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RISS 인기검색어
- 검색키워드
- 저자 : Nassr Eldin Mohammed Ahmed Shrif (검색결과 1 건)
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Studies on Pharmacogenetics of Warfarin Therapy in Adult Sudanese Patients
Nassr Eldin Mohammed Ahmed Shrif 성균관대학교 일반대학원 2011 국내박사
Background: Warfarin is the most widely prescribed oral anticoagulant used for the treatment and primary prevention of thromboembolic in many conditions. However, treatment with warfarin is complicated because it has narrow therapeutic index and exhibits greater than 10-fold inter-individual and inter-ethnic variability in therapeutic dose response, and due to adverse reaction associated with warfarin treatment, it requires close monitoring by frequent measurements of prothrombin time (PT). Among more than 30 genes, genetic polymorphisms in cytochrome P450, subfamily IIC, polypeptide 9 (CYP2C9) and vitamin k epoxide reductase complex subunit 1 (VKORC1) are repeatedly shown to affect the inter-individual variability of warfarin dose response in Caucasians, Asians and to lesser extent African Americans. Hence, it was recommended by the FDA to incorporate these genetic data to guide warfarin dosing. Sudan, the largest country in the Africa and has one of the most genetically diverse populations , is underrepresented, similar to other African populations, in warfarin pharmacogenetics studies .The VKORC1 and CYP2C9 polymorphisms have never be investigated in Sudanese populations. Objectives: The aim of this study was to characterize the contribution of genetic polymorphisms of CYP2C9, VKORC1 polymorphism and haplotypes and clinical factors to warfarin dose variability among adult Sudanese patients. The ultimate goal is to guide warfarin dose management in Sudanese patients in view to develop personalized dosing algorithm. Methods: 20 VKORC1 tag SNPs and Seven CYP2C9 polymorphisms (*2, *3, *5, *6,*8, *9 and *11) were genotyped in 203 warfarin treated patients and 180 healthy Sudanese. The association of SNPs, clinical and demographic factors with warfarin dose and their size effect were comprehensively assessed using univariate and multivariate analysis. Back ward elimination technique was used to select variables that jointly predict warfarin dose variability in Sudanese patients. Results: Patients with CYP2C9*2,*5,*6, or *11 variant required daily warfarin that was 21% lower than needed by those with CYP2C9*1/*1 (4.7 mg/day Vs 5.8 mg/day, p <0.001). Five common VKORC1 SNPs associated with low warfarin dose and Six SNPs with higher doses. Unlike to Caucasians and Asians, VKORC1 SNPs were divided into two haplotype blocks in Sudanese. Haplotypes from each haplotype block were not more informative than single SNPs. According to the multiple linear regressions, rs8050984, rs7294 and rs7199949 in the VKORC1 and POL3S genes (P= <0.001, <0.001, <0.001, respectively), CYP2C9 genotype (*2, *5, *6, *11; P <0.001), body weight (P=0.02) and target INR (P=0.006) were jointly contributed and explained about 36% of total warfarin dose variation (R square=0.36, adjusted R2 square=0.33, F=13.9, p <0.0001). Conclusion: Our data revealed that VKORC1 and CYP2C9 polymorphisms are important factors that influence warfarin dose response in Sudanese while studied clinical and demographic factors have minor effect. Our data suggest that combinations of the SNPs may improve predicting warfarin dose requirement. Background: Warfarin is the most widely prescribed oral anticoagulant used for the treatment and primary prevention of thromboembolic in many conditions. However, treatment with warfarin is complicated because it has narrow therapeutic index and exhibits greater than 10-fold inter-individual and inter-ethnic variability in therapeutic dose response, and due to adverse reaction associated with warfarin treatment, it requires close monitoring by frequent measurements of prothrombin time (PT). Among more than 30 genes, genetic polymorphisms in cytochrome P450, subfamily IIC, polypeptide 9 (CYP2C9) and vitamin k epoxide reductase complex subunit 1 (VKORC1) are repeatedly shown to affect the inter-individual variability of warfarin dose response in Caucasians, Asians and to lesser extent African Americans. Hence, it was recommended by the FDA to incorporate these genetic data to guide warfarin dosing. Sudan, the largest country in the Africa and has one of the most genetically diverse populations , is underrepresented, similar to other African populations, in warfarin pharmacogenetics studies .The VKORC1 and CYP2C9 polymorphisms have never be investigated in Sudanese populations. Objectives: The aim of this study was to characterize the contribution of genetic polymorphisms of CYP2C9, VKORC1 polymorphism and haplotypes and clinical factors to warfarin dose variability among adult Sudanese patients. The ultimate goal is to guide warfarin dose management in Sudanese patients in view to develop personalized dosing algorithm. Methods: 20 VKORC1 tag SNPs and Seven CYP2C9 polymorphisms (*2, *3, *5, *6,*8, *9 and *11) were genotyped in 203 warfarin treated patients and 180 healthy Sudanese. The association of SNPs, clinical and demographic factors with warfarin dose and their size effect were comprehensively assessed using univariate and multivariate analysis. Back ward elimination technique was used to select variables that jointly predict warfarin dose variability in Sudanese patients. Results: Patients with CYP2C9*2,*5,*6, or *11 variant required daily warfarin that was 21% lower than needed by those with CYP2C9*1/*1 (4.7 mg/day Vs 5.8 mg/day, p <0.001). Five common VKORC1 SNPs associated with low warfarin dose and Six SNPs with higher doses. Unlike to Caucasians and Asians, VKORC1 SNPs were divided into two haplotype blocks in Sudanese. Haplotypes from each haplotype block were not more informative than single SNPs. According to the multiple linear regressions, rs8050984, rs7294 and rs7199949 in the VKORC1 and POL3S genes (P= <0.001, <0.001, <0.001, respectively), CYP2C9 genotype (*2, *5, *6, *11; P <0.001), body weight (P=0.02) and target INR (P=0.006) were jointly contributed and explained about 36% of total warfarin dose variation (R square=0.36, adjusted R2 square=0.33, F=13.9, p <0.0001). Conclusion: Our data revealed that VKORC1 and CYP2C9 polymorphisms are important factors that influence warfarin dose response in Sudanese while studied clinical and demographic factors have minor effect. Our data suggest that combinations of the SNPs may improve predicting warfarin dose requirement.
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