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

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

Mohamed Hossam A Shahin et al. Thromb Haemost. 2013 Jun.

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.

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Figures

Figure 1
Figure 1. World map showing VKORC1 Asp36Tyr geographical distribution

Populations having the variant were listed in a descending order according to the VKORC1 Asp36Tyr frequency in each studied population. Populations having the VKORC1 Asp36Tyr highest frequency were represented by dark gray color, followed by lighter gray colors in populations with lower frequency. Cross hatches represent populations in which this variant was not detected . The countries in bold italic represent the seven populations included in our study; the remainder represent previously studied populations (14-16, 21, 22, 32, 33).★ Jewish and Israeli populations include: Ashkenazi Jews (4%), Israeli Jews (1.5%), Arab Muslims in Israel (1%), Sephardic Jews (0.5%) and North African Jews (0.5%).

Figure 2
Figure 2. Box plot showing the effect of VKORC1 Asp36Tyr polymorphism on warfarin dose requirements in Egyptians

The box represents the values from the 25 to 75% percentile. The horizontal line represents the median. The diamond represents the mean. The vertical line extends from the minimum to the maximum value, excluding outlier and extreme values which are marked as closed circles. Nonparametric test (Mann-Whitney U test) was used to compare the warfarin dose requirements between the two groups, showing a significant difference of P = 0.03.

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