Key result
CYP4F2 rs2108622 variant is linked to ~15% lower INR variability in European-Americans on warfarin.
Why the study?
Do genetic variants in CYP2C9, VKORC1, CYP4F2, GGCX, EPHX1, and CALU affect INR variability and time in therapeutic range after the warfarin dose-titration phase in African-Americans and European-Americans?
Observational (n=1,083)
No
Do genetic variants in CYP2C9, VKORC1, CYP4F2, GGCX, EPHX1, and CALU affect INR variability and time in therapeutic range after the warfarin dose-titration phase in African-Americans and European-Americans?
Genetic variants in CYP4F2 and GGCX differentially affect the stability of anticoagulation after the warfarin dose-titration phase in European-Americans and African-Americans, respectively.
Ancestry-specific variants may influence post-titration warfarin stability; leaves open validation before incorporation into dosing algorithms.
OBJECTIVES: Genetic factors contribute considerably toward variability in warfarin dose requirements and are important in the dose-titration phase; their effects on the stability of anticoagulation later in therapy are not known. METHODS: Using deidentified electronic medical records linked to a DNA-biobank, we studied 140 African-Americans and 943 European-Americans after the warfarin dose-titration phase. We genotyped 12 single nucleotide polymorphisms in genes (CYP2C9, VKORC1, CYP4F2, GGCX, EPHX1, CALU) associated with altered warfarin dose requirements and tested their associations with international normalized ratio variability (INRVAR) and percent time in therapeutic range in European-Americans and African-Americans. RESULTS: One allele copy of rs2108622 in CYP4F2 was associated with a 15% [95% confidence interval (CI): 1-26, P=0.03] decrease in the median INRVAR in European-Americans. In African-Americans, GGCX variants rs11676382 and rs699664 were associated with 4.16-fold (95% CI: 1.45-11.97, P=0.009) and 1.50-fold (95% CI: 1.07-2.08, P=0.02) changes in the median INRVAR per variant allele copy, respectively; rs11676382 was also significantly associated with a 23.19% (95% CI: 5.89-40.48, P=0.01) decrease in time in therapeutic range. The total variation in INRVAR explained by both clinical factors and rs2108622 was 5.2% for European-Americans. In African-Americans, the inclusion of GGCX variants rs11676382 and rs699664, and the CYP2C9*8 variant rs7900194 explained ∼29% of the variation in INRVAR. CONCLUSION: The stability of anticoagulation after the warfarin dose-titration phase is differentially affected by variants in CYP4F2 in European-Americans and GGCX loci in African-Americans.
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Iwuchukwu et al. (2016) conducted an observational in Patients on long-term warfarin therapy (n=1,083). Genetic variants in CYP4F2 (rs2108622) and GGCX (rs11676382, rs699664) vs. Wild-type/major allele genotypes was evaluated on International normalized ratio variability (INRVAR) after the warfarin dose-titration phase in European-Americans (15% decrease, 95% CI 1-26, p=0.03). The CYP4F2 variant rs2108622 was associated with a 15% decrease in median INR variability in European-Americans, while GGCX variants were associated with up to a 4.16-fold increase in African-Americans on long-term warfarin.
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