Genetic variants associated with warfarin dose in African-American individuals

A genome-wide association study

Minoli A. Perera, Larisa H. Cavallari, Nita A. Limdi, Eric R. Gamazon, Anuar Konkashbaev, Roxana Daneshjou, Anna Pluzhnikov, Dana C. Crawford, Jelai Wang, Nianjun Liu, Nicholas Tatonetti, Stephane Bourgeois, Harumi Takahashi, Yukiko Bradford, Benjamin M. Burkley, Robert J. Desnick, Jonathan L. Halperin, Sherief I. Khalifa, Taimour Y. Langaee, Steven A. Lubitz & 22 others Edith A. Nutescu, Matthew Oetjens, Mohamed H. Shahin, Shitalben R. Patel, Hersh Sagreiya, Matthew Tector, Karen E. Weck, Mark J. Rieder, Stuart A. Scott, Alan H.B. Wu, James K. Burmester, Mia Wadelius, Panos Deloukas, Michael J. Wagner, Taisei Mushiroda, Michiaki Kubo, Dan M. Roden, Nancy J. Cox, Russ B. Altman, Teri E. Klein, Yusuke Nakamura, Julie A. Johnson

Research output: Contribution to journalArticle

138 Citations (Scopus)

Abstract

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 fi rst for VKORC1 -1639G?A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecifi ed a genome-wide signifi cance 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 prespecifi ed conditioning in the discovery cohort, we identifi ed an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide signifi cance (p=1·51×10-8). This association was confi rmed 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 eff ect 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.

Original languageEnglish
Pages (from-to)790-796
Number of pages7
JournalThe Lancet
Volume382
Issue number9894
DOIs
Publication statusPublished - 01-01-2013

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Genome-Wide Association Study
Warfarin
African Americans
Pharmacogenetics
Single Nucleotide Polymorphism
Genome
Chromosomes, Human, Pair 10
National Institutes of Health (U.S.)
Cohort Studies
Alleles
Genotype
Regression Analysis
Cytochrome P-450 CYP2C9

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Perera, M. A., Cavallari, L. H., Limdi, N. A., Gamazon, E. R., Konkashbaev, A., Daneshjou, R., ... Johnson, J. A. (2013). Genetic variants associated with warfarin dose in African-American individuals: A genome-wide association study. The Lancet, 382(9894), 790-796. https://doi.org/10.1016/S0140-6736(13)60681-9
Perera, Minoli A. ; Cavallari, Larisa H. ; Limdi, Nita A. ; Gamazon, Eric R. ; Konkashbaev, Anuar ; Daneshjou, Roxana ; Pluzhnikov, Anna ; Crawford, Dana C. ; Wang, Jelai ; Liu, Nianjun ; Tatonetti, Nicholas ; Bourgeois, Stephane ; Takahashi, Harumi ; Bradford, Yukiko ; Burkley, Benjamin M. ; Desnick, Robert J. ; Halperin, Jonathan L. ; Khalifa, Sherief I. ; Langaee, Taimour Y. ; Lubitz, Steven A. ; Nutescu, Edith A. ; Oetjens, Matthew ; Shahin, Mohamed H. ; Patel, Shitalben R. ; Sagreiya, Hersh ; Tector, Matthew ; Weck, Karen E. ; Rieder, Mark J. ; Scott, Stuart A. ; Wu, Alan H.B. ; Burmester, James K. ; Wadelius, Mia ; Deloukas, Panos ; Wagner, Michael J. ; Mushiroda, Taisei ; Kubo, Michiaki ; Roden, Dan M. ; Cox, Nancy J. ; Altman, Russ B. ; Klein, Teri E. ; Nakamura, Yusuke ; Johnson, Julie A. / Genetic variants associated with warfarin dose in African-American individuals : A genome-wide association study. In: The Lancet. 2013 ; Vol. 382, No. 9894. pp. 790-796.
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abstract = "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 fi rst for VKORC1 -1639G?A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecifi ed a genome-wide signifi cance 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 prespecifi ed conditioning in the discovery cohort, we identifi ed an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide signifi cance (p=1·51×10-8). This association was confi rmed 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 eff ect 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.",
author = "Perera, {Minoli A.} and Cavallari, {Larisa H.} and Limdi, {Nita A.} and Gamazon, {Eric R.} and Anuar Konkashbaev and Roxana Daneshjou and Anna Pluzhnikov and Crawford, {Dana C.} and Jelai Wang and Nianjun Liu and Nicholas Tatonetti and Stephane Bourgeois and Harumi Takahashi and Yukiko Bradford and Burkley, {Benjamin M.} and Desnick, {Robert J.} and Halperin, {Jonathan L.} and Khalifa, {Sherief I.} and Langaee, {Taimour Y.} and Lubitz, {Steven A.} and Nutescu, {Edith A.} and Matthew Oetjens and Shahin, {Mohamed H.} and Patel, {Shitalben R.} and Hersh Sagreiya and Matthew Tector and Weck, {Karen E.} and Rieder, {Mark J.} and Scott, {Stuart A.} and Wu, {Alan H.B.} and Burmester, {James K.} and Mia Wadelius and Panos Deloukas and Wagner, {Michael J.} and Taisei Mushiroda and Michiaki Kubo and Roden, {Dan M.} and Cox, {Nancy J.} and Altman, {Russ B.} and Klein, {Teri E.} and Yusuke Nakamura and Johnson, {Julie A.}",
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Perera, MA, Cavallari, LH, Limdi, NA, Gamazon, ER, Konkashbaev, A, Daneshjou, R, Pluzhnikov, A, Crawford, DC, Wang, J, Liu, N, Tatonetti, N, Bourgeois, S, Takahashi, H, Bradford, Y, Burkley, BM, Desnick, RJ, Halperin, JL, Khalifa, SI, Langaee, TY, Lubitz, SA, Nutescu, EA, Oetjens, M, Shahin, MH, Patel, SR, Sagreiya, H, Tector, M, Weck, KE, Rieder, MJ, Scott, SA, Wu, AHB, Burmester, JK, Wadelius, M, Deloukas, P, Wagner, MJ, Mushiroda, T, Kubo, M, Roden, DM, Cox, NJ, Altman, RB, Klein, TE, Nakamura, Y & Johnson, JA 2013, 'Genetic variants associated with warfarin dose in African-American individuals: A genome-wide association study', The Lancet, vol. 382, no. 9894, pp. 790-796. https://doi.org/10.1016/S0140-6736(13)60681-9

Genetic variants associated with warfarin dose in African-American individuals : A genome-wide association study. / Perera, Minoli A.; Cavallari, Larisa H.; Limdi, Nita A.; Gamazon, Eric R.; Konkashbaev, Anuar; Daneshjou, Roxana; Pluzhnikov, Anna; Crawford, Dana C.; Wang, Jelai; Liu, Nianjun; Tatonetti, Nicholas; Bourgeois, Stephane; Takahashi, Harumi; Bradford, Yukiko; Burkley, Benjamin M.; Desnick, Robert J.; Halperin, Jonathan L.; Khalifa, Sherief I.; Langaee, Taimour Y.; Lubitz, Steven A.; Nutescu, Edith A.; Oetjens, Matthew; Shahin, Mohamed H.; Patel, Shitalben R.; Sagreiya, Hersh; Tector, Matthew; Weck, Karen E.; Rieder, Mark J.; Scott, Stuart A.; Wu, Alan H.B.; Burmester, James K.; Wadelius, Mia; Deloukas, Panos; Wagner, Michael J.; Mushiroda, Taisei; Kubo, Michiaki; Roden, Dan M.; Cox, Nancy J.; Altman, Russ B.; Klein, Teri E.; Nakamura, Yusuke; Johnson, Julie A.

In: The Lancet, Vol. 382, No. 9894, 01.01.2013, p. 790-796.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic variants associated with warfarin dose in African-American individuals

T2 - A genome-wide association study

AU - Perera, Minoli A.

AU - Cavallari, Larisa H.

AU - Limdi, Nita A.

AU - Gamazon, Eric R.

AU - Konkashbaev, Anuar

AU - Daneshjou, Roxana

AU - Pluzhnikov, Anna

AU - Crawford, Dana C.

AU - Wang, Jelai

AU - Liu, Nianjun

AU - Tatonetti, Nicholas

AU - Bourgeois, Stephane

AU - Takahashi, Harumi

AU - Bradford, Yukiko

AU - Burkley, Benjamin M.

AU - Desnick, Robert J.

AU - Halperin, Jonathan L.

AU - Khalifa, Sherief I.

AU - Langaee, Taimour Y.

AU - Lubitz, Steven A.

AU - Nutescu, Edith A.

AU - Oetjens, Matthew

AU - Shahin, Mohamed H.

AU - Patel, Shitalben R.

AU - Sagreiya, Hersh

AU - Tector, Matthew

AU - Weck, Karen E.

AU - Rieder, Mark J.

AU - Scott, Stuart A.

AU - Wu, Alan H.B.

AU - Burmester, James K.

AU - Wadelius, Mia

AU - Deloukas, Panos

AU - Wagner, Michael J.

AU - Mushiroda, Taisei

AU - Kubo, Michiaki

AU - Roden, Dan M.

AU - Cox, Nancy J.

AU - Altman, Russ B.

AU - Klein, Teri E.

AU - Nakamura, Yusuke

AU - Johnson, Julie A.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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 fi rst for VKORC1 -1639G?A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecifi ed a genome-wide signifi cance 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 prespecifi ed conditioning in the discovery cohort, we identifi ed an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide signifi cance (p=1·51×10-8). This association was confi rmed 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 eff ect 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.

AB - 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 fi rst for VKORC1 -1639G?A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecifi ed a genome-wide signifi cance 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 prespecifi ed conditioning in the discovery cohort, we identifi ed an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide signifi cance (p=1·51×10-8). This association was confi rmed 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 eff ect 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=84883135237&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(13)60681-9

DO - 10.1016/S0140-6736(13)60681-9

M3 - Article

VL - 382

SP - 790

EP - 796

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 9894

ER -

Perera MA, Cavallari LH, Limdi NA, Gamazon ER, Konkashbaev A, Daneshjou R et al. Genetic variants associated with warfarin dose in African-American individuals: A genome-wide association study. The Lancet. 2013 Jan 1;382(9894):790-796. https://doi.org/10.1016/S0140-6736(13)60681-9