Document Detail


Genetic and nongenetic factors associated with warfarin dose requirements in Egyptian patients.
MedLine Citation:
PMID:  21228733     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND OBJECTIVE: Warfarin is a commonly used oral anticoagulant with a narrow therapeutic index and various genetic and clinical factors that influence interpatient variability in dose requirements. This study investigated the impact of genetic and nongenetic factors on warfarin dose requirements in Egyptians.
METHODS: DNA was extracted from 207 patients taking warfarin for more than 2 months and genotyped for VKORC1 (3673 G>A), CYP2C9 *2*3*4*5*8, CYP4F2 (V33M; rs2108622), APOE (rs429358, rs7412), and CALU(rs339097) gene polymorphisms. Linear regression modeling was conducted to identify the genetic and nongenetic factors that independently influence warfarin dose requirements.
RESULTS: VKORC1 3673 AA or GA genotype (P<0.0001), one or two variant alleles of CYP2C9 gene (P=0.0004), APOE ε2 haplotype (P=0.01), and increasing age (P<0.0001) were all associated with lower warfarin dose, whereas smoking (P=0.025) and pulmonary embolism (P=0.0059) showed association with higher warfarin doses. These factors explained 31% of the warfarin dose variability. This is the first independent confirmation of the association of the CALU rs339097 variant with higher warfarin dose requirement, although inclusion of this single nucleotide polymorphism in the multiple regression model failed to achieve significance (P=0.066). CYP4F2 (V33M) polymorphism was not significant (P=0.314), despite its high frequency in the studied population (42%).
CONCLUSION: The study shows that VKORC1, CYP2C9 polymorphisms, APOE ε2 variant, and several clinical/demographic variables are important determinants of warfarin dose requirements in Egyptian patients. The percentage of variability explained by these factors is lower than in those of European ancestry, but similar to the variability explained in Asians and African ancestry.
Authors:
Mohamed Hossam A Shahin; Sherief I Khalifa; Yan Gong; Lamiaa N Hammad; Mohamed T H Sallam; Mostafa El Shafey; Shawky S Ali; Mohamed-Eslam F Mohamed; Taimour Langaee; Julie A Johnson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pharmacogenetics and genomics     Volume:  21     ISSN:  1744-6880     ISO Abbreviation:  Pharmacogenet. Genomics     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-02-04     Completed Date:  2011-05-24     Revised Date:  2013-07-02    
Medline Journal Info:
Nlm Unique ID:  101231005     Medline TA:  Pharmacogenet Genomics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  130-5     Citation Subset:  IM    
Affiliation:
Department of Pharmacy Practice and Clinical Pharmacy, Faculty of Pharmacy, Misr International University, Cairo, Egypt.
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MeSH Terms
Descriptor/Qualifier:
Adult
Anticoagulants / administration & dosage*
Apolipoproteins E / genetics*
Aryl Hydrocarbon Hydroxylases / genetics*
Calcium-Binding Proteins / genetics
Cytochrome P-450 Enzyme System / genetics
Dose-Response Relationship, Drug
Egypt
Female
Genetic Association Studies*
Humans
Linear Models
Male
Middle Aged
Mixed Function Oxygenases / genetics*
Polymorphism, Genetic
Polymorphism, Single Nucleotide / genetics
Pulmonary Embolism / metabolism
Smoking / metabolism
Warfarin / administration & dosage*
Grant Support
ID/Acronym/Agency:
U01 GM074492/GM/NIGMS NIH HHS; U01 GM074492/GM/NIGMS NIH HHS; U01 GM074492-05/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Anticoagulants; 0/Apolipoproteins E; 0/CALU protein, human; 0/Calcium-Binding Proteins; 81-81-2/Warfarin; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases; EC 1.14.13.30/CYP4F2 protein, human; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP2C9 protein, human; EC 1.14.99.-/vitamin K epoxidase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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