Skip to main content

Interethnic differences in UGT1A4 genetic polymorphisms between Mexican Mestizo and Spanish populations

Abstract

UDP-glucuronosyltransferase 1A4 (UGT1A4) is a phase II drug-metabolizing enzyme that catalyzes the glucuronidation of many clinically-important drugs. Interethnic differences in the genetic polymorphism of UGT1A4 have been reported; however, there is no information in Mexican Mestizos (MMs) and Spaniards (SPs). Furthermore, MM is an admixed population with 26 % of Caucasian genes mainly from Spain. Therefore, this study aimed to investigate the potential differences between 318 SPs and 248 MMs healthy individuals regarding UGT1A4*1b, UGT1A4*2 and UGT1A4*3 alleles and to compare the observed frequencies with those previously reported in different populations. The allelic frequencies of the three UGT1A4 polymorphisms showed interethnic differences between MMs and SPs (p < 0.05). The analyzed SNPs variants in this genetic region were not in linkage disequilibrium (LD) for the MM population, suggesting that these mutations have arisen independently in the same genetic background. In contrast, UGT1A4*2 and UGT1A4*3 were in LD in the SP population. Comparison of present data with other in different ethnic groups revealed that the frequencies of UGT1A4*2 and UGT1A4*3 in SP were similar to other Caucasians and higher than in Asians, whereas in MMs were lower than in Caucasians and higher than in Asians only for UGT1A4*2. Present results could be helpful to improve the use of UGT1A4 drug substrates in order to adjust them to the ethnic background of a given population, specifically for Hispanics.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. Ménard V, Girard H, Harvey M, Pérusse L, Guillemette C (2009) Analysis of inherited genetic variations at the UGT1 locus in the French-Canadian population. Hum Mutat 30:677–687

    PubMed  Article  Google Scholar 

  2. Bock KW (2010) Functions and transcriptional regulation of adult human hepatic UDP-glucuronosyl-transferases (UGTs): mechanisms responsible for interindividual variation of UGT levels. Biochem Pharmacol 80:771–777

    PubMed  Article  CAS  Google Scholar 

  3. Hahn KK, Wolff JJ, Kolesar JM (2006) Pharmacogenetics and irinotecan therapy. Am J Health Syst Pharm 63:2211–2217

    PubMed  Article  CAS  Google Scholar 

  4. Zhang W, Liu W, Innocenti F, Ratain MJ (2007) Searching for tissue-specific expression pattern-linked nucleotides of UGT1A isoforms. PLoS ONE 2:e396

    PubMed  Article  Google Scholar 

  5. Laverdière I, Caron P, Harvey M, Lévesque E, Guillemette C (2011) In vitro investigation of human UDP-glucuronosyltransferase isoforms responsible for tacrolimus glucuronidation: predominant contribution of UGT1A4. Drug Metab Dispos 39:1127–1130

    PubMed  Article  Google Scholar 

  6. López M, Dorado P, Monroy N, Alonso ME, Jung-Cook H, Machín E, Peñas-Lledó E, Llerena A (2011) Pharmacogenetics of the antiepileptic drugs phenytoin and lamotrigine. Drug Metab Drug Interact 26:5–12

    Article  Google Scholar 

  7. Kaivosaari S, Finel M, Koskinen M (2011) N-glucuronidation of drugs and other xenobiotics by human and animal UDP-glucuronosyltransferases. Xenobiotica 41:652–669

    PubMed  Article  CAS  Google Scholar 

  8. Mohamed ME, Frye RF (2011) Inhibitory effects of commonly used herbal extracts on UGT1A4, 1A6, and 1A9 enzyme activities. Drug Metab Dispos 39:1522–1528

    PubMed  Article  CAS  Google Scholar 

  9. Nakajima M, Sakata N, Ohashi N, Kume T, Yokoi T (2002) Involvement of multiple UDP-glucuronosyltransferase 1A isoforms in glucuronidation of 5-(4′-hydroxyphenyl)-5-phenylhydantoin in human liver microsomes. Drug Metab Dispos 30:1250–1256

    PubMed  Article  CAS  Google Scholar 

  10. Ehmer U, Vogel A, Schütte JK, Krone B, Manns MP, Strassburg CP (2004) Variation of hepatic glucuronidation: novel functional polymorphisms of the UDP-glucuronosyltransferase UGT1A4. Hepatology 39:970–977

    PubMed  Article  CAS  Google Scholar 

  11. Gulcebi MI, Ozkaynakcı A, Goren MZ, Aker RG, Ozkara C, Onat FY (2011) The relationship between UGT1A4 polymorphism and serum concentration of lamotrigine in patients with epilepsy. Epilepsy Res 95:1–8

    PubMed  Article  CAS  Google Scholar 

  12. Erickson-Ridout KK, Zhu J, Lazarus P (2011) Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants. Pharmacogenet Genomics 21:539–551

    PubMed  Article  CAS  Google Scholar 

  13. Zhou J, Argikar UA, Remmel RP (2011) Functional analysis of UGT1A4 (P24T) and UGT1A4 (L48 V) variant enzymes. Pharmacogenomics 12:1671–1679

    PubMed  Article  CAS  Google Scholar 

  14. Wiener D, Doerge DR, Fang JL, Upadhyaya P, Lazarus P (2004) Characterization of N-glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in human liver: importance of UDP-glucuronosyltransferase 1A4. Drug Metab Dispos 32:72–79

    PubMed  Article  CAS  Google Scholar 

  15. Saeki M, Saito Y, Jinno H et al (2005) Genetic variations and haplotypes of UGT1A4 in a Japanese population. Drug Metab Pharmacokinet 20:144–151

    PubMed  Article  Google Scholar 

  16. Ghotbi R, Mannheimer B, Aklillu E et al (2010) 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 66:465–474

    PubMed  Article  CAS  Google Scholar 

  17. Benoit-Biancamano MO, Adam JP, Bernard O, Court MH, Leblanc MH, Caron P, Guillemette C (2009) A pharmacogenetics study of the human glucuronosyltransferase UGT1A4. Pharmacogenet Genomics 19:945–954

    PubMed  Article  CAS  Google Scholar 

  18. Mori A, Maruo Y, Iwai M, Sato H, Takeuchi Y (2005) UDP-glucuronosyltransferase 1A4 polymorphisms in a Japanese population and kinetics of clozapine glucuronidation. Drug Metab Dispos 33:672–675

    PubMed  Article  CAS  Google Scholar 

  19. Thomas SS, Li SS, Lampe JW, Potter JD, Bigler J (2006) Genetic variability, haplotypes, and htSNPs for exons 1 at the human UGT1A locus. Hum Mut 27:717

    PubMed  Article  Google Scholar 

  20. Saeki M, Saito Y, Jinno H et al (2006) Haplotype structures of the UGT1A gene complex in a Japanese population. Pharmacogenomics J 6:63–75

    PubMed  Article  CAS  Google Scholar 

  21. Yea SS, Lee SS, Kim WY, Liu KH, Kim H et al (2008) Genetic variations and haplotypes of UDP-glucuronosyltransferase 1A locus in a Korean population. Ther Drug Monit 30:23–34

    PubMed  Article  CAS  Google Scholar 

  22. Hakooz N, Alzubiedi S, Yousef AM, Arafat T, Dajani R, Ababneh N, Ismail S (2012) UDP-glucuronosyltransferase 1A4 (UGT1A4) polymorphisms in a Jordanian population. Mol Biol Rep 39:7763–7768

    PubMed  Article  CAS  Google Scholar 

  23. 1000 Genomes Project. http://www.1000genomes.org/

  24. http://www.pharmacogenomics.pha.ulaval.ca/webdav/site/pharmacogenomics/shared/Nomenclature/UGT1A/UGT1A4.htm

  25. Haploview v4.0 software. http://www.broadinstitute.org/scientific-community/science/programs/medical-and-population-genetics/haploview/haploview

  26. Phase v2.1 software. http://www.stat.washington.edu/stephens/phase/download.html

  27. Juárez-Cedillo T, Zúñiga J, Acuña-Alonzo V, Pérez-Hernández N, Rodríguez-Pérez JM et al (2008) Genetic admixture and diversity estimations in the Mexican-Mestizo population from Mexico City using 15 STR polymorphic markers. Forensic Sci Int Genet 2:e37–e39

    PubMed  Article  Google Scholar 

Download references

Acknowledgments

The study has been partly supported by the Institute of Health Carlos III-FIS and the European Union (FEDER) Grants PI10/02758, PI10/02010 and CP06/00030 (P. Dorado) and from PRIS Extremadura, Consejería de Sanidad y Dependencia, FundeSalud PRIS10043 and PRIS11051 Gobierno de Extremadura AEXCID Cooperacion Extremeña (11IA002); by a Grant from Consejo Nacional de Ciencia y Tecnología de Mexico (CONACYT #167261) and was coordinated in the SIFF-RIBEF network (Red Iberoamericana de Farmacogenética y Farmacogenomica; www.ribef.com). The technical assistance of Esther Machín, Inés López and Beatriz Grillo is gratefully acknowledged.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Adrián LLerena.

Additional information

Marisol López and Pedro Dorado contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

López, M., Dorado, P., Ortega, A. et al. Interethnic differences in UGT1A4 genetic polymorphisms between Mexican Mestizo and Spanish populations. Mol Biol Rep 40, 3187–3192 (2013). https://doi.org/10.1007/s11033-012-2393-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-012-2393-2

Keywords

  • UGT1A4
  • Glucuronidation
  • Interethnic differences
  • Mexican-Mestizo
  • Spaniards