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.
Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data Original Article, N Engl J Med 2009:360;753-764.. In Table 2 (page 758), the mean absolute errors in both cohorts should have ...been expressed as means with 95% confidence intervals rather than as means ±SE. The change affects the data in Table 2, the column heads, and the first footnote. In the first paragraph of the Doses Predicted by the Three Models subsection of Results (page 758), the parenthetical data should have read, “(8.5 mg per week 95% confidence interval {CI}, 8.0 to 9.0) vs. 9.9 mg per week 95% CI, 9.3 to 10.4 and 13.0 mg per week 95% CI, 12.4 to 13.6, respectively; P<0.001 for both comparisons).” In addition, in the International Warfarin Pharmacogenetics Consortium pharmacogenetic dosing algorithm in Supplementary Appendix 2, the example given for CYP2C9 should have been represented as *C/*C instead of *C*C. The data have been validated and further examples for use added. The article has been corrected and Supplementary Appendix 2 replaced at NEJM.org.
PI-30 Kroetz, D. L.; Yu, Z.; Langaee, T. Y. ...
Clinical pharmacology and therapeutics,
02/2006, Letnik:
79, Številka:
2
Journal Article
Recenzirano
BACKGROUND/AIMS
CYP2J2 catalyzes the formation of epoxyeicosatrienoic acids (EETs) with antihypertensive properties. The effects of the EETs are attenuated through hydrolysis by soluble epoxide ...hydrolase (sEH encoded by EPHX2). This study examined whether genetic variants of CYP2J2 and EPHX2 with decreased function/expression in vitro are associated with hypertension (HTN).
METHODS
Hypertensive (HT; n=199) and normotensive (NT; n=125) African Americans (AA) and HT (n=187) and NT (n=175) Caucasians (CA) between 35–65 years of age were studied. NT had BP< 140/90 mmHg and no primary family history of HTN. The following variants were genotyped by pyrosequencing: in AA the 372C>T (Arg103Cys) and 925G>A (Arg287Gln) variants of EPHX2, and in AA and CA the CYP2J2*7 promoter allele. Minor allele frequencies (MAFs) were compared between NT and HT using a Chi‐square test and differences in blood pressure between genotype groups was compared with a t‐test.
RESULTS
The MAF (see Table) for the EPHX2 and CYP2J2 variants were similar in NT and HT. DBP and SBP were not associated with the EPHX2 or CYP2J2 genotypes or EPHX2 diplotypes.
EPHX2 372C>T
EPHX2 925G>A
CYP2J2*7
NT AA
11%
9.2%
12%
HT AA
9.6%
8.7%
12%
NT CA
8.6%
HT CA
8.8%
CONCLUSIONS
Functionally significant genetic variants of CYP2J2 and EPHX2 are not associated with HTN in AA and CA. The importance of these variants in the progression of cardiac endpoints associated with HTN is being investigated.
Clinical Pharmacology & Therapeutics (2005) 79, P15–P15; doi: 10.1016/j.clpt.2005.12.051
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