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. AY587020⁶ ), *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 

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.