Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study

Abstract

Summary Background VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. Methods We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥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 (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 −1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p<5×10−8 in the discovery cohort and p<0·0038 in the replication cohort. Findings The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism 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/week and those homozygous 9·34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). Interpretation A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3. Incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population. Funding National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust.

Priority pharmacogenetics for the African continent: focus on CYP450

“…Considering that CYP2C9*2 and *3 are present at low frequencies in populations of Bantu/Niger-Congo origin, it is recommended that the pharmacogenetics of this enzyme be investigated in more detail in the sub-Saharan region. This is supported by the recent report by Perera and colleagues [50], in which a novel and independent predictor of warfarin metabolism in Africa Americans was identified by means of genome wide association studies. The single nucleotide polymorphism, which is present in the CYP2C cluster, was significantly associated with the need for a dose reduction of warfarin.…”

Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity

“…These associations were also confirmed by several genome-wide studies [Takeuchi et al, 2009;Perera et al, 2013;Parra et al, 2015].…”

Warfarin pharmacogenomics and African ancestry

“…Platelets contain 4 major v-SNAREs (vesicle-associated membrane protein-2, -3, -7, and -8); each contributes to platelet function. 4,[5][6][7][8] is thought to be the dominant form, mediating the fast secretion events. VAMP-7 mediates secretion from a spatially distinct population of granules.…”

“…These data might also explain phenotypes where secretion in suspension is modestly affected but bleeding is significant. 8 Defects in secretion polarization may not be readily detected in suspension assays but could be critical in vivo. The most exciting implication of this work is the realization that platelets are not only detecting biochemical changes in the vasculature, but are also deciphering spatial and physical cues.…”

“…The race-stratified genotype-guided dosing algorithm included recently discovered genetic variants that have been associated with warfarin response in African Americans. 7,8 Limdi et al's cohort was composed of 1357 participants, 44% of whom were African American. In this diverse cohort, the COAG algorithm (race-combined approach) demonstrated variability in usefulness based upon race.…”