Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans.
OBJECTIVE
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.
Ghotbi
Roza
R
Division of Clinical Pharmacology, Karolinska University Hospital-Huddinge, Karolinska Institutet, C1-68, 141 86, Stockholm, Sweden.
Christensen
Magnus
M
Roh
Hyung-Keun
HK
Ingelman-Sundberg
Magnus
M
Aklillu
Eleni
E
Bertilsson
Leif
L
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D044466:Asian People; D002110:Caffeine / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007723:Korea; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D013548:Sweden; D044465:White People
D002110:Caffeine; D019388:Cytochrome P-450 CYP1A2