Influence of UDP-Glucuronosyltransferase Polymorphisms on Stable Warfarin Doses in Patients with Mechanical Cardiac Valves.
AIM
This study aimed to evaluate the effect of uridine diphosphate (UDP)-glucuronosyltransferase (UGT) polymorphisms on warfarin dosing requirements in patients with mechanical cardiac valves.


METHODS
A total of 191 patients with stable warfarin doses from the EAST Group of Warfarin were included in this study. The influence of genetic polymorphisms on stable warfarin doses was investigated by genotyping 6 single nucleotide polymorphisms (SNPs): vitamin K epoxide reductase complex 1 (VKORC1) rs9934438, cytochrome P450 (CYP) 2C9 rs1057910, CYP4F2 rs2108622, and UGT1A1 (rs887829, rs4148323, and rs4124874). An additional subgroup analysis was carried out using patients with wild-type homozygote carriers of CYP2C9.


RESULTS
One UGT1A1 SNP of rs887829 (C>T) exhibited significant association with stable warfarin doses in the study population and subgroup. Patients with the T allele in UGT1A1 rs887829 (CT or TT) required higher doses than those with the CC genotype in the study population (6.3 ± 2.4 mg vs. 5.2 ± 1.6 mg, P = 0.003). Similarly, in the subpopulation of AA carriers in the CYP2C9 gene, patients with the T allele required significantly higher doses of warfarin than those with other genotypes of rs887829 (6.5 ± 2.4 vs. 5.3 ± 1.5 mg, P = 0.002). Approximately 45.1% of overall interindividual variability in warfarin dose requirement was explained by the multivariate regression model. VKORC1, CYP2C9, UGT1A1 rs887829, age, and CYP4F2 accounted for 28.2%, 6.6%, 5.5%, 3.0%, and 1.8% of the variability, respectively.


CONCLUSION
Our results suggest that UGT1A1 could be a determinant of stable warfarin doses.
['An|Sook Hee|SH|', 'Chang|Byung Chul|BC|', 'Lee|Kyung Eun|KE|', 'Gwak|Hye Sun|HS|']
D000368:Aged D000925:Anticoagulants D001777:Blood Coagulation D065729:Cytochrome P-450 CYP2C9 D003577:Cytochrome P-450 Enzyme System D000072470:Cytochrome P450 Family 4 D054796:Drug Dosage Calculations D016903:Drug Monitoring D005260:Female D005787:Gene Frequency D005838:Genotype D014453:Glucuronosyltransferase D006350:Heart Valve Prosthesis D019918:Heart Valve Prosthesis Implantation D006801:Humans D019934:International Normalized Ratio D016014:Linear Models D008297:Male D008875:Middle Aged D015999:Multivariate Analysis D010597:Pharmacogenetics D010641:Phenotype D020641:Polymorphism, Single Nucleotide D056910:Republic of Korea D013927:Thrombosis D016896:Treatment Outcome D064417:Vitamin K Epoxide Reductases D014859:Warfarin
Polymorphism Warfarin Uridine diphosphate (UDP)-Glucuronosyltransferase (UGT) Cytochrome P450 subfamily 2C polypeptide 9 (CYP2C9)