Original Article Differences in CYP2C9 Genotype and Enzyme Activity Between Swedes and Koreans of Relevance for Personalized Medicine: Role of Ethnicity, Genotype, Smoking, Age, and Sex Fazleen H.M. Hatta, 1,2 * Mia Lundblad, 1 * Margareta Ramsjo, 1 * Ju-Hee Kang, 3 Hyung-Keun Roh, 4 Leif Bertilsson, 1 Erik Eliasson, 1 and Eleni Aklillu 1 Abstract Global personalized medicine demands the characterization of person-to-person and between-population differ- ences in drug pharmacokinetics and pharmacodynamics. CYP2C9 pharmacokinetic pathway is subject to mod- ulation 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 assed 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. Introduction T he cytochrome P450 isoenzyme CYP2C9, one of the most abundant CYP enzymes in the liver, plays important roles in the metabolism of many therapeutically important drugs, including nonsteroidal anti-inflammatories, oral anti- coagulants, and oral hypoglycemics (He et al., 2011; Rettie and Jones, 2005). CYP2C9 is genetically polymorphic and displays wide between-patient differences in its metabolic activity, which can result in difficulties for rational dosing, inadequate therapeutic effect, or toxicity (Ninomiya et al., 2000; Wadelius et al., 2004). Induction and/or inhibition of CYP enzymes are the usual mechanisms by which concomi- tant medications can cause variations between patients in drug elimination capacity. Interactions between the genetic, envi- ronmental (e.g., dietary, lifestyle, socio-culture background) and biological (e.g., gender, age) factors add up to the com- plexity of this variation and may explain why a group of people from a certain population or ethnic background have different metabolic or adverse event profiles compared to others. 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. 3 Department of Clinical Pharmacology, Inha University School of Medicine and Clinical Pharmacology, Inha University Hospital, Inha University, Incheon, Korea. 4 Department of Internal Medicine, Division of Clinical Pharmacology, Gachon University Hospital, Incheon, Korea. *These three authors share first authorship of this article. OMICS A Journal of Integrative Biology Volume 19, Number 6, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/omi.2015.0022 1