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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3903-3904. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Aklillu, E. Articles by Gak, E. Search for Related Content PubMed PubMed Citation Articles by Aklillu, E. Articles by Gak, E. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CORRESPONDENCE VKORC1 Asp36Tyr warfarin resistance marker is common in Ethiopian individuals To the editor: Warfarin is the mainstay of oral anticoagulation worldwide. However, its use is complicated by a narrow therapeutic index with potentially severe adverse effects and high interindividual variability in dose requirements. The explanation for this variability is multifactorial and determined by genetic factors, concomitant drugs, age, diet, and race. African-American patients are more warfarin resistant than whites, while Chinese and Japanese are mostly warfarin sensitive.1,2 Extensive research in this field yielded several important genetic markers of warfarin dose response, predominantly including markers of warfarin sensitivity caused by common polymorphisms in the major warfarin target gene VKORC1 and its metabolizing enzyme CYP2C9. We previously reported that a coding VKORC1 Asp36Tyr polymorphism is yet another important marker, specifically indicative of warfarin resistance. Asp36Tyr was relatively common (4% of the patients) and was significantly overrepresented in patients with higher warfarin dose requirements (> 70 mg/week; odds ratio 13.0; 95% confidence limit 1.3-124.2).3 We also found that Asp36Tyr was exceptionally common in Jews of Ethiopian origin (allele frequency 15%) and to lesser extent in Ashkenazi Jews (4%). In all carriers and homozygotes, Asp36Tyr was related to the ancestral VKORC1*1 haplotype.4 The major drawback of this study was its innate biasing inclusion of patients and individuals from the Jewish population. We presently report that Asp36Tyr is also found in Ethiopian non-Jewish individuals with the same allele frequency (15%) and on the background of the same haplotype, VKORC1*1. This study was approved by the ethics committee of Karolinska Institutet and informed consent was obtained in accordance with the Declaration of Helsinki. While screening a series of 154 Ethiopian individuals for the presence of Asp36Tyr using RsaI restriction fragment length polymorphism (RFLP) analysis, we discovered 39 heterozygotes and 3 homozygotes. Table 1 shows previous data on the distribution of CYP2C9*2 and *3 variants of warfarin sensitivity in the same series,5 together with the present findings on the VKORC1 Asp36Tyr polymorphism. Distributions of all alleles were consistent with the Hardy-Weinberg equilibrium. Further direct sequence analysis of Asp36Tyr homozygotes excluded the presence of VKORC1*2 (6484T according to VKORC1 Acc. Num. AY587020 [GenBank] 6), *3 (9041A) and *4 (6009T) markers, thus by default supporting the presence of the VKORC1*1 haplotype together with Asp36Tyr (5417T). The VKORC1*1 wild type haplotype was previously reported to be a variant exclusively characteristic of individuals of African descent.4 View this table: [in this window] [in a new window]   Table 1. Distribution of genotypes of CYP2C9*2, *3 and VKORC1 Asp36Tyr genotypes in Ethiopians   We hope that our findings will prompt further research of this polymorphism in other ethnic groups of African origin and African-Americans in particular. We hypothesize that Asp36Tyr may be relevant to other population groups of whom warfarin resistance is characteristic, such as Indians.7 The issue of incompatibility of present knowledge with prediction of warfarin dose response in patients of African origin has been raised in several recent studies.8–10 It has been suggested that African ethnic groups preserve specific characteristic polymorphisms that are rare in other populations. We presently suggest that the VKORC1 Asp36Tyr polymorphism is one such candidate. Our previous findings suggested that Asp36Tyr is a dominant factor overriding the dose-reducing effects of other known CYP2C9 and VKORC1 markers and contributing as much as 18% to warfarin dose-response variability.3 We believe that inclusion of the VKORC1 Asp36Tyr marker in the future pharmacogenetic approach to personalized warfarin therapy is important, particularly for prevention of risks of rethrombosis. Authorship Contribution: E.A. provided and previously characterized the Ethiopian samples. C.L. performed the polymorphism analysis. R.L. and H.H. contributed to the study design, E.G. designed the research and wrote the manuscript. Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Eva Gak, Genetics Institute, Sheba Medical Center, Tel Hashomer 52621, Israel; e-mail: Eva.Gak{at}sheba.health.gov.il. Eleni Aklillu, Cheryl Leong, Ronen Loebstein, Hillel Halkin, and Eva Gak References Absher RK, Moore ME, Parker MH. Patient-specific factors predictive of warfarin dosage requirements. Ann Pharmacother 2002; 36:1512–1517.[Abstract] Takahashi H, Wilkinson GR, Nutescu EA, et al. Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics 2006; 16:101–110.[Medline] [Order article via Infotrieve] Loebstein R, Dvoskin I, Halkin H, et al. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood 2007; 109:2477–2480.[Abstract/Free Full Text] Geisen C, Watzka M, Sittinger K, et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost 2005; 94:773–779.[Medline] [Order article via Infotrieve] Scordo G, Aklillu E, Yasar Ü, Dahl M, Spina E, Ingelman-Sundberg M. Genetic polymorphism of Cytochrome P450 2C9 in a Caucasian and a Black-African population. Br J Clin Pharmacol 2001; 52:447–450.[CrossRef][Medline] [Order article via Infotrieve] National Center for Biotechnology Information. GenBank. http://www.ncbi.nlm.gov/sites/entrez Accessed February 2008. Gan GG, Teh A, Goh KY, et al. Racial background is a determinant factor in the maintenance dosage of warfarin. Int J Hematol 2003; 78:84–86.[Medline] [Order article via Infotrieve] Kealey C, Chen Z, Christie J, et al. Warfarin and cytochrome P450 2C9 genotype: possible ethnic variation in warfarin sensitivity. Pharmacogenomics 2007; 8:217–225.[CrossRef][Medline] [Order article via Infotrieve] Schelleman H, Chen Z, Kealey C, et al. Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians. Clin Pharmacol Ther 2007; 81:742–747.[CrossRef][Medline] [Order article via Infotrieve] Kimmel SE, Christie J, Kealey C, et al. Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans. Pharmacogenomics J 2008; 8:53–60.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Aklillu, E. Articles by Gak, E. Search for Related Content PubMed PubMed Citation Articles by Aklillu, E. Articles by Gak, E. Social Bookmarking                   What's this?

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