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Genetic Variants Associated With Warfarin Dose in African-American Individuals: A Genome-Wide Association Study
Study Questions:
What are the genetic variants contributing to warfarin dose requirements in African Americans?
Methods:
The authors did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (ages ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham. Patients enrolled at IWPC sites, but who were not used for discovery made up the independent replication cohort. All participants were genotyped. The investigators did a stepwise conditional analysis, conditioning first for VKORC1 –1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. They prespecified a genome-wide significance threshold of p < 5 × 10–8 in the discovery cohort and p < 0.0038 in the replication cohort.
Results:
The discovery cohort contained 533 participants, and the replication cohort contained 432 participants. After the prespecified conditioning in the discovery cohort, the authors identified an association between a novel single nucleotide polymorphism (SNP) in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p = 1.51 × 10–8). This association was confirmed in the replication cohort (p = 5.04 × 10–5); analysis of the two cohorts together produced a p value of 4.5 × 10–12. Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6.92 mg/wk and those homozygous, 9.34 mg/wk. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement).
Conclusions:
The authors concluded that a novel CYP2C SNP exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3.
Perspective:
The study suggests that VKORC1 genotype is the primary genetic determinant of variability in warfarin dose requirements in African Americans. A SNP upstream of CYP2C18, rs12777823, was significantly associated with warfarin dose requirement in African Americans, and was independent of previous associations with VKORC1 and CYP2C9. These findings suggest that warfarin dose variability is affected by variants other than the well-established VKORC1 and CYP2C9 ones in African Americans, and these new variants could potentially improve dose prediction in these individuals. Ongoing randomized controlled trials (COAG and EU-PACT) are assessing the clinical utility of genotype-guided warfarin dosing, and will define their future role.
Keywords: Chromosomes, Human, Pair 10, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Warfarin, United States
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