, 85(6), 623-627.
[37]
Meza-Junco, J.; Chu, Q.S.C.; Christensen, O.; Rajagopalan, P.; Das, S.; Stefanyschyn, R.; Sawyer, M.B. UGT1A1 Polymorphism and Hyperbilirubinemia in a Patient Who Received Sorafenib. Cancer Chemother. Pharmacol., 2009, 65(1), 1-4.
[38]
Ghosal, A.; Hapangama, N.; Yuan, Y.; Achanfuo-Yeboah, J.; Iannucci, R.; Chowdhury, S.; Alton, K.; Patrick, J.E.; Zbaida, S. Identification of Human UDP-Glucuronosyltransferase Enzyme(s) Responsible for the Glucuronidation of Ezetimibe (Zetia). Drug Metab. Dispos., 2004, 32(3), 314-320.
[39]
Gan, J.; Chen, W.; Shen, H.; Gao, L.; Hong, Y.; Tian, Y.; Li, W.; Zhang, Y.; Tang, Y.; Zhang, H.; Humphreys, W.G. Rodrigues; A.D. Repaglinide-Gemfibrozil Drug Interaction: Inhibition of Repaglinide Glucuronidation as a Potential Additional Contributing Mechanism. Br. J. Clin. Pharmacol., 2010, 70(6), 870-880.
[40]
Ebner, T.; Remmel, R.P.; Burchell, B. Human Bilirubin UDP-Glucuronosyltransferase Catalyzes the Glucuronidation of Ethinylestradiol. Mol. Pharmacol., 1993, 43(4), 649-654.
[41]
Hu, M.; Tomlinson, B. Effects of Statin Treatments and Polymorphisms in UGT1A1 and SLCO1B1 on Serum Bilirubin Levels in Chinese Patients with Hypercholesterolaemia. Atherosclerosis, 2012, 223(2), 427-432.
[42]
Rios, G.R.; Tephly, T.R. Inhibition and Active Sites of UDP-Glucuronosyltransferases 2B7 and 1A1. Drug Metab. Dispos., 2002, 30(12), 1364-1367.
[43]
Chouinard, S.; Tessier, M.; Vernouillet, G.; Gauthier, S.; Labrie, F.; Barbier, O.; Belanger, A. Inactivation of the Pure Antiestrogen Fulvestrant and Other Synthetic Estrogen Molecules by UDP-Glucuronosyltransferase 1A Enzymes Expressed in Breast Tissue. Mol. Pharmacol., 2006, 69(3), 908-920.
[44]
Joo, J.; Kim, Y.W.; Wu, Z.; Shin, J.H.; Lee, B.; Shon, J.C.; Lee, E.Y.; Phuc, N.M.; Liu, K.H. Screening of Non-Steroidal Anti-Inflammatory Drugs for Inhibitory Effects on the Activities of Six UDP-Glucuronosyltransferases (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) Using LC-MS/MS. Biopharm. Drug Dispos., 2015, 36(4), 258-264.
[45]
Liu, Y.; Ramírez, J.; House, L.; Ratain, M.J. Comparison of the Drug-Drug Interactions Potential of Erlotinib and Gefitinib via Inhibition of UDP-Glucuronosyltransferases. Drug Metab. Dispos., 2010, 38(1), 32-39.
[46]
Trontelj, J.; Marc, J.; Zavratnik, A.; Bogataj, M.; Mrhar, A. Effects of UGT1A1*28 Polymorphism on Raloxifene Pharmacokinetics and Pharmacodynamics. Br. J. Clin. Pharmacol., 2009, 67(4), 437-444.
[47]
Ishii, Y.; Koba, H.; Kinoshita, K.; Oizaki, T.; Iwamoto, Y.; Takeda, S.; Miyauchi, Y.; Nishimura, Y.; Egoshi, N.; Taura, F.; Morimoto, S.; Ikushiro, S.; Nagata, K.; Yamazoe, Y.; Mackenzie, P.I.; Yamada, H. Alteration of the Function of the UDP-Glucuronosyltransferase 1A Subfamily by Cytochrome P450 3A4: Different Susceptibility for UGT Isoforms and UGT1A1/7 Variants. Drug Metab. Dispos., 2014, 42(2), 229-238.
[48]
Uchaipichat, V.; Suthisisang, C.; Miners, J.O. The Glucuronidation of R- and S-Lorazepam: Human Liver Microsomal Kinetics, UDP-Glucuronosyltransferase Enzyme Selectivity, and Inhibition by Drugs. Drug Metab. Dispos., 2013, 41(6), 1273-1284.
[49]
Li, J.H. Influence of Telmisartan on the Metabolism of Glucose-Lowering Drugs. Latin American Journal of Pharmacy, 2018, 37(3), 484-488.
[50]
Lankisch, T.O.; Behrens, G.; Ehmer, U.; Mobius, U.; Rockstroh, J.; Wehmeier, M.; Kalthoff, S.; Freiberg, N.; Manns, M.P.; Schmidt, R.E.; Strassburg, C.P. Gilbert’s Syndrome and Hyperbilirubinemia in Protease Inhibitor Therapy--an Extended Haplotype of Genetic Variants Increases Risk in Indinavir Treatment. J. Hepatol., 2009, 50(5), 1010-1018.
[51]
Han, S.X.; Wang, L.; Wu, D.Q. The Association between UGT1A7 Polymorphism and Cancer Risk: A Meta-Analysis. Cancer Epidemiol., 2012, 36(4), 201-206.
[52]
Zheng, Z.; Park, J.Y.; Guillemette, C.; Schantz, S.P.; Lazarus, P. Tobacco Carcinogen-Detoxifying Enzyme UGT1A7 and Its Association With Orolaryngeal Cancer Risk. JNCI J. Natl. Cancer Inst., 2001, 93(18), 1411-1418.
[53]
Bock, K.W.; Raschko, F.T.; Gschaidmeier, H.; Seidel, A.; Oesch, F.; Grove, A.D.; Ritter, J.K. Mono- and Diglucuronide Formation from Benzo[a]Pyrene and Chrysene Diphenols by AHH-1 Cell-Expressed UDP-Glucuronosyltransferase UGT1A7. Biochem. Pharmacol., 1999, 57(6), 653-656.
[54]
Deming, S.L.; Zheng, W.; Xu, W.H.; Cai, Q.; Ruan, Z.; Xiang, Y.B.; Shu, X.O. UGT1A1 Genetic Polymorphisms, Endogenous Estrogen Exposure, Soy Food Intake, and Endometrial Cancer Risk. Cancer Epidemiol. Biomarkers Prev., 2008, 17(3), 563-570.
[55]
Wellstein, A.; Giaccone, G.; Atkins, M.B.; Sausville, E.A. Cytotoxic Drugs.InGoodman & Gilman’s: The Pharmacological Basis of Therapeutics; Brunton, L.L.; Hilal-Dandan, R.; Knollmann, B.C., Eds.; McGraw-Hill Education: New York, NY, 2017.
[56]
Cavallari, L.H.; Lam, Y.W.F. Pharmacogenetics.InPharmacotherapy: A Pathophysiologic Approach; DiPiro, J.T.; Talbert, R.L.; Yee, G.C.; Matzke, G.R.; Wells, B.G.; Posey, L.M., Eds.; The McGraw-Hill Companies: New York, NY, 2014.
[57]
Barbarino, J.M.; Haidar, C.E.; Klein, T.E.; Altman, R.B. PharmGKB Summary: Very Important Pharmacogene Information for UGT1A1. Pharmacogenet. Genomics, 2014, 24(3), 177-183.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 20
ISSUE: 5
Year: 2019
Page: [399 - 410]
Pages: 12
DOI: 10.2174/1389200220666190528085151
Price: $58

Article Metrics

PDF: 10
HTML: 2