We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

The future of warfarin pharmacogenetics in under-represented minority groups

    Larisa H Cavallari

    * Author for correspondence

    Department of Pharmacy Practice, University of Illinois at Chicago, College of Pharmacy, 833 South Wood Street, Room 164, Chicago, IL 60612-7230, USA.

    &
    Minoli A Perera

    Department of Medicine, University of Chicago, Chicago, IL, USA

    Published Online:https://doi.org/10.2217/fca.12.31

    Genotype-based dosing recommendations are provided in the US FDA-approved warfarin labeling. However, data that informed these recommendations were from predominately Caucasian populations. Studies show that variants contributing to warfarin dose requirements in Caucasians provide similar contributions to dose requirements in US Hispanics, but significantly lesser contributions in African–Americans. Further data demonstrate that variants occurring commonly in individuals of African ancestry, but rarely in other racial groups, significantly influence dose requirements in African–Americans. These data suggest that it is important to consider variants specific for African–Americans when implementing genotype-guided warfarin dosing in this population.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    References

    • Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with a trial fibrillation. Circulation115(21),2689–2696 (2007).
    • Hylek EM, Go AS, Chang Y et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N. Engl. J. Med.349(11),1019–1026 (2003).
    • Wadelius M, Chen LY, Lindh JD et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood113(4),784–792 (2009).
    • Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N. Engl. J. Med.365(21),2002–2012 (2011).
    • Ansell J, Hirsh J, Hylek E et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest133(Suppl. 6),S160–S198 (2008).
    • Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation107(12),1692–1711 (2003).
    • Klein TE, Altman RB, Eriksson N et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N. Engl. J. Med.360(8),753–764 (2009).
    • Absher RK, Moore ME, Parker MH. Patient-specific factors predictive of warfarin dosage requirements. Ann. Pharmacother.36(10),1512–1517 (2002).
    • Limdi NA, Limdi MA, Cavallari L et al. Warfarin dosing in patients with impaired kidney function. Am. J. Kidney Dis.56(5),823–831 (2010).
    • 10  Huang SW, Chen HS, Wang XQ et al. Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: a prospective study in Chinese patients. Pharmacogenet. Genomics19(3),226–234 (2009).
    • 11  Gage BF, Eby C, Johnson JA et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin. Pharmacol. Ther.84(3),326–331 (2008).
    • 12  Anderson JL, Horne BD, Stevens SM et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation116(22),2563–2570 (2007).
    • 13  Burmester JK, Berg RL, Yale SH et al. A randomized controlled trial of genotype-based coumadin initiation. Genet. Med.13(6),509–518 (2011).
    • 14  Rieder MJ, Reiner AP, Gage BF et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N. Engl. J. Med.352(22),2285–2293 (2005).
    • 15  Cooper GM, Johnson JA, Langaee TY et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood112(4),1022–1027 (2008).
    • 16  Cha PC, Mushiroda T, Takahashi A et al. Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese. Hum. Mol. Genet.19(23),4735–4744 (2011).
    • 17  Takeuchi F, McGinnis R, Bourgeois S et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet.5(3),E1000433 (2009).
    • 18  Limdi NA, Arnett DK, Goldstein JA et al. Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulation attainment and maintenance among European–Americans and African–Americans. Pharmacogenomics9(5),511–526 (2008).
    • 19  Scordo MG, Pengo V, Spina E et al. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin. Pharmacol. Ther.72(6),702–710 (2002).
    • 20  Takahashi H, Kashima T, Nomizo Y et al. Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes. Clin. Pharmacol. Ther.63(5),519–528 (1998).
    • 21  Cavallari LH, Langaee TY, Momary KM et al. Genetic and clinical predictors of warfarin dose requirements in African Americans. Clin. Pharmacol. Ther.87(4),459–464 (2010).▪ Demonstrates significantly lower warfarin dose requirements in African–Americans with the CYP2C9*8 allele.
    • 22  Limdi NA, McGwin G, Goldstein JA et al. Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African–American and European–American patients on warfarin. Clin. Pharmacol. Ther.83(2),312–321 (2007).▪ One of the largest studies evaluating bleeding risk conferred by the CYP2C9 and VKORC1 genotypes in both African–Americans and Caucasians. The investigators found that CYP2C9, but not VKORC1, influences bleeding risk.
    • 23  Rost S, Fregin A, Ivaskevicius V et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature427(6974),537–541 (2004).
    • 24  D’Andrea G, D’Ambrosio RL, Di Perna P et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood105(2),645–649 (2005).
    • 25  Wang D, Chen H, Momary KM et al. Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement. Blood112(4),1013–1021 (2008).
    • 26  Limdi NA, Wadelius M, Cavallari L et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood115(18),3827–3834 (2010).▪▪ Showed that the VKORC1 -1639G>A (or 1173C>T) single-nucleotide polymorphisms is predictive of warfarin dose requirements across racial groups, but provides lesser contributions to warfarin dose variability in African–Americans compared with Caucasians or Asians, largely because of its lower frequency in the former racial group.
    • 27  Coumadin ®, package insert. Bristol-Myers Squibb, Princeton, NJ, USA.
    • 28  Gage BF, Eby C, Milligan PE et al. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb. Haemost.91(1),87–94 (2004).
    • 29  Lenzini P, Wadelius M, Kimmel S et al. Integration of genetic, clinical, and INR data to refine warfarin dosing. Clin. Pharmacol. Ther.87(5),572–578 (2010).
    • 30  Horne BD, Lenzini PA, Wadelius M et al. Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb. Haemost.107(2),232–240 (2012).
    • 31  Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet353(9154),717–719 (1999).
    • 32  Lindh JD, Holm L, Andersson ML, Rane A. Influence of CYP2C9 genotype on warfarin dose requirements – a systematic review and meta-analysis. Eur. J. Clin. Pharmacol.65(4),365–375 (2009).
    • 33  Cavallari LH, Momary KM, Patel SR et al. Pharmacogenomics of warfarin dose requirements in Hispanics. Blood Cells Mol. Dis.46(2),147–150 (2011).▪ One of the only studies to examine warfarin pharmacogenetics in US Hispanics.
    • 34  Perera MA, Gamazon E, Cavallari LH et al. The missing association: sequencing-based discovery of novel SNPs in VKORC1 and CYP2C9 that affect warfarin dose in African Americans. Clin. Pharmacol. Ther.89(3),408–415 (2011).▪ The investigators identified novel CYP2C9 and VKORC1 variants associated with warfarin dose requirements in African–Americans through a targeted resequencing approach.
    • 35  Limdi NA, Beasley TM, Crowley MR et al.VKORC1 polymorphisms, haplotypes and haplotype groups on warfarin dose among African–Americans and European–Americans. Pharmacogenomics9(10),1445–1458 (2008).
    • 36  Marsh S, King CR, Porche-Sorbet RM, Scott-Horton TJ, Eby CS. Population variation in VKORC1 haplotype structure. J. Thromb. Haemost.4(2),473–474 (2006).
    • 37  Voora D, Koboldt DC, King CR et al. A polymorphism in the VKORC1 regulator calumenin predicts higher warfarin dose requirements in African Americans. Clin. Pharmacol. Ther.87(4),445–451 (2010).
    • 38  Cavallari LH, Perera M, Wadelius M et al. Association of the GGCX (CAA)16/17 repeat polymorphism with higher warfarin dose requirements in African Americans. Pharmacogenet. Genomics22(2),152–158 (2012).
    • 39  Caldwell MD, Awad T, Johnson JA et al.CYP4F2 genetic variant alters required warfarin dose. Blood111(8),4106–4112 (2008).
    • 40  Schneider D, Lilienfeld DE, Im W. The epidemiology of pulmonary embolism: racial contrasts in incidence and in-hospital case fatality. J. Natl Med. Assoc.98(12),1967–1972 (2006).
    • 41  Roger VL, Go AS, Lloyd-Jones DM et al. Heart disease and stroke statistics – 2011 update: a report from the American Heart Association. Circulation123(4),E18–E209 (2011).
    • 42  White RH, Dager WE, Zhou H, Murin S. Racial and gender differences in the incidence of recurrent venous thromboembolism. Thromb. Haemost.96(3),267–273 (2006).
    • 43  Morgenstern LB, Smith MA, Lisabeth LD et al. Excess stroke in Mexican Americans compared with non-Hispanic Whites: the brain attack surveillance in corpus christi project. Am. J. Epidemiol.160(4),376–383 (2004).
    • 44  Lisabeth LD, Smith MA, Sanchez BN, Brown DL. Ethnic disparities in stroke and hypertension among women: the BASIC project. Am. J. Hypertens.21(7),778–783 (2008).
    • 45  Lisabeth LD, Risser JM, Brown DL et al. Stroke burden in Mexican Americans: the impact of mortality following stroke. Ann. Epidemiol.16(1),33–40 (2006).
    • 46  White RH, Keenan CR. Effects of race and ethnicity on the incidence of venous thromboembolism. Thromb. Res.123(Suppl. 4),S11–S17 (2009).
    • 47  Price AL, Weale ME, Patterson N et al. Long-range LD can confound genome scans in admixed populations. Am. J. Hum. Genet.83(1),132–135; author reply 135–139 (2008).
    • 48  Caldwell MD, Berg RL, Zhang KQ et al. Evaluation of genetic factors for warfarin dose prediction. Clin. Med. Res.5(1),8–16 (2007).
    • 49  Momary KM, Shapiro NL, Viana MA et al. Factors influencing warfarin dose requirements in African–Americans. Pharmacogenomics8(11),1535–1544 (2007).
    • 50  Millican E, Jacobsen-Lenzini PA, Milligan PE et al. Genetic-based dosing in orthopaedic patients beginning warfarin therapy. Blood110(5),1511–1515 (2007).
    • 51  Schelleman H, Chen J, Chen Z et al. Dosing algorithms to predict warfarin maintenance dose in Caucasians and African Americans. Clin. Pharmacol. Ther.84(3),332–339 (2008).
    • 52  Gan GG, Phipps ME, Lee MM et al. Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations. Ann. Hematol.90(6),635–641 (2011).
    • 53  Zhao F, Loke C, Rankin SC et al. Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose. Clin. Pharmacol. Ther.76(3),210–219 (2004).
    • 54  Yu HC, Chan TY, Critchley JA, Woo KS. Factors determining the maintenance dose of warfarin in Chinese patients. QJM89(2),127–135 (1996).
    • 55  Tishkoff SA, Dietzsch E, Speed W et al. Global patterns of linkage disequilibrium at the CD4 locus and modern human origins. Science271(5254),1380–1387 (1996).
    • 56  Dickmann LJ, Rettie AE, Kneller MB et al. Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans. Mol. Pharmacol.60(2),382–387 (2001).
    • 57  Allabi AC, Gala JL, Horsmans Y. CYP2C9 CYP2C19, ABCB1 (MDR1) genetic polymorphisms and phenytoin metabolism in a Black Beninese population. Pharmacogenet. Genomics15(11),779–786 (2005).
    • 58  Blaisdell J, Jorge-Nebert LF, Coulter S et al. Discovery of new potentially defective alleles of human CYP2C9. Pharmacogenetics14(8),527–537 (2004).
    • 59  Allabi AC, Gala JL, Horsmans Y et al. Functional impact of CYP2C95, CYP2C96, CYP2C98, and CYP2C911in vivo among black Africans. Clin. Pharmacol. Ther.76(2),113–118 (2004).
    • 60  Lui Y, Hyun-Young J, Takahashi H et al. Decreased warfarin clearance with the CYP2C9 R150H (*8) polymorphism. Clin. Pharmacol. Ther.91(4),660–665 (2012).
    • 61  Mitchell C, Gregersen N, Krause A. Novel CYP2C9 and VKORC1 gene variants associated with warfarin dosage variability in the South African black population. Pharmacogenomics12(7),953–963 (2011).
    • 62  McDonald MG, Rieder MJ, Nakano M, Hsia CH, Rettie AE. CYP4F2 is a vitamin K1 oxidase: an explanation for altered warfarin cose in carriers of the V433M variant. Mol. Pharmacol.75(6),1337–1346 (2009).
    • 63  Wajih N, Sane DC, Hutson SM, Wallin R. The inhibitory effect of calumenin on the vitamin K-dependent γ-carboxylation system. Characterization of the system in normal and warfarin-resistant rats. J. Biol. Chem.279(24),25276–25283 (2004).
    • 64  Shahin MH, Khalifa SI, Gong Y et al. Genetic and nongenetic factors associated with warfarin dose requirements in Egyptian patients. Pharmacogenet. Genomics21(3),130–135 (2011).
    • 65  Rost S, Fregin A, Koch D et al. Compound heterozygous mutations in the γ-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors. Br. J. Haematol.126(4),546–549 (2004).
    • 66  Kimura R, Miyashita K, Kokubo Y et al. Genotypes of vitamin K epoxide reductase, γ-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thromb. Res.120(2),181–186 (2007).
    • 67  Chen LY, Eriksson N, Gwilliam R et al. Gamma-glutamyl carboxylase (GGCX) microsatellite and warfarin dosing. Blood106(10),3673–3674 (2005).
    • 68  King CR, Deych E, Milligan P et al. γ-glutamyl carboxylase and its influence on warfarin dose. Thromb. Haemost.104(4),750–754 (2010).
    • 69  Schwarz UI, Ritchie MD, Bradford Y et al. Genetic determinants of response to warfarin during initial anticoagulation. N. Engl. J. Med.358(10),999–1008 (2008).
    • 70  Wu AH, Wang P, Smith A et al. Dosing algorithm for warfarin using CYP2C9 and VKORC1 genotyping from a multi-ethnic population: comparison with other equations. Pharmacogenomics9(2),169–178 (2008).
    • 71  Lubitz SA, Scott SA, Rothlauf EB et al. Comparative performance of gene-based warfarin dosing algorithms in a multiethnic population. J. Thromb. Haemost.8(5),1018–1026 (2010).
    • 72  Huang RS, Johnatty SE, Gamazon ER et al. Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients. Clin. Cancer. Res.17(16),5490–5500 (2011).
    • 73  Gamazon ER, Zhang W, Konkashbaev A et al. SCAN: SNP and copy number annotation. Bioinformatics26(2),259–262 (2010).
    • 74  Innocenti F, Cooper GM, Stanaway IB et al. Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. PLoS Genet.7(5),E1002078 (2011).
    • 75  Perera MA, Limdi NA, Cavallari L et al. Novel SNPs associated with warfarin dose in a large multicenter cohort of African Americans: Genome wide association study and replication results. Circulation124(Suppl. 1),15518 (2011).
    • 76  Gamazon ER, Skol AD, Perera MA. The limits of genome-wide methods for pharmacogenomics. Pharmacogenet. Genomics22(4),261–272 (2012).
    • 77  Cavallari LH, Shin J, Perera MA. Role of pharmacogenomics in the management of traditional and novel oral anticoagulants. Pharmacotherapy31(12),1192–1207 (2011).
    • 78  Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schunemann HJ. Executive summary: antithrombotic therapy and prevention of thrombosis (9th Edition). American College of Chest Physicians evidence-based clinical practice guidelines. Chest141(Suppl. 2),S7–S47 (2012).
    • 79  Flockhart DA, O’Kane D, Williams MS et al. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet. Med.10(2),139–150 (2008).
    • 80  Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin. Pharmacol. Ther.83(3),460–470 (2008).
    • 81  Epstein RS, Moyer TP, Aubert RE et al. Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo warfarin effectiveness study). J. Am. Coll. Cardiol.55(25),2804–2812 (2010).▪ This comparative effectiveness study demonstrates a reduction in overall hospitalization and hospitalization for bleeding or thrombosis with genotype-guided warfarin therapy.
    • 82  French B, Joo J, Geller NL et al. Statistical design of personalized medicine interventions: the Clarification of Optimal Anticoagulation through Genetics (COAG) trial. Trials11,108 (2010).
    • 83  Johnson JA, Gong L, Whirl-Carrillo M et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin. Pharmacol. Ther.90(4),625–629 (2011).▪▪ An expert consensus panel provides recommendations for applying genetic information to guide warfarin dosing.
    • 84  Finkelman BS, Gage BF, Johnson JA, Brensinger CM, Kimmel SE. Genetic warfarin dosing: tables versus algorithms. J. Am. Coll. Cardiol.57(5),612–618 (2011).
    • 101  Warfarin dosing. www.warfarindosing.org
    • 102  Database of single nucleotide polymorphisms. Bethesda (MD): National Center for Biotechnology Information, National Library of Medicine. dbSNP accession: ss5586420, ss52052050, ss76884483, ss105439387, ss105440151, ss13761958, ss10622649, ss2494699, ss3027906 (dbSNP Build ID:132). www.ncbi.nlm.nih.gov/snp
    • 103  US Census Bureau. 1970, 1980, and 2000 decennial censuses: population projections, 1 July 2010–1 July 2050. www.census.gov