Skip to main content

Genetic variability among Mexican Mestizo and Amerindian populations based on three ABCB1 polymorphisms

Abstract

The most widely studied polymorphisms of the ABCB1 gene are rs1128503 (c.1236C>T), rs2032582 (c.2677G>T/A), and rs1045642 (c.3435C>T). Although variation in ABCB1 allele frequencies among Mexican Mestizos (admixed) from different regions has been observed, Mexican Amerindians have been poorly studied. We aimed to describe the genetic variability of these three ABCB1 polymorphisms in a total sample of 273 Mexican volunteers that included Mestizos from the state of Yucatán, and Amerindians from seven populations (Tarahumara, Mayo, Huichol, Purépecha, Nahua, Tojolabal, and Maya). Genotypes were determined by means of Taq Man probes (qPCR). Genotype distribution was in Hardy–Weinberg equilibrium for all three ABCB1polymorphisms in the eight Mexican populations analyzed. For c.1236C>T and c.3435C>T, the heterozygous C/T was the most frequent genotype in the majority of the studied Mexican populations (range 30.8–65.4%), while heterozygous G/T was the most common genotype for c.2677G>T/A (range 25.9–51.2%), mainly followed by G/G (range 3.2–47.1%) and T/T (range 7.0–35.5%). 12 haplotypes were estimated from the three ABCB1 polymorphisms analyzed, with TTT the most frequent haplotype (mean, 37.0%). Genetic differentiation was demonstrated among the studied Mexican populations (Fst p value < 0.0001), which could imply a diverse drug response or a risk for adverse drug reactions to ABCB1 substrates. Although differences among Amerindians are probably due to genetic drift effects, for Mestizos this could imply variation in admixture composition. In conclusion, interpopulation variability in the observed frequencies of ABCB1 polymorphisms among Mexican Mestizos and Amerindians allow predicting diverse drug responses to ABCB1 substrates in these populations.

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

Fig. 1
Fig. 2

References

  1. Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, Altman RB (2011) Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics 21(3):152–161

    CAS  Article  Google Scholar 

  2. Chen Z, Shi T, Zhang L et al (2016) Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: a review of the past decade. Cancer Lett 370(1):153–164

    CAS  Article  Google Scholar 

  3. Chen Z, Zhang L, Yang C, Jiang Z, Shen H, Gui G (2017) Effect of MDR1 C1236T polymorphism on cyclosporine pharmacokinetics. A systematic review and meta-analysis. Medicine (Baltimore) 96(47):e8700. https://doi.org/10.1097/MD.0000000000008700

    CAS  Article  Google Scholar 

  4. Kim RB (2002) Drugs as P-glycoprotein substrates, inhibitors, and inducers. Drug Metab 34:47–54

    CAS  Article  Google Scholar 

  5. León-Cachón RBR, Ascacio-Martínez JA, Gamino-Peña ME et al (2016) A pharmacogenetic pilot study reveals MTHFR. DRD3, and MDR1 polymorphisms as biomarker candidates for slow atorvastatin metabolizers. BMC Cancer 16:74. https://doi.org/10.1186/s12885-016-2062-2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Dutheil F, Jacob A, Dauchy S, Beaune P, Scherrmann JM, Declèves X, Loriot MA (2010) ABC transporters and cytochromes P450 in the human central nervous system: influence on brain pharmacokinetics and contribution to neurodegenerative disorders. Expert Opin Drug Metab Toxicol 6(10):1161–1174. https://doi.org/10.1517/17425255.2010.510832

    CAS  Article  PubMed  Google Scholar 

  7. Elali A, Rivest S (2013) The role of ABCB1 and ABCA1 in beta-amyloid clearance at the neurovascular unit in Alzheimer’s disease. Front Physiol 4:45

    Article  Google Scholar 

  8. Calderón-Cruz B, Rodríguez-Galván K, Manzo-Francisco LA et al (2015) C3435T polymorphism of the ABCB1 gene is associated with poor clopidogrel responsiveness in a Mexican population undergoing percutaneous coronary intervention. Thromb Res 136(5):894–898. https://doi.org/10.1016/j.thromres.2015.08.025

    CAS  Article  PubMed  Google Scholar 

  9. Zhang YT, Yang LP, Shao H, Li KX, Sun CH, Shi LW (2008) ABCB1 polymorphisms may have a minor effect on cyclosporine blood concentrations in myasthenia gravis patients. Brit J Clin Pharmacol 66:240–246

    CAS  Article  Google Scholar 

  10. Tovilla-Zárate CA, Vargas I, Hernández S et al (2014) Association study between the MDR1 gene and clinical characteristics in schizophrenia. Rev Bras Psiquiatr 36(3):227–232. https://doi.org/10.1590/1516-4446-2013-1270

    Article  PubMed  Google Scholar 

  11. Ortega-Vázquez A, Dorado P, Fricke-Galindo I et al (2016) CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy. Pharmacogenomics J 9(3):286–292. https://doi.org/10.1038/tpj.2015.45

    CAS  Article  Google Scholar 

  12. Kim RB, Leake BF, Choo EF et al (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70(2):189–199

    CAS  Article  Google Scholar 

  13. Rubi-Castellanos R, Martínez-Cortés G, Muñoz-Valle JF, González-Martín A, Cerda-Flores RM, Anaya-Palafox M, Rangel-Villalobos H (2009) Pre-Hispanic mesoamerican demography approximates the present-day ancestry of Mestizos throughout the territory of Mexico. Am J Phys Anthropol 139(3):284–294. https://doi.org/10.1002/ajpa.20980

    Article  PubMed  Google Scholar 

  14. Rangel-Villalobos H, Martínez-Sevilla VM, Martínez-Cortés G, Aguilar-Velázquez JA, Sosa-Macías M, Rubi-Castellanos R, González-Martín A (2016) Importance of the geographic barriers to promote gene drift and avoid pre- and post-Columbian gene flow in Mexican native groups: evidence from forensic STR Loci. Am J Phys Anthropol 160(2):298–316. https://doi.org/10.1002/ajpa.22969

    Article  PubMed  Google Scholar 

  15. Fricke-Galindo I, Jung-Cook H, LLerena A, López-López M (2016) Interethnic variability of pharmacogenetic biomarkers in Mexican healthy volunteers: a report from the RIBEF (Ibero-American Network of Pharmacogenetics and Pharmacogenomics). Drug Metab Pers Ther 31(2):61–81. https://doi.org/10.1515/dmpt-2015-0030.Review

    CAS  Article  PubMed  Google Scholar 

  16. Vargas-Alarcón G, Ramírez-Bello J, de la Peña A et al (2014) Distribution of ABCB1, CYP3A5, CYP2C19, and P2RY12 gene polymorphisms in a Mexican Mestizos population. Mol Biol Rep 19(10):7023–7029.

    Article  Google Scholar 

  17. Gutiérrez-Rubio SA, Quintero-Ramos A, Durán-Cárdenas A et al (2015) 1236 C/T and 3435 C/T polymorphisms of the ABCB1 gene in Mexican breast cancer patients. Genet Mol Res 14(1):1250–1259. https://doi.org/10.4238/2015

    Article  PubMed  Google Scholar 

  18. Escalante-Santiago D, Feria-Romero IA, Ribas-Aparicio RM et al (2014) MDR-1 and MRP2 gene polymorphisms in Mexican epileptic pediatric patients with complex partial seizures. Front Neurol 5:184. https://doi.org/10.3389/fneur.2014.00184

    Article  PubMed  PubMed Central  Google Scholar 

  19. Rodríguez-Castillo JA, Arce-Mendoza AY, Quintanilla-Siller A, Rendon A, Salinas-Carmona MC, Rosas-Taraco AG (2015) Possible association of rare polymorphism in the ABCB1 gene with rifampin and ethambutol drug-resistant tuberculosis. Tuberculosis (Edinb) 95(5):532–537. https://doi.org/10.1016/j.tube.2015.04.004

    CAS  Article  Google Scholar 

  20. Marsh S, King CR, Van Booven DJ, Revollo JY, Gilman RH, McLeod HL (2015) Pharmacogenomic assessment of Mexican and Peruvian populations. Pharmacogenomics 16(5):441–448

    CAS  Article  Google Scholar 

  21. Zaruma-Torres F, Lares-Asseff I, Lima A et al (2016) Genetic polymorphisms associated to folate transport as predictors of increased risk for acute lymphoblastic leukemia in Mexican children. Front Pharmacol 7:238. https://doi.org/10.3389/fphar.2016.00238

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Jin SS, Song WJ (2017) Association between MDR1 C3435T polymorphism and colorectal cancer risk: a meta-analysis. Medicine (Baltimore) 96(51):e9428. https://doi.org/10.1097/MD.0000000000009428

    CAS  Article  Google Scholar 

  23. Acuña-Alonzo V, Flores-Dorantes T, Kruit JK et al (2010) A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans. Hum Mol Genet 19:2877–2885

    Article  Google Scholar 

  24. Williams AL, Jacobs SB, Moreno-Macías H et al (2014) Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico. Nature 506:97–101

    CAS  Article  Google Scholar 

  25. Peakall R, Smouse PE (2012) GenAlEx 6.5: genetic analysis in Excel. Population genetic software for teaching and research-an update. Bioinformatics 28(19):2537–2539

    CAS  Article  Google Scholar 

  26. Excoffier L, Laval G, Schneider S (2005) Arlequin ver. 3.0: An integrated software package for population genetics data analysis. Evol Bioinform Online 1:47–50

    CAS  Article  Google Scholar 

  27. Yoo J, Lee Y, Kim Y, Rha SY, Kim Y (2008) SNPAnalyzer 2.0: a web-based integrated workbench for linkage disequilibrium analysis and association analysis. BMC Bioinform 9:290. https://doi.org/10.1186/1471-2105-9-290

    CAS  Article  Google Scholar 

  28. Macías-Gómez NM, Gutiérrez-Angulo M, Leal-Ugarte E et al (2014) MDR1 C3435T polymorphism in Mexican patients with breast cancer. Genet Mol Res 13(3):5018–5024. https://doi.org/10.4238/2014.July.4.17

    Article  PubMed  Google Scholar 

  29. Leal-Ugarte E, Gutiérrez-Angulo M, Macías-Gómez NM et al (2008) MDR1 C3435T polymorphism in Mexican children with acute lymphoblastic leukemia and in healthy individuals. Hum Biol 80(4):449–455. https://doi.org/10.3378/1534-6617-80.4.449

    Article  PubMed  Google Scholar 

  30. Santos PC, Soares RA, Santos DB et al (2011) CYP2C19 and ABCB1 gene polymorphisms are differently distributed according to ethnicity in the Brazilian general population. BMC Medical Genetics 12:13. https://doi.org/10.1186/1471-2350-12-13

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Dudarewicz M, Barańska M, Rychlik-Sych M et al (2012) C3435T polymorphism of the ABCB1/MDR1 gene encoding P-glycoprotein in patients with inflammatory bowel disease in a Polish population. Pharmacol Rep 64(2):343–350

    CAS  Article  Google Scholar 

  32. Balram C, Sharma A, Sivathasan C et al (2003) Frequency of C3435T single nucleotide MDR1 genetic polymorphism in an Asian population: phenotypic–genotypic correlates. Br J Clin Pharmacol 56(1):78–83. https://doi.org/10.1046/j.1365-2125.2003.01820.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Ameyaw MM, Regateiro F, Li T et al (2001) MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics 11(3):217–221

    CAS  Article  Google Scholar 

  34. Silva-Zolezzi I, Hidalgo-Miranda A, Estrada-Gil J (2009) Analysis of genomic diversity in Mexican Mestizo populations to develop genomic medicine in Mexico. Proc Natl Acad Sci USA 106(21):8611–8616. https://doi.org/10.1073/pnas.0903045106

    Article  PubMed  Google Scholar 

  35. Moreno-Estrada A, Gignoux CR, Fernández-López JC et al (2014) The genetics of Mexico recapitulates Native American substructure and affects biomedical traits. Science 344:1280–1285. (https://doi.org/10.1126/science.1251688)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are grateful for the generous participation of indigenous volunteers in this study. We also thank CONACYT-México (Grant #167261) for financial support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marisol López-López.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflicts of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Favela-Mendoza, A.F., Rangel-Villalobos, H., Fricke-Galindo, I. et al. Genetic variability among Mexican Mestizo and Amerindian populations based on three ABCB1 polymorphisms. Mol Biol Rep 45, 2525–2533 (2018). https://doi.org/10.1007/s11033-018-4419-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-018-4419-x

Keywords

  • ABCB1
  • Polymorphism
  • Mexican population
  • Mestizos
  • Amerindians
  • Pharmacogenetics