Pharmaceutical Research

, Volume 33, Issue 11, pp 2644–2652 | Cite as

Exploring Variation in Known Pharmacogenetic Variants and its Association with Drug Response in Different Mexican Populations

  • Vanessa Gonzalez-Covarrubias
  • José Jaime Martínez-Magaña
  • Regina Coronado-Sosa
  • Beatriz Villegas-Torres
  • Alma D. Genis-Mendoza
  • Pablo Canales-Herrerias
  • Humberto Nicolini
  • Xavier Soberón
Research Paper



Information on genetic variants that affect the pharmacokinetics and pharmacodynamics (PK/PD) of drugs in different populations from Mexico is still an ongoing endeavor. Here, we investigate allele frequencies on pharmacogenetic targets in Mexican Mestizos and Natives from three different States and its association with drug efficacy in individuals receiving either anticoagulants or antipsychotic drugs.


Natives from three different states and Mestizo patients receiving acenocoumarol or antipsychotics were genotyped using the DMET microarray (Affymetrix).


We provide a collection of genetic variants that indicate that there are 3-times more variation than similarities between populations from Mexico and major continental groups. These differences were observed in several relevant targets including ABCB1, SLCO1A1, NAT2, UGTs, TYMS, VKORC1, and NR1I3. Moreover, Mexican Mestizos also showed allele frequency differences when compared to Natives for variants on DPYD, ADH1A, CYP3A4, SLC28A3, and SLC28A1. Significant allele differences also arose among the three Native groups here studied, mostly for transporters of the ABC-binding cassette and the solute carrier gene family. Finally, we explored genotype-drug response associations and pinpointed variants on FMOs (coumarins), and GSTM1 (haloperidol).


These findings confirm previous results and further delve into the pharmacogenetics of Mexican populations including different Native groups.


antipsychotics coumarins Mexican populations pharmacogenetics 



Absorption, distribution, metabolism, and elimination


Adverse drug reactions


Flavin monooxygenase


Glutathione S-Transferase Mu 1


International normalized ratio (INR) is a calculation based on prothrombin time





Supplementary material

11095_2016_1990_MOESM1_ESM.xlsx (236 kb)
ESM 1(XLSX 236 kb)


  1. 1.
    Relling MV, Klein TE. CPIC: clinical pharmacogenetics implementation consortium of the pharmacogenomics research network. Clin Pharmacol Ther. 2011;89(3):464–7.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Sudmant PH, Rausch T, Gardner EJ, Handsaker RE, Abyzov A, Huddleston J, et al. An integrated map of structural variation in 2,504 human genomes. Nature. 2015;526(7571):75–81.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Cavallari LH, Momary KM, Patel SR, Shapiro NL, Nutescu E, Viana MAG. Pharmacogenomics of Warfarin dose requirements in Hispanics. Blood Cell Mol Dis. 2011;46(2):147–50.CrossRefGoogle Scholar
  4. 4.
    Cavallari LH, Perera MA. The future of warfarin pharmacogenetics in under-represented minority groups. Futur Cardiol. 2012;8(4):563–76.CrossRefGoogle Scholar
  5. 5.
    Villegas-Torres B, Sanchez-Giron F, Jaramillo-Villafuerte K, Soberon X, Gonzalez-Covarrubias V. Genotype frequencies of VKORC1 and CYP2C9 in Native and Mestizo populations from Mexico, potential impact for coumarin dosing. Gene. 2015;558(2):235–40.CrossRefPubMedGoogle Scholar
  6. 6.
    Lazalde-Ramos BP, Martinez-Fierro ML, Galaviz-Hernandez C, Garza-Veloz I, Naranjo MEG, Sosa-Macias M, et al. CYP2D6 gene polymorphisms and predicted phenotypes in eight indigenous groups from northwestern Mexico. Pharmacogenomics. 2014;15(3):339–48.CrossRefPubMedGoogle Scholar
  7. 7.
    Daar AS, Singer PA. Pharmacogenetics and geographical ancestry: implications for drug development and global health. Nat Rev Genet. 2005;6(3):241–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Flockhart DA, Skaar T, Berlin DS, Klein TE, Nguyen AT. Clinically available pharmacogenomics tests. Clin Pharmacol Ther. 2009;86(1):109–13.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Fricke-Galindo I, Jung-Cook H, A LL, Lopez-Lopez M. Interethnic variability of pharmacogenetic biomarkers in Mexican healthy volunteers: a report from the RIBEF (Ibero-American Network of Pharmacogenetics and Pharmacogenomics). Drug Metabol Personal Ther. 2016.Google Scholar
  10. 10.
    Bonifaz-Pena V, Contreras AV, Struchiner CJ, Roela RA, Furuya-Mazzotti TK, Chammas R, et al. Exploring the distribution of genetic markers of pharmacogenomics relevance in Brazilian and Mexican populations. PLoS ONE. 2014;9(11):e112640.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Cespedes-Garro C, Fricke-Galindo I, Naranjo ME, Rodrigues-Soares F, Farinas H, de Andres F, et al. Worldwide interethnic variability and geographical distribution of CYP2C9 genotypes and phenotypes. Expert Opin Drug Metab Toxicol. 2015;11(12):1893–905.CrossRefPubMedGoogle Scholar
  12. 12.
    Giacomini KM, Brett CM, Altman RB, Benowitz NL, Dolan ME, Flockhart DA, et al. The pharmacogenetics research network: from SNP discovery to clinical drug response. Clin Pharmacol Ther. 2007;81(3):328–45.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Jittikoon J, Mahasirimongkol S, Charoenyingwattana A, Chaikledkaew U, Tragulpiankit P, Mangmool S, et al. Comparison of genetic variation in drug ADME-related genes in Thais with Caucasian, African and Asian HapMap populations. J Hum Genet. 2015.Google Scholar
  14. 14.
    Wakil SM, Nguyen C, Muiya NP, Andres E, Lykowska-Tarnowska A, Baz B, et al. The Affymetrix DMET Plus platform reveals unique distribution of ADME-related variants in ethnic Arabs. Dis Markers. 2015;2015:542543.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Yi S, An H, Lee H, Lee S, Ieiri I, Lee Y, et al. Korean, Japanese, and Chinese populations featured similar genes encoding drug-metabolizing enzymes and transporters: a DMET Plus microarray assessment. Pharmacogenet Genomics. 2014;24(10):477–85.PubMedGoogle Scholar
  16. 16.
    Aminkeng F, Ross CJD, Rassekh SR, Brunham LR, Sistonen J, Dube MP, et al. Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent. Pharmacogenomics J. 2014;14(2):160–70.CrossRefPubMedGoogle Scholar
  17. 17.
    Cavallari LH, Perera MA. The future of warfarin pharmacogenetics in under-represented minority groups. Futur Cardiol. 2013;8(4):563–7.CrossRefGoogle Scholar
  18. 18.
    Cuautle-Rodriguez P, Llerena A, Molina-Guarneros J. Present status and perspective of pharmacogenetics in Mexico. Drug Metabol Drug Interact. 2013. p. 37.Google Scholar
  19. 19.
    Marsh S, King CR, Van Booven DJ, Revollo JY, Gilman RH, McLeod HL. Pharmacogenomic assessment of Mexican and Peruvian populations. Pharmacogenomics. 2015;16(5):441–8.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Jackson JN, Long KM, He Y, Motsinger-Reif AA, McLeod HL, Jack J. A comparison of DMET Plus microarray and genome-wide technologies by assessing population substructure. Pharmacogenet Genomics. 2016.Google Scholar
  21. 21.
    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(5):536–42.CrossRefPubMedGoogle Scholar
  22. 22.
    Kwara A, Lartey M, Boamah I, Rezk NL, Oliver-Commey J, Kenu E, et al. Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB/HIV-coinfected Ghanaian patients: UGT2B7*1c Is associated with faster zidovudine clearance and glucuronidation. J Clin Pharmacol. 2009;49(9):1079–90.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Chen D, Guo F, Shi J, Zhang C, Wang Z, Fan J, et al. Association of hemoglobin levels, CYP3A5, and NR1I3 gene polymorphisms with tacrolimus pharmacokinetics in liver transplant patients. Drug Metab Pharmacokinet. 2014;29(3):249–53.CrossRefPubMedGoogle Scholar
  24. 24.
    Barrera LA, Vedenko A, Kurland JV, Rogers JM, Gisselbrecht SS, Rossin EJ, et al. Survey of variation in human transcription factors reveals prevalent DNA binding changes. Science. 2016;351(6280):1450–4.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Del Re M, Quaquarini E, Sottotetti F, Michelucci A, Palumbo R, Simi P, et al. Uncommon dihydropyrimidine dehydrogenase mutations and toxicity by fluoropyrimidines: a lethal case with a new variant. Pharmacogenomics. 2016;17(1):5–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Rumiato E, Boldrin E, Amadori A, Saggioro D. DMET (Drug-Metabolizing Enzymes and Transporters) microarray analysis of colorectal cancer patients with severe 5-fluorouracil-induced toxicity. Cancer Chemother Pharmacol. 2013;72(2):483–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Teh LK, Hamzah S, Hashim H, Bannur Z, Zakaria ZA, Hasbullani Z, et al. Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients. Ther Drug Monit. 2013;35(5):624–30.PubMedGoogle Scholar
  28. 28.
    Zhang W, Zhang W-J, Zhu J, Kong F-C, Li Y-Y, Wang H-Y, et al. Genetic polymorphisms are associated with variations in warfarin maintenance dose in Han Chinese patients with venous thromboembolism. Pharmacogenomics. 2012;13(3):309–21.CrossRefPubMedGoogle Scholar
  29. 29.
    Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–7.CrossRefGoogle Scholar
  30. 30.
    Limdi NA, Wadelius M, Cavallari L, Eriksson N, Crawford DC, Lee M-TM, et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood. 2010;115(18):3827–34.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Moreno-Estrada A, Gignoux CR, Fernandez-Lopez JC, Zakharia F, Sikora M, Contreras AV, et al. The genetics of Mexico recapitulates Native American substructure and affects biomedical traits. Science. 2014;344(6189):1280–5.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Ortega-Vazquez A, Dorado P, Fricke-Galindo I, Jung-Cook H, Monroy-Jaramillo N, Martinez-Juarez IE, et al. CYP2C9, CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy. Pharmacogenomics J. 2015.Google Scholar
  33. 33.
    Silva-Zolezzi I, Hidalgo-Miranda A, Estrada-Gil J, Fernandez-Lopez JC, Uribe-Figueroa L, Contreras A, et al. Analysis of genomic diversity in Mexican Mestizo populations to develop genomic medicine in Mexico. Proc Natl Acad Sci. 2009;106(21):8611–6.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Spear BB, Heath-Chiozzi M, Huff J. Clinical application of pharmacogenetics. Trends Mol Med. 2001;7(5):201–4.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Vanessa Gonzalez-Covarrubias
    • 1
  • José Jaime Martínez-Magaña
    • 2
  • Regina Coronado-Sosa
    • 1
  • Beatriz Villegas-Torres
    • 3
  • Alma D. Genis-Mendoza
    • 2
    • 4
  • Pablo Canales-Herrerias
    • 1
  • Humberto Nicolini
    • 2
    • 4
  • Xavier Soberón
    • 1
  1. 1.Laboratorio de FarmacogenómicaInstituto Nacional de Medicina Genómica (INMEGEN)Ciudad de MexicoMexico
  2. 2.Laboratorio de Genomica de Enfermedades Psiquiatricas y NeurodegenerativasInstituto Nacional de Medicina Genomica (INMEGEN)Ciudad de MexicoMexico
  3. 3.Laboratorio de Diagnostico GenomicoInstituto Nacional de Medicina Genómica (INMEGEN)Ciudad de MexicoMexico
  4. 4.Servicios de Atención Psiquiatrica (SAP) Secretaria de SaludCiudad de MexicoMexico

Personalised recommendations