Novel CYP2C9 and VKORC1 Gene Variants Associated with Warfarin Dosage Variability in the South African Black Population

Abstract

Aim: Warfarin is a widely used therapeutic agent for long-term oral anticoagulation worldwide. Its administration is challenging owing to its narrow therapeutic range and serious adverse effects. Several environmental factors and numerous genes, of which CYP2C9 and VKORC1 are the most important, have been associated with interindividual dosage variability. Many studies have been conducted to understand warfarin dosage variability better, the majority of which have been focused on the Caucasian and African–American populations. Very little information is available regarding genetic influences of warfarin dosage variability in the South African black population. Materials & methods: In this study, we genotyped 213 South African black individuals for CYP2C9 and VKORC1 variants and a small subset of environmental factors that may be responsible for warfarin dosage variability. Results: We observed 26 novel SNPs and seven previously described CYP2C9 variants and three previously described but no novel VKORC1 SNPs. Only 11 of the CYP2C9 variants and two of the VKORC1 variants were observed at high enough allele frequencies to assess their impact on warfarin dosage. Conclusion: We demonstrate that CYP2C9*8 and two novel CYP2C9 SNPs (g.16179 and g.46028) are associated with a decrease in warfarin dosage, β-blockers are independently associated with a decrease in warfarin dosage and two known VKORC1 variants (rs7200749 and rs7294) are associated with an increase in warfarin dosage. The CYP2C9 and VKORC1 variants and a small subset of environmental factors used in the study explain approximately 45% of warfarin dosage variability in the South African black population.

Original submitted 11 January 2011; Revision submitted 21 February 2011

KEYWORDS::

• CYP2C9
• VKORC1
• warfarin

Acknowledgements

The authors would like to acknowledge Thandi Zwane, an MRC research assistant at the National Health Laboratory Service in Johannesburg, South Africa, for collecting all the blood samples and medical information from all of the patients used in this study; Lize van der Merwe for assistance with the statistics and editing of the paper and Zane Lombard for information regarding the rs9923231 VKORC1 variant, proofreading and editing of the paper.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.