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

Minoli A Perera PharmD a †, Larisa H Cavallari PharmD b †, Nita A Limdi PharmD c †, Eric R Gamazon MS a, Anuar Konkashbaev MS a, Roxana Daneshjou BS e, Anna Pluzhnikov PhD a, Dana C Crawford PhD g, Jelai Wang BS d, Nianjun Liu PhD d, Nicholas Tatonetti PhD e, Stephane Bourgeois MS i, Prof Harumi Takahashi PhD j, Yukiko Bradford MS g, Benjamin M Burkley MS k, Prof Robert J Desnick MD l, Prof Jonathan L Halperin m, Prof Sherief I Khalifa n, Taimour Y Langaee PhD k, Steven A Lubitz MD o, Prof Edith A Nutescu PharmD b, Matthew Oetjens BS g, Mohamed H Shahin MS k, Shitalben R Patel MS b, Hersh Sagreiya MD e, Matthew Tector PhD p, Prof Karen E Weck MD q r, Mark J Rieder PhD t, Stuart A Scott PhD l, Alan HB Wu PhD u, James K Burmester PhD v, Mia Wadelius MD w, Panos Deloukas PhD i, Michael J Wagner PhD s, Taisei Mushiroda PhD x, Michiaki Kubo MD x, Prof Dan M Roden MD h, Prof Nancy J Cox PhD a, Prof Russ B Altman MD e, Teri E Klein PhD f, Prof Yusuke Nakamura MD x, Prof Julie A Johnson PharmD k

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.

Network for Health Research, and the Wellcome Trust.