Journal of Applied Genetics

, Volume 55, Issue 2, pp 163–171 | Cite as

The VKORC1 Asp36Tyr variant and VKORC1 haplotype diversity in Ashkenazi and Ethiopian populations

  • Sophia Sominsky
  • Michael Korostishevsky
  • Daniel Kurnik
  • Eleni Aklillu
  • Yoram Cohen
  • Gie Ken-Dror
  • Ronen Loebstein
  • Hillel Halkin
  • Eva GakEmail author
Human Genetics • Original Paper


The vitamin K epoxide reductase (VKORC1) is a key enzyme in the vitamin K cycle impacting various biological processes. VKORC1 genetic variability has been extensively studied in the context of warfarin pharmacogenetics revealing different distributions of VKORC1 haplotypes in various populations. We previously identified the VKORC1 Asp36Tyr mutation that was associated with warfarin resistance and with distinctive ethnic distribution. In this study, we performed haplotype analysis using Asp36Tyr and seven other VKORC1 markers in Ashkenazi and Ethiopian-Jewish and non-Jewish individuals. The VKORC1 variability was represented by nine haplotypes (V1-V9) that could be grouped into two distinct clusters (V1-V3 and V4-V9) with intra-cluster difference limited to two nucleotide changes. Phylogeny analysis suggested that these haplotypes could have developed from an ancestral variant, the common V8 haplotype (40 % in all population samples), after ten single mutation events. Asp36Tyr was exclusive to the V5 haplotype of the second cluster. Two haplotypes V5 and V4, distinguished only by Asp36Tyr, were prevalent in both Ethiopian population samples. The V2 haplotype, belonging to the first cluster, was the second most prevalent haplotype in the Ashkenazi population sample (15.8 %) but relatively uncommon in the Ethiopian origin (4.5-4.7 %). We discuss the genetic diversity among studied populations and its potential impact on warfarin-dose management in certain populations of African and European origin.


Allele frequencies Gene flow Haplotype analysis Population genetics Warfarin (Coumarin) resistance 



We thank Dr. Collen Masimirembwa and his group for providing DNA samples from the African Biobank.


This study was supported by the Israeli Ministry of Industry Nofar program #39410. This study was performed in partial fulfilment of the requirements for Ms Sominsky’s M.Sc. thesis, submitted to the Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Israel.

Conflict of interest

Dr. Gak holds a 40 % stake in patent PCT application no. WO2007IL00405, filed in March 2007, entitled “Methods and kits for determining predisposition to warfarin resistance”, which includes the VKORC1 D36Y variant. None of the other authors have any conflicts of interest to report.


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Copyright information

© Institute of Plant Genetics, Polish Academy of Sciences, Poznan 2014

Authors and Affiliations

  • Sophia Sominsky
    • 1
  • Michael Korostishevsky
    • 2
  • Daniel Kurnik
    • 3
    • 7
  • Eleni Aklillu
    • 5
  • Yoram Cohen
    • 6
  • Gie Ken-Dror
    • 4
  • Ronen Loebstein
    • 3
    • 7
  • Hillel Halkin
    • 3
    • 7
  • Eva Gak
    • 1
    Email author
  1. 1.Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  2. 2.Department of Anatomy and Anthropology, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.Department of Internal Medicine, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  4. 4.Department of Epidemiology, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  5. 5.Division of Clinical Pharmacology, Department of Laboratory MedicineKarolinska InstituteStockholmSweden
  6. 6.Cancer Research Center, Sheba Medical CenterTel HashomerIsrael
  7. 7.Institute of Clinical Pharmacology and Toxicology, Sheba Medical CenterTel HashomerIsrael

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