CYP4F2 rs2108622: a minor significant genetic factor of warfarin dose in Han Chinese patients with mechanical heart valve replacement

Abstract

KeywordsCYP2C9, CYP4F2, Chinese, mechanical heart valve replacement, VKORC1, warfarin ---------------------------------------------------------------------- Received WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Genetic polymorphisms of VKORC1 and CYP2C9 are known to influence warfarin dosage.• Recent studies among Caucasians showed that polymorphisms of CYP4F2 also play a role in warfarin pharmacogenetics.• The contribution of CYP4F2 variants to the variability inwarfarin dose requirement in Chinese subjects remains to be investigated. WHAT THIS STUDY ADDS• This research was to study the effect of CYP4F2 variants on warfarin requirements in the Han Chinese population.• This study developed a multiple regression model including CYP2C9, VKORC1 3673G>A, CYP4F2 genotypes and age, weight, combination use of amiodarone which could explain 56.1% of the individual variability in warfarin dose CYP4F2 could explain 4% of the variance in warfarin dose.• We found that one novel genotypic polymorphism 5417G>T for Asp36Tyr, which was identified as an important marker of warfarin resistance, was absent in the Han Chinese population in our study. AIMSThe objective of this study was to assess the effect of the CYP4F2 on the daily stable warfarin dose requirement in Han Chinese patients with mechanical heart valve replacement (MHVR). METHODS From March 2007 to November 2008, 222Han Chinese MHVR patients were recruited in our study. VKORC1 3673G>A, 5417G>T, CYP2C9 *3 and CYP4F2 rs2108622 were genotyped by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP). Polymorphisms of VKORC1 9041G>A were detected by direct sequencing. Multiple linear regression analysis was used to investigate the contribution of CYP4F2. RESULTSThe CYP4F2 rs2108622 CT/TT group took a significantly higher stable warfarin dose (3.2 mg day CONCLUSIONCYP4F2 is a minor significant factor of individual variability in the stable warfarin dose in Han Chinese patients with MHVR. The effect of CYP2C9 and VKORC1 genotypes on variability in the stable warfarin dose had also been confirmed.

Pharmacogenetics-based warfarin dose prediction algorithm for patients with heart valve replacement in Southeast China

“…Perini et al (2010) studied a mixed population and reported no significant effect of CYP4F2 polymorphism on warfarin dose, which contradicts with the results of two studies conducted on Chinese populations (Cen et al, 2010;Li et al, 2012). The results of this study showed that CYP4F2 had a significant effect on warfarin dose.…”

“…The results of this study showed that CYP4F2 had a significant effect on warfarin dose. CYP4F2 mutations might increase the required dose of warfarin, which is consistent with that reported by Cen et al (2010) and Li et al (2012). The heterozygous mutations of CYP4F2 had little influence, whereas the homozygous mutations of CYP4F2 could significantly influence the steady-state warfarin dose.…”

Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population

“…An association between the CYP4F2 variant (rs2108622) and warfarin dose was subsequently confirmed in a meta-analysis involving more than 9000 participants from 30 studies [80] . Although the association of CYP4F2 is significant, the effect size is much lower than those contributed of VKORC1 and CYP2C9 in Han Chinese in South China [81] , and its clinical use …”

VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children

“…The VKORC1 and CYP2C9 genotype results were validated using control samples that had been genotyped as part of a previous study. 14 CYP4F2 genotypes were validated by regenotyping 26 samples in duplicate by PCR-restriction fragment length polymorphism analysis as described by Cen et al 15 …”