European Journal of Clinical Pharmacology

, Volume 66, Issue 9, pp 859–864 | Cite as

Discovery of the nonfunctional CYP2D6*31 allele in Spanish, Puerto Rican, and US Hispanic populations

  • Andrea GaedigkEmail author
  • Maria Isidoro-García
  • Robin E. Pearce
  • Santiago Sánchez
  • Virginia García-Solaesa
  • Carolina Lorenzo-Romo
  • Gloria Gonzalez-Tejera
  • Susan Corey



CYP2D6*31 (4042G>A, R440H) is an allelic variant of the highly polymorphic cytochrome P450 2D6 enzyme that has been associated with reduced functional activity. The US Food and Drug Administration (FDA)-cleared AmpliChip CYP450 test detects the 4042G>A single nucleotide polymorphism (SNP) but an allele assignment could not be made in two Spanish and two Puerto Rican individuals heterozygous for 4042G>A, resulting in no-calls. We aimed to resolve the CYP2D6*31 no-calls, determine the allele haplotype, and corroborate that CYP2D6*31 is associated with a poor metabolizer phenotype.


CYP2D6 genotyping was carried out using the AmpliChip CYP450 test and long-range polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) platforms. Allele haplotype was determined by cloning and sequence analysis. Allele frequencies were determined in five population samples.


A 6.6-kb long-range PCR product comprising the entire CYP2D6 gene and flanking regions was sequenced to determine the CYP2D6*31 haplotype. Identical sequences were obtained from both Puerto Ricans selected for sequence analysis. One Spanish individual with a CYP2D6*4/*31 genotype was phenotyped as a poor metabolizer with the CYP2D6 probe drug dextromethorphan (urinary ratio DM/DX=0.71). The frequency of CYP2D6*31 was determined in 176 Spanish (0.57%), 50 Puerto Rican (2.0%), and 150 Hispanic (0.33%) people. CYP2D6*31 was absent in 237 North American Caucasians and 154 African Americans.


CYP2D6*31 was associated with poor metabolism of dextromethorphan in vivo, which is consistent with a previous report classifying this allelic variant as nonfunctional. The discovery of CYP2D6*31 in Spanish people only (or of Spanish ancestry) suggests that it may contribute to CYP2D6 variability in individuals of Spanish ancestry.


CYP2D6 CYP2D6*31 AmpliChip CYP450 test Phenotype Dextromethorphan 



We are grateful to Liliane Ndjountché for technical assistance and J. Steven Leeder, PharmD, PhD, for critically reviewing the manuscript. We also express our gratitude to Dr. José Luis Ramos Castellanos and Dr. José Navajo Galindo for support of the research activities. We also thank Roche Diagnostics staff (Spain and Pleasanton, CA, USA) for their technical and administrative support. Partially supported by grant number P20 RR11126 from the National Center for Research Resources, a component of the National Institutes of Health.


  1. 1.
    Sistonen J, Sajantila A, Lao O, Corander J, Barbujani G, Fuselli S (2007) CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet Genomics 17(2):93–101PubMedGoogle Scholar
  2. 2.
    Zanger UM, Raimundo S, Eichelbaum M (2004) Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Exp Pathol Pharmacol 369:23–37CrossRefPubMedGoogle Scholar
  3. 3.
    Zanger UM, Turpeinen M, Klein K, Schwab M (2008) Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem 392:1093–1108CrossRefPubMedGoogle Scholar
  4. 4.
    Marez D, Legrand M, Sabbagh N, Guidice J-M, Spire C, Lafitte J-J et al (1997) Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics 7:193–202CrossRefPubMedGoogle Scholar
  5. 5.
    Allorge D, Breant D, Harlow J, Chowdry J, Lo-Guidice JM, Chevalier D et al (2005) Functional analysis of CYP2D6.31 variant: homology modeling suggests possible disruption of redox partner interaction by Arg440His substitution. Proteins 59(2):339–346CrossRefPubMedGoogle Scholar
  6. 6.
    RocheMolecularSystems. AmpliChip CYP450 Test. 2008;CE-IVDGoogle Scholar
  7. 7.
    Gaedigk A, Bradford LD, Marcucci KA, Leeder JS (2002) Unique CYP2D6 activity distribution and genotype-phenotype discordance in African Americans. Clin Pharmacol Ther 72:76–89CrossRefPubMedGoogle Scholar
  8. 8.
    Leeder JS, Pearce RE, Gaedigk A, Modak A, Rosen DI (2008) Evaluation of a [13C]-dextromethorphan breath test to assess CYP2D6 phenotype. J Clin Pharmacol 48(9):1041–1051CrossRefPubMedGoogle Scholar
  9. 9.
    Blake MJ, Gaedigk A, Pearce RE, Bomgaars LR, Christensen ML, Stowe C et al (2007) Ontogeny of dextromethorphan O-and N-demethylation in the first year of life. Clin Pharmacol Ther 81(4):510–516CrossRefPubMedGoogle Scholar
  10. 10.
    Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS (2008) The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther 83:234–242CrossRefPubMedGoogle Scholar
  11. 11.
    Yasui-Furukori N, Hidestrand M, Spina E, Facciola G, Scordo MG, Tybring G (2001) Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes. Drug Metab Dispos 29(10):1263–1268PubMedGoogle Scholar
  12. 12.
    Eap CB, Bondolfi G, Zullino D, Bryois C, Fuciec M, Savary L et al (2001) Pharmacokinetic drug interaction potential of risperidone with cytochrome P450 isozymes as assessed by the dextromethorphan, the caffeine, and the mephenytoin test. Ther Drug Monit 23(3):228–231CrossRefPubMedGoogle Scholar
  13. 13.
    Heller T, Kirchheiner J, Armstrong VW, Luthe H, Tzvetkov M, Brockmoller J et al (2006) AmpliChip CYP450 GeneChip: a new gene chip that allows rapid and accurate CYP2D6 genotyping. Ther Drug Monit 28(5):673–677CrossRefPubMedGoogle Scholar
  14. 14.
    Rebsamen MC, Desmeules J, Daali Y, Chiappe A, Diemand A, Rey C et al (2009) The AmpliChip CYP450 test: cytochrome P450 2D6 genotype assessment and phenotype prediction. Pharmacogenomics J 9(1):34–41CrossRefPubMedGoogle Scholar
  15. 15.
    de Leon J, Susce MT, Johnson M, Hardin M, Maw L, Shao A et al (2009) DNA microarray technology in the clinical environment: the AmpliChip CYP450 test for CYP2D6 and CYP2C19 genotyping. CNS Spectr 14(1):19–34PubMedGoogle Scholar
  16. 16.
    Candiotti KA, Yang Z, Rodriguez Y, Crescimone A, Sanchez GC, Takacs P et al (2009) The impact of CYP2D6 genetic polymorphisms on postoperative morphine consumption. Pain Med 10(5):799–805CrossRefPubMedGoogle Scholar
  17. 17.
    Adams SM, Bosch E, Balaresque PL, Ballereau SJ, Lee AC, Arroyo E et al (2008) The genetic legacy of religious diversity and intolerance: paternal lineages of Christians, Jews, and Muslims in the Iberian Peninsula. Am J Hum Genet 83(6):725–736CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Andrea Gaedigk
    • 1
    Email author
  • Maria Isidoro-García
    • 2
  • Robin E. Pearce
    • 1
  • Santiago Sánchez
    • 3
  • Virginia García-Solaesa
    • 2
  • Carolina Lorenzo-Romo
    • 3
  • Gloria Gonzalez-Tejera
    • 4
  • Susan Corey
    • 5
  1. 1.Division of Developmental Pharmacology & Experimental TherapeuticsChildren’s Mercy Hospital and ClinicsKansas CityUSA
  2. 2.Department of Clinical BiochemistryUniversity Hospital of SalamancaSalamancaSpain
  3. 3.Department of PsychiatryUniversity Hospital of SalamancaSalamancaSpain
  4. 4.Department of PsychiatryUniversity of Puerto Rico School of MedicineSan JuanPuerto Rico
  5. 5.Department of Pharmacology & ToxicologyUniversity of Puerto Rico School of MedicineSan JuanPuerto Rico

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