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European Journal of Clinical Pharmacology

, Volume 63, Issue 6, pp 537–546 | Cite as

Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans

  • Roza Ghotbi
  • Magnus Christensen
  • Hyung-Keun Roh
  • Magnus Ingelman-Sundberg
  • Eleni AklilluEmail author
  • Leif Bertilsson
Pharmacogenetics

Abstract

Objectives

To investigate the CYP1A2 genotype-phenotype relationship and to compare CYP1A2 genetic polymorphisms and enzyme activity in terms of the effect of smoking and oral contraceptive (OC) use in Swedes and Koreans.

Methods

CYP1A2 enzyme activity was determined in 194 and 150 healthy Swedish and Korean subjects, respectively, on the basis of the 4-h plasma paraxanthine/caffeine (17X/137X) ratio determined using high-performance liquid chromatography. Genotyping for the −3860G>A, −2467delT, −739 T>G, −729 C>T, −163C>A and −3113A>G polymorphisms was performed by PCR-restriction fragment length polymorphism analysis.

Results

The mean 17X/137X ratio was 1.54-fold higher in Swedes than in Koreans (mean difference: 0.16; 95% CI of the mean difference: 0.12, 0.20; p < 0.0001). Smokers had a significantly higher 17X/137X ratio (higher CYP1A2 activity) than non-smokers, while Swedish OC users had a significantly lower 17X/137X ratio than non-users (mean difference: 0.31, 95% CI of the mean difference: 0.23, 0.39; p < 0.0001). No effect of gender differences on enzyme activity was observed. Four known (CYP1A2*1A, *1D, *1F, and *1L) and two novel haplotypes (CYP1A2*1V and CYP1A2*1W) were found. CYP1A2*1K was rare in Swedes and absent in Koreans. No significant genotype-phenotype relationship was observed, with the exception of CYP1A2*1F in Swedish smokers, where it was associated with higher enzyme inducibility (p = 0.02). Koreans displayed a significantly lower mean 17X/137X ratio than Swedes having the same CYP1A2 genotype, smoking habit and OC use.

Conclusions

We found significant differences in CYP1A2 enzyme activity between Swedes and Koreans that could not be explained by environmental factors or the CYP1A2 haplotypes examined, despite differences in allele frequencies. None of the investigated CYP1A2 haplotypes are critical in inducing variations in enzyme activity, with the exception of CYP1A2*1F.

Keywords

Caffeine CYP1A2 Haplotype Phenotype Polymorphism 

Notes

Acknowledgment

We thank Birgitta Ask and Jolanta Widen for their excellent technical assistance. The study was supported by the Swedish Research Council, Medicine, 3902, and by NIH (R01 GM60548).

Conflict of interest statement

The authors have identified no conflicts of interest in relation to this manuscript. This study complies with the current laws of Sweden and Korea, where it was performed, inclusive of ethics approvals.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Roza Ghotbi
    • 1
  • Magnus Christensen
    • 1
  • Hyung-Keun Roh
    • 2
  • Magnus Ingelman-Sundberg
    • 3
  • Eleni Aklillu
    • 1
    Email author
  • Leif Bertilsson
    • 1
  1. 1.Division of Clinical Pharmacology, Karolinska University Hospital-HuddingeKarolinska InstitutetStockholmSweden
  2. 2.Department of Internal Medicine, Division of Clinical PharmacologyInha University HospitalIncheonSouth Korea
  3. 3.Section of Pharmacogenetics, Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden

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