title: VKORC1 Asp36Tyr geographic distribution and its impact on warfarin dose requirements in Egyptians.
abstract: The VKORC1 Asp36Tyr single nucleotide polymorphism (SNP) is one of the most promising predictors of high warfarin dose, but data on its population prevalence is incomplete. We determined the frequency of this SNP in participants from seven countries on four continents and investigated its effect on warfarin dose requirement. One thousand samples were analysed to define the population prevalence of this SNP. Those samples included individuals from Egypt, Ghana, Sudan, Kenya, Saudi Arabia, Peru and African Americans from the United States. A total of 206 Egyptian samples were then used to investigate the effect of this SNP on warfarin dose requirements. This SNP was most frequent among Kenyans and Sudanese, with a minor allele frequency (MAF) of 6% followed by Saudi Arabians and Egyptians with a MAF of 3% and 2.5%, respectively. It was not detected in West Africans, based on our data from Ghana, and a large cohort of African Americans. Egyptian carriers of the VKORC1 Tyr36 showed higher warfarin dose requirement (57.1 ± 29.4 mg/week) than those with the Asp36Asp genotype (35.8 ± 16.6 mg/week; p=0.03). In linear regression analysis, this SNP had the greatest effect size among the genetic factors (16.6 mg/week increase in dose per allele), and improved the warfarin dose variability explained in Egyptians (model R2 from 31% to 36.5%). The warfarin resistant VKORC1 Asp36Tyr appears to be confined to north-eastern Africa and nearby Middle-Eastern populations, but in those populations where it is present, it has a significant influence on warfarin dose requirement and the percent of warfarin dose variability that can be explained.
authors.affiliation: Center for Pharmacogenomics, University of Florida, Health Science Center, PO Box 100486, Gainesville, FL 32610, USA.
authors.forename: Mohamed Hossam A
authors.initials: MH
authors.lastname: Shahin
authors.forename: Larisa H
authors.initials: LH
authors.lastname: Cavallari
authors.forename: Minoli A
authors.initials: MA
authors.lastname: Perera
authors.forename: Sherief I
authors.initials: SI
authors.lastname: Khalifa
authors.forename: Anne
authors.initials: A
authors.lastname: Misher
authors.forename: Taimour
authors.initials: T
authors.lastname: Langaee
authors.forename: Shitalben
authors.initials: S
authors.lastname: Patel
authors.forename: Kimberly
authors.initials: K
authors.lastname: Perry
authors.forename: David O
authors.initials: DO
authors.lastname: Meltzer
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000483:Alleles; D015331:Cohort Studies; D004534:Egypt; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D005843:Geography; D006801:Humans; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D013923:Thromboembolism / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D014859:Warfarin; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases