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

      research-article
      Author(s): a , † , b , † , c , † , a , a , e , a , g , d , d , e , i , j , g , k , l , m , n , k , o , b , g , k , b , e , p , q , r , t , l , u , v , w , i , s , x , x , h , a , e , f , x , k , *
      Publication date PMC-release:
      Journal: Lancet
      Publisher: Lancet Publishing Group

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          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 C YP2C9*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.

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          Most cited references24

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          Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.

          Alan R Shuldiner, Jeffrey R O'Connell, Kevin P Bliden … (2009)
          Clopidogrel therapy improves cardiovascular outcomes in patients with acute coronary syndromes and following percutaneous coronary intervention by inhibiting adenosine diphosphate (ADP)-dependent platelet activation. However, nonresponsiveness is widely recognized and is related to recurrent ischemic events. To identify gene variants that influence clopidogrel response. In the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study (2006-2008), we administered clopidogrel for 7 days to 429 healthy Amish persons and measured response by ex vivo platelet aggregometry. A genome-wide association study was performed followed by genotyping the loss-of-function cytochrome P450 (CYP) 2C19*2 variant (rs4244285). Findings in the PAPI Study were extended by examining the relation of CYP2C19*2 genotype to platelet function and cardiovascular outcomes in an independent sample of 227 patients undergoing percutaneous coronary intervention. ADP-stimulated platelet aggregation in response to clopidogrel treatment and cardiovascular events. Platelet response to clopidogrel was highly heritable (h(2) = 0.73; P < .001). Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance (P = 1.5 x 10(-13) for rs12777823, additive model). The rs12777823 polymorphism was in strong linkage disequilibrium with the CYP2C19*2 variant, and was associated with diminished clopidogrel response, accounting for 12% of the variation in platelet aggregation to ADP (P = 4.3 x 10(-11)). The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention (P = .02). Furthermore, patients with the CYP2C19*2 variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death during 1 year of follow-up (hazard ratio, 2.42; 95% confidence interval, 1.18-4.99; P = .02). CYP2C19*2 genotype was associated with diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes.
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            Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation.

            Elaine Hylek, Carmella Evans-Molina, Carol Shea … (2007)
            Warfarin is effective in the prevention of stroke in atrial fibrillation but is under used in clinical care. Concerns exist that published rates of hemorrhage may not reflect real-world practice. Few patients > or = 80 years of age were enrolled in trials, and studies of prevalent use largely reflect a warfarin-tolerant subset. We sought to define the tolerability of warfarin among an elderly inception cohort with atrial fibrillation. Consecutive patients who started warfarin were identified from January 2001 to June 2003 and followed for 1 year. Patients had to be > or = 65 years of age, have established care at the study institution, and have their warfarin managed on-site. Outcomes included major hemorrhage, time to termination of warfarin, and reason for discontinuation. Of 472 patients, 32% were > or = 80 years of age, and 91% had > or = 1 stroke risk factor. The cumulative incidence of major hemorrhage for patients > or = 80 years of age was 13.1 per 100 person-years and 4.7 for those or = 80 years, and international normalized ratio (INR) > or = 4.0 were associated with increased risk despite trial-level anticoagulation control. Within the first year, 26% of patients > or = 80 years of age stopped taking warfarin. Perceived safety issues accounted for 81% of them. Rates of major hemorrhage and warfarin termination were highest among patients with CHADS2 scores (an acronym for congestive heart failure, hypertension, age > or = 75, diabetes mellitus, and prior stroke or transient ischemic attack) of > or = 3. Rates of hemorrhage derived from younger noninception cohorts underestimate the bleeding that occurs in practice. This finding coupled with the short-term tolerability of warfarin likely contributes to its underutilization. Stroke prevention among elderly patients with atrial fibrillation remains a challenging and pressing health concern.
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              Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation.

              Elaine Hylek, Alan S Go, Yuchiao Chang … (2003)
              The incidence of stroke in patients with atrial fibrillation is greatly reduced by oral anticoagulation, with the full effect seen at international normalized ratio (INR) values of 2.0 or greater. The effect of the intensity of oral anticoagulation on the severity of atrial fibrillation-related stroke is not known but is central to the choice of the target INR. We studied incident ischemic strokes in a cohort of 13,559 patients with nonvalvular atrial fibrillation. Strokes were identified through hospitalization data bases and validated on the basis of medical records, which also provided information on the use of warfarin or aspirin, the INR at admission, and coexisting illnesses. The severity of stroke was graded according to a modified Rankin scale. Thirty-day mortality was ascertained from hospitalization and mortality files. Of 596 ischemic strokes, 32 percent occurred during warfarin therapy, 27 percent during aspirin therapy, and 42 percent during neither type of therapy. Among patients who were taking warfarin, an INR of less than 2.0 at admission, as compared with an INR of 2.0 or greater, independently increased the odds of a severe stroke in a proportional-odds logistic-regression model (odds ratio, 1.9; 95 percent confidence interval, 1.1 to 3.4) across three severity categories and the risk of death within 30 days (hazard ratio, 3.4; 95 percent confidence interval, 1.1 to 10.1). An INR of 1.5 to 1.9 at admission was associated with a mortality rate similar to that for an INR of less than 1.5 (18 percent and 15 percent, respectively). The 30-day mortality rate among patients who were taking aspirin at the time of the stroke was similar to that among patients who were taking warfarin and who had an INR of less than 2.0. Among patients with nonvalvular atrial fibrillation, anticoagulation that results in an INR of 2.0 or greater reduces not only the frequency of ischemic stroke but also its severity and the risk of death from stroke. Our findings provide further evidence against the use of lower INR target levels in patients with atrial fibrillation. Copyright 2003 Massachusetts Medical Society
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                Author and article information

                Contributors
                Julie A Johnson
                Journal
                Journal ID (nlm-ta): Lancet
                Journal ID (iso-abbrev): Lancet
                Title: Lancet
                Publisher: Lancet Publishing Group
                ISSN (Print): 0140-6736
                ISSN (Electronic): 1474-547X
                Publication date PMC-release: 31 August 2013
                Publication date (Print): 31 August 2013
                Volume: 382
                Issue: 9894
                Pages: 790-796
                Affiliations
                [a ]Section of Genetic Medicine, Department of Medicine, University of Chicago, IL, USA
                [b ]Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL, USA
                [c ]Department of Neurology and Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
                [d ]Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA
                [e ]Department of Bioengineering, Stanford University, Stanford, CA, USA
                [f ]Department of Genetics, Stanford University, Stanford, CA, USA
                [g ]Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA
                [h ]Department of Medicine and Department of Pharmacology, Vanderbilt University, Nashville, TN, USA
                [i ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK
                [j ]Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan
                [k ]Center for Pharmacogenomics, Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA
                [l ]Department of Genetics and Genomics Sciences, Mount Sinai School of Medicine, New York, NY, USA
                [m ]The Zena and Michael A Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY, USA
                [n ]Pharmaceutical Sciences Section, College of Pharmacy, Qatar University, Doha, Qatar
                [o ]Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
                [p ]Aurora St Luke's Medical Center, Milwaukee, WI, USA
                [q ]Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill; Chapel Hill, NC, USA
                [r ]Department of Genetics, University of North Carolina at Chapel Hill; Chapel Hill, NC, USA
                [s ]School of Pharmacy, University of North Carolina at Chapel Hill; Chapel Hill, NC, USA
                [t ]Department of Genome Sciences, University of Washington, Seattle, WA, USA
                [u ]Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA
                [v ]Marshfield Clinic Research Foundation, Marshfield, WI, USA
                [w ]Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden
                [x ]RIKEN Center for Genomic Medicine, Yokohama, Japan
                Author notes
                [* ]Correspondence to: Prof Julie A Johnson, Center for Pharmacogenomics, Department of Pharmacotherapy and Translational Research, University of Florida, Box 100486, Gainesville, FL 32610–0486, USA johnson@ 123456cop.ufl.edu
                [†]

                Contributed equally

                Article
                Publisher ID: S0140-6736(13)60681-9
                DOI: 10.1016/S0140-6736(13)60681-9
                PMC ID: 3759580
                PubMed ID: 23755828
                SO-VID: 7897c864-bc07-4d53-93dd-7328b84dad71
                Copyright © © 2013 Elsevier Ltd. All rights reserved.
                License:

                This document may be redistributed and reused, subject to certain conditions.

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