title: Differences in CYP2C9 Genotype and Enzyme Activity Between Swedes and Koreans of Relevance for Personalized Medicine: Role of Ethnicity, Genotype, Smoking, Age, and Sex.
abstract: Global personalized medicine demands the characterization of person-to-person and between-population differences in drug pharmacokinetics and pharmacodynamics. CYP2C9 pharmacokinetic pathway is subject to modulation by both genetic and environmental factors. CYP2C9 genotype-based dose recommendations (e.g., for warfarin) is advocated. However, the overall contribution of genotype for variation in enzyme activity may differ between populations. We evaluated the importance of ethnicity, genotype, smoking, body weight, age, and sex for CYP2C9 enzyme activity. CYP2C9 genotype and phenotype was determined in 148 Swedes and 146 Koreans using losartan as a probe. CYP2C9 enzyme activity was assessed using urinary losartan/metabolite E-3174 ratio. The frequency of CYP2C9 defective variant alleles (*2 and *3) was significantly higher in Swedes (10.8% and 12.5%) than in Koreans (0% and 5.8%). In matched genotypes, CYP2C9 enzyme activity was significantly lower in Swedes compared to Koreans (p<0.0001). In a univariate analysis, age, weight, ethnicity, genotype, and smoking were significant predictors of CYP2C9 phenotype. A stepwise multivariate analysis indicated ethnicity, genotype, and smoking remained as significant predictors of CYP2C9 enzyme activity, accounting for 50% of the total variance. In both study populations, CYP2C9 genotype was a significant predictor of CYP2C9 enzyme activity, but its contribution in explaining the total variance was lower in Koreans (26.6%) than Swedes (40%). In conclusion, we report significantly lower CYP2C9 enzyme activity in Swedes compared to Koreans, partly but not exclusively due to CYP2C9 pharmacogenetic variations. Ethnicity and environment factors need to be considered together with genotype for population-specific dose optimization and global personalized medicine.
authors.affiliation: 1 Department of Laboratory Medicine, Karolinska Institutet, Division of Clinical Pharmacology, Karolinska University Hospital , Huddinge, Sweden .|2 Integrative Pharmacogenomics Institute (iPROMISE), Faculty of Pharmacy, Universiti Teknologi MARA , Selangor, Malaysia .
authors.forename: Fazleen H M
authors.initials: FH
authors.lastname: Hatta
authors.affiliation: 1 Department of Laboratory Medicine, Karolinska Institutet, Division of Clinical Pharmacology, Karolinska University Hospital , Huddinge, Sweden .
authors.forename: Mia
authors.initials: M
authors.lastname: Lundblad
authors.affiliation: 1 Department of Laboratory Medicine, Karolinska Institutet, Division of Clinical Pharmacology, Karolinska University Hospital , Huddinge, Sweden .
authors.forename: Margareta
authors.initials: M
authors.lastname: Ramsjo
authors.affiliation: 3 Department of Clinical Pharmacology, Inha University School of Medicine and Clinical Pharmacology, Inha University Hospital, Inha University , Incheon, Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.affiliation: 4 Department of Internal Medicine, Division of Clinical Pharmacology, Gachon University Hospital , Incheon, Korea.
authors.forename: Hyung-Keun
authors.initials: HK
authors.lastname: Roh
authors.affiliation: 1 Department of Laboratory Medicine, Karolinska Institutet, Division of Clinical Pharmacology, Karolinska University Hospital , Huddinge, Sweden .
authors.forename: Leif
authors.initials: L
authors.lastname: Bertilsson
authors.affiliation: 1 Department of Laboratory Medicine, Karolinska Institutet, Division of Clinical Pharmacology, Karolinska University Hospital , Huddinge, Sweden .
authors.forename: Erik
authors.initials: E
authors.lastname: Eliasson
authors.affiliation: 1 Department of Laboratory Medicine, Karolinska Institutet, Division of Clinical Pharmacology, Karolinska University Hospital , Huddinge, Sweden .
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
mesh_terms: D000328:Adult; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D007723:Korea; D008297:Male; D015999:Multivariate Analysis; D010641:Phenotype; D057285:Precision Medicine / Q000379:methods*; D012907:Smoking; D055815:Young Adult
chemical_list: D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A