VKORC1 Asp36Tyr geographic distribution and its impact on warfarin dose requirements in Egyptians

Mohamed Hossam A. Shahin; Larisa H. Cavallari; Minoli A. Perera; Sherief I. Khalifa; Anne Misher; Taimour Langaee; Shitalben Patel; Kimberly Perry; David O. Meltzer; Howard L. McLeod; Julie A. Johnson

doi:10.1160/TH12-10-0789

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 109(06): 1045-1050
DOI: 10.1160/TH12-10-0789

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

VKORC1 Asp36Tyr geographic distribution and its impact on warfarin dose requirements in Egyptians

Mohamed Hossam A. Shahin

¹Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida, USA

,

Larisa H. Cavallari

²Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, Illinois, USA

,

Minoli A. Perera

³Department of Medicine, University of Chicago, Chicago, Illinois, USA

,

Sherief I. Khalifa

⁴Pharmaceutical Sciences Section, College of Pharmacy, Qatar University, Doha, Qatar

,

Anne Misher

⁵Univeristy of North Carolina Institute for Pharmacogenomics and Individualized Therapy, Chapel Hill, North Carolina, USA

,

Taimour Langaee

¹Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida, USA

,

Shitalben Patel

²Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, Illinois, USA

,

Kimberly Perry

³Department of Medicine, University of Chicago, Chicago, Illinois, USA

,

David O. Meltzer

³Department of Medicine, University of Chicago, Chicago, Illinois, USA

,

Howard L. McLeod

⁵Univeristy of North Carolina Institute for Pharmacogenomics and Individualized Therapy, Chapel Hill, North Carolina, USA

,

Julie A. Johnson

¹Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida, USA

› Author Affiliations

Abstract

Summary

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.

Keywords

Warfarin - pharmacogenetics - VKORC1 Asp36Tyr - polymorphism - Egyptians

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References

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