Exploiting Common Genetic Variation to Make Anticoagulation Safer
2009; Lippincott Williams & Wilkins; Volume: 40; Issue: 3_suppl_1 Linguagem: Inglês
10.1161/strokeaha.108.533190
ISSN1524-4628
Tópico(s)Pharmacogenetics and Drug Metabolism
ResumoHomeStrokeVol. 40, No. 3_suppl_1Exploiting Common Genetic Variation to Make Anticoagulation Safer Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBExploiting Common Genetic Variation to Make Anticoagulation Safer The Genes for Cerebral Hemorrhage on Anticoagulation (GOCHA) Collaborative Group The Genes for Cerebral Hemorrhage on Anticoagulation (GOCHA) Collaborative Group From the Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston, Mass; and the Program in Medical and Population Genetics, Broad Institute, Cambridge, Mass. Originally published15 Jan 2009https://doi.org/10.1161/STROKEAHA.108.533190Stroke. 2009;40:S64–S66Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 15, 2009: Previous Version 1 Within the past 2 years, genomewide association studies have identified nearly 200 new chromosomal regions at which variation in DNA sequence influences risk of common human diseases as well as traits such as height and eye color. The success of the genomewide association study method, particularly given the limited success of previous approaches to find these "culprit" loci, has heightened optimism for the development of so-called personalized medicine. Perhaps more than any area, the field of anticoagulation and making it safer has raised hopes for using genetic information to improve individual patient outcomes.Discoveries, before the genomewide association study era, that common DNA sequence variants in CYP2C9 and VKORC1 play a substantial role in determining an individual's warfarin dose requirement, led to an update of the US Food and Drug Administration label for Coumadin/warfarin suggesting that clinicians consider genetic testing before initiating warfarin.1 Although these discoveries represent a crucial first step toward the application of genetic information to make anticoagulation safer, it is clear that identifying an individual patient's risk for hemorrhage on anticoagulation or thromboembolism in atrial fibrillation (and other diseases) will require many more genetic discoveries.What Causes Hemorrhage in Patients Receiving Anticoagulation?Broadly speaking, the risk of bleeding on anticoagulation can be broken down into 2 general mechanisms: those related to the effects of anticoagulation itself on coagulation factors and clot formation and those related to specific conditions that increase risk of bleeding regardless of whether anticoagulation is present. Warfarin metabolism and sensitivity genes such as CYP2C9 and VKORC1 are likely to increase bleeding through the former mechanism. Randomized clinical trials in patients with deep vein thrombosis, artificial heart valves, ischemic stroke, atrial fibrillation, or antiphospholipid antibody syndrome with previous thromboembolism have consistently demonstrated an increased risk of bleeding among patients in whom the target intensity of anticoagulation is higher.2 Thus, individuals with genetic variants that result in heightened sensitivity to low doses of warfarin, and are therefore presumably at greater risk for supratherapeutic anticoagulation, are likely to be at increased risk of bleeding on warfarin. Indeed, variants in these 2 genes appear to influence risk of bleeding during the initiation phase of warfarin, when risk of "overshoot" is highest.3–8 Although the increased risk of bleeding attributable to VKORC1 appears to be limited to the initiation phase of anticoagulant therapy, CYP2C9 sequence variants may be associated with a continued risk of hemorrhage during the maintenance phase of anticoagulant therapy.5,9–11 Clinical trials are currently being organized to determine whether testing for polymorphisms in CYP2C9 and VKORC1 followed by genotype-guided warfarin dose selection will result in fewer warfarin-related hemorrhages and improved patient outcomes.Although identifying those individuals at increased risk for all types of warfarin-related hemorrhage is clearly important, the health effects of these hemorrhages can vary enormously depending on the site and organ system involved. Minor hemorrhages often result in little more than a brief temporary cessation of anticoagulation. Major hemorrhages, on the other hand, are life-threatening and can lead to death or lasting disability. Among major hemorrhages, intracranial hemorrhages are the only bleeding complications that regularly produce deficits that exceed those produced by the ischemic strokes anticoagulant therapy is designed to prevent.12,13 Furthermore, the overwhelming majority of fatal or disabling hemorrhagic events on anticoagulation are due to nontraumatic intracranial hemorrhage with few, if any, persisting deficits arising from major extracranial bleeding.14 Clearly, if genetic information could be harnessed to prevent intracranial hemorrhages, a substantial alteration in the risk-benefit balance of anticoagulation could be achieved.Warfarin Sensitivity Genes and Risk of Intracranial HemorrhageSeveral observations suggest that screening for warfarin metabolism and sensitivity genes such as CYP2C9 and VKORC1 is unlikely to identify those individuals at high risk for warfarin-related intracranial hemorrhage. Such hemorrhages (approximately one third are subdural in location, two thirds intracerebral), although generally rare in the setting of clinical trials, appear to increase markedly in frequency with advancing age.15 Among 13559 patients with nonvalvular atrial fibrillation followed in the Kaiser Permanente Health System, risk of intracranial hemorrhage, both related and unrelated to anticoagulation, doubled among those ≥80 years of age16 (Figure). Furthermore, fully two thirds of these hemorrhages occur when the intensity of anticoagulation is in the therapeutic, not supratherapeutic, range.12,13 Finally, data from the Genes for Cerebral Hemorrhage on Anticoagulation (GOCHA) Collaborative (Table), in which consecutive subjects with intracerebral hemorrhage are enrolled through emergency departments at participating centers, demonstrates that >70% of these warfarin-related hemorrhages occur in patients who have been taking warfarin 1 year or longer, and >90% occur after 3 months of therapy, suggesting that any intervention to adjust initial warfarin dose based on genetic information is unlikely to prevent the vast majority of intracerebral hemorrhages. Download figureDownload PowerPointFigure. Annual risk of nontraumatic intracranial hemorrhage among 13559 patients with nonvalvular atrial fibrillation followed in the Kaiser Permanente Health System. Risk of hemorrhage, both on and off warfarin, rises sharply in the oldest group of patients. Reprinted from Fang MC, Go AS, Hylek EM, Chang Y, Henault LE, Jensvold NG, Singer DE. Age and the risk of warfarin-associated hemorrhage: the anticoagulation and risk factors in atrial fibrillation study. J Am Geriatr Soc. 2006;54:1231–1236.Table. Warfarin-Related Intracerebral Hemorrhage*ICHControl Subjects*Patients assembled thus far by the GOCHA Collaborative (see Appendix for participating investigators).N237234Age, mean±SD75±1074±10Female, %47Hypertension8276ICH location, % Lobar44 Deep40 Infratentorial16Duration of warfarin therapy at time of ICH, % ≤3 months83 3 months to 1 year2142 ≥1 year7155International normalized ratio at time of ICH, median (range)2.8 (1.4–20)2.3 (1.3–10)Genes for Age-Related Brain Conditions and Risk for Warfarin-Related Intracerebral HemorrhageTaken together, these data suggest that risk of warfarin-related intracranial hemorrhage is strongly related to age-associated factors, particular those involved in brain aging. Established links among severity of leukoaraiosis, cerebral amyloid angiopathy, and risk for warfarin-related intracerebral hemorrhage (ICH) highlight 2 conditions for which genetic discoveries could indeed yield novel testing approaches to stratify patients for risk of ICH on warfarin.17 Although testing for APOE e2 or e4, polymorphisms known to influence risk of cerebral amyloid angiopathy do not appear to have a role in screening patients before initiating anticoagulation,18 it is clear that there are additional genetic risk factors for cerebral amyloid angiopathy yet to be discovered.There is, as of yet, no established panel of genetic variants that can aid in making the decision whether to offer anticoagulation to patients with, for example, atrial fibrillation. Nonetheless, clinicians can expect to hear of novel discoveries that could change this situation. The GOCHA collaborative, working within the loosely defined International Stroke Genetics Consortium (www.strokegenetics.org), has initiated the largest genomewide association study for intracerebral hemorrhage ever undertaken. Having learned the lessons of successful genomewide association studies in multiple common diseases, GOCHA investigators are assembling the thousands of cases necessary to perform a well-powered search for those common genetic variants that alter risk of ICH and warfarin-related ICH and could someday be combined with CYP2C9, VKORC1, and APOE to build an individualized screen for patients about to start anticoagulation.AppendixThe Genes for Cerebral Hemorrhage on Anticoagulation (GOCHA) Collaborative GroupMassachusetts General Hospital: Yuchiao Chang, PhD; Lynelle Cortellini; Steven M. Greenberg, MD, PhD; Jonathan Rosand, MD, MSc; Daniel Singer, MD, and Kristen Schwab. Beth Israel-Deaconess Medical Center: Magdy Selim, MD. Mayo Clinic, Jacksonville, Fla: James Meschia, MD. University of Cincinnati: Mark H. Eckman, MD. University of Florida: Scott Silliman, MD. University of Michigan: Devon Brown, MD. University of Virginia: W. Bradford Worrall, MD, MSc. University of Washington: David Tirschwell, MD, MSc. Washington University, St Louis: Brian F. Gage, MD, MSc.*See Appendix.Sources of FundingSupported by the National Institutes of Neurological Disorders and Stroke (R01 NS04217, R01 NS059727) and the Deane Institute for Integrative Study of Atrial Fibrillation and Stroke.DisclosuresNone.FootnotesCorrespondence to Jonathan Rosand, MD, MSc, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, CPZN 6818, Boston, MA 02114. E-mail [email protected] References 1 US Food and Drug Administration. Coumadin labeling NDA 9-218/S-105, 2007.Google Scholar2 Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th ed. Chest. 2008; 133: 257S–298S.CrossrefMedlineGoogle Scholar3 Adcock DM, Koftan C, Crisan D, Kiechle FL. Effect of polymorphisms in the cytochrome p450 cyp2c9 gene on warfarin anticoagulation. Arch Pathol Lab Med. 2004; 128: 1360–1363.MedlineGoogle Scholar4 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. Lancet. 1999; 353: 717–719.CrossrefMedlineGoogle Scholar5 Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, Rettie AE. Association between cyp2c9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA. 2002; 287: 1690–1698.CrossrefMedlineGoogle Scholar6 Margaglione M, Colaizzo D, D'Andrea G, Brancaccio V, Ciampa A, Grandone E, Di Minno G. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost. 2000; 84: 775–778.CrossrefMedlineGoogle Scholar7 Taube J, Halsall D, Baglin T. Influence of cytochrome p-450 cyp2c9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood. 2000; 96: 1816–1819.CrossrefMedlineGoogle Scholar8 Visser LE, van Schaik RH, van Vliet M, Trienekens PH, De Smet PA, Vulto AG, Hofman A, van Duijn CM, Stricker BH. The risk of bleeding complications in patients with cytochrome p450 cyp2c9*2 or cyp2c9*3 alleles on acenocoumarol or phenprocoumon. Thromb Haemost. 2004; 92: 61–66.MedlineGoogle Scholar9 Limdi NA, McGwin G, Goldstein JA, Beasley TM, Arnett DK, Adler BK, Baird MF, Acton RT. 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. 2008; 83: 312–321.CrossrefMedlineGoogle Scholar10 Sanderson S, Emery J, Higgins J. Cyp2c9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med. 2005; 7: 97–104.CrossrefMedlineGoogle Scholar11 Visser LE, van Vliet M, van Schaik RH, Kasbergen AA, De Smet PA, Vulto AG, Hofman A, van Duijn CM, Stricker BH. The risk of overanticoagulation in patients with cytochrome p450 cyp2c9*2 or cyp2c9*3 alleles on acenocoumarol or phenprocoumon. Pharmacogenetics. 2004; 14: 27–33.CrossrefMedlineGoogle Scholar12 Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004; 164: 880–884.CrossrefMedlineGoogle Scholar13 Fang MC, Chang Y, Hylek EM, Rosand J, Greenberg SM, Go AS, Singer DE. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med. 2004; 141: 745–752.CrossrefMedlineGoogle Scholar14 Fang MC, Go AS, Chang Y, Hylek EM, Henault LE, Jensvold NG, Singer DE. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med. 2007; 120: 700–705.CrossrefMedlineGoogle Scholar15 Singer DE, Albers GW, Dalen JE, Fang MC, Go AS, Halperin JL, Lip GYH, Manning WJ. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th ed. Chest. 2008; 133: 546S–592.CrossrefMedlineGoogle Scholar16 Fang MC, Go AS, Hylek EM, Chang Y, Henault LE, Jensvold NG, Singer DE. Age and the risk of warfarin-associated hemorrhage: the anticoagulation and risk factors in atrial fibrillation study. J Am Geriatr Soc. 2006; 54: 1231–1236.CrossrefMedlineGoogle Scholar17 Rost NS, Greenberg SM, Rosand J. The genetic architecture of intracerebral hemorrhage. Stroke. 2008; 39: 2166–2173.LinkGoogle Scholar18 Eckman MH, Wong LKS, Soo YOY, Lam W, Yang SR, Greenberg SM, Rosand J. Patient-specific decision making for warfarin therapy in nonvalvular atrial fibrillation: how will screening with genetics and imaging help? Stroke. 2008; 39: 3308–3315.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Falcone G, Kirsch E, Acosta J, Noche R, Leasure A, Marini S, Chung J, Selim M, Meschia J, Brown D, Worrall B, Tirschwell D, Jagiella J, Schmidt H, Jimenez‐Conde J, Fernandez‐Cadenas I, Lindgren A, Slowik A, Gill D, Holmes M, Phuah C, Petersen N, Matouk, MD C, Gunel M, Sansing L, Bennett D, Chen Z, Sun L, Clarke R, Walters R, Gill T, Biffi A, Kathiresan S, Langefeld C, Woo D, Rosand J, Sheth K and Anderson C (2020) Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage , Annals of Neurology, 10.1002/ana.25740, 88:1, (56-66), Online publication date: 1-Jul-2020. Radmanesh F, Falcone G, Anderson C, Battey T, Ayres A, Vashkevich A, McNamara K, Schwab K, Romero J, Viswanathan A, Greenberg S, Goldstein J, Rosand J and Brouwers H (2014) Risk Factors for Computed Tomography Angiography Spot Sign in Deep and Lobar Intracerebral Hemorrhage Are Shared, Stroke, 45:6, (1833-1835), Online publication date: 1-Jun-2014. Radmanesh F, Devan W, Anderson C, Rosand J and Falcone G (2014) Accuracy of imputation to infer unobserved APOE epsilon alleles in genome-wide genotyping data, European Journal of Human Genetics, 10.1038/ejhg.2013.308, 22:10, (1239-1242), Online publication date: 1-Oct-2014. Wilson D, Charidimou A and Werring D (2014) Advances in understanding spontaneous intracerebral hemorrhage: insights from neuroimaging, Expert Review of Neurotherapeutics, 10.1586/14737175.2014.918506, 14:6, (661-678), Online publication date: 1-Jun-2014. Devan W, Falcone G, Anderson C, Jagiella J, Schmidt H, Hansen B, Jimenez-Conde J, Giralt-Steinhauer E, Cuadrado-Godia E, Soriano C, Ayres A, Schwab K, Kassis S, Valant V, Pera J, Urbanik A, Viswanathan A, Rost N, Goldstein J, Freudenberger P, Stögerer E, Norrving B, Tirschwell D, Selim M, Brown D, Silliman S, Worrall B, Meschia J, Kidwell C, Montaner J, Fernandez-Cadenas I, Delgado P, Greenberg S, Roquer J, Lindgren A, Slowik A, Schmidt R, Woo D, Rosand J and Biffi A (2013) Heritability Estimates Identify a Substantial Genetic Contribution to Risk and Outcome of Intracerebral Hemorrhage, Stroke, 44:6, (1578-1583), Online publication date: 1-Jun-2013.Falcone G, Biffi A, Devan W, Brouwers H, Anderson C, Valant V, Ayres A, Schwab K, Rost N, Goldstein J, Viswanathan A, Greenberg S, Selim M, Meschia J, Brown D, Worrall B, Silliman S, Tirschwell D and Rosand J (2013) Burden of Blood Pressure–Related Alleles Is Associated With Larger Hematoma Volume and Worse Outcome in Intracerebral Hemorrhage, Stroke, 44:2, (321-326), Online publication date: 1-Feb-2013.Woo D, Deka R, Falcone G, Flaherty M, Haverbusch M, Martini S, Greenberg S, Ayres A, Sauerbeck L, Kissela B, Kleindorfer D, Moomaw C, Anderson C, Broderick J, Rosand J, Langefeld C and Woo J (2013) Apolipoprotein E, Statins, and Risk of Intracerebral Hemorrhage, Stroke, 44:11, (3013-3017), Online publication date: 1-Nov-2013. Kirchhof P, Breithardt G, Aliot E, Al Khatib S, Apostolakis S, Auricchio A, Bailleul C, Bax J, Benninger G, Blomstrom-Lundqvist C, Boersma L, Boriani G, Brandes A, Brown H, Brueckmann M, Calkins H, Casadei B, Clemens A, Crijns H, Derwand R, Dobrev D, Ezekowitz M, Fetsch T, Gerth A, Gillis A, Gulizia M, Hack G, Haegeli L, Hatem S, Georg Hausler K, Heidbuchel H, Hernandez-Brichis J, Jais P, Kappenberger L, Kautzner J, Kim S, Kuck K, Lane D, Leute A, Lewalter T, Meyer R, Mont L, Moses G, Mueller M, Munzel F, Nabauer M, Nielsen J, Oeff M, Oto A, Pieske B, Pisters R, Potpara T, Rasmussen L, Ravens U, Reiffel J, Richard-Lordereau I, Schafer H, Schotten U, Stegink W, Stein K, Steinbeck G, Szumowski L, Tavazzi L, Themistoclakis S, Thomitzek K, Van Gelder I, von Stritzky B, Vincent A, Werring D, Willems S, Lip G and Camm A (2013) Personalized management of atrial fibrillation: Proceedings from the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association consensus conference, Europace, 10.1093/europace/eut232, 15:11, (1540-1556), Online publication date: 1-Nov-2013. Falcone G, Biffi A, Devan W, Jagiella J, Schmidt H, Kissela B, Hansen B, Jimenez-Conde J, Giralt-Steinhauer E, Elosua R, Cuadrado-Godia E, Soriano C, Ayres A, Schwab K, Pera J, Urbanik A, Rost N, Goldstein J, Viswanathan A, Pichler A, Enzinger C, Norrving B, Tirschwell D, Selim M, Brown D, Silliman S, Worrall B, Meschia J, Kidwell C, Montaner J, Fernandez-Cadenas I, Delgado P, Broderick J, Greenberg S, Roquer J, Lindgren A, Slowik A, Schmidt R, Flaherty M, Kleindorfer D, Langefeld C, Woo D and Rosand J (2012) Burden of Risk Alleles for Hypertension Increases Risk of Intracerebral Hemorrhage, Stroke, 43:11, (2877-2883), Online publication date: 1-Nov-2012. Cervera Á, Amaro S and Chamorro Á (2011) Oral anticoagulant-associated intracerebral hemorrhage, Journal of Neurology, 10.1007/s00415-011-6153-3, 259:2, (212-224), Online publication date: 1-Feb-2012. Biffi A, Anderson C, Jagiella J, Schmidt H, Kissela B, Hansen B, Jimenez-Conde J, Pires C, Ayres A, Schwab K, Cortellini L, Pera J, Urbanik A, Romero J, Rost N, Goldstein J, Viswanathan A, Pichler A, Enzinger C, Rabionet R, Norrving B, Tirschwell D, Selim M, Brown D, Silliman S, Worrall B, Meschia J, Kidwell C, Broderick J, Greenberg S, Roquer J, Lindgren A, Slowik A, Schmidt R, Woo D and Rosand J (2011) APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: a genetic association study, The Lancet Neurology, 10.1016/S1474-4422(11)70148-X, 10:8, (702-709), Online publication date: 1-Aug-2011. Biffi A, Sonni A, Anderson C, Kissela B, Jagiella J, Schmidt H, Jimenez-Conde J, Hansen B, Fernandez-Cadenas I, Cortellini L, Ayres A, Schwab K, Juchniewicz K, Urbanik A, Rost N, Viswanathan A, Seifert-Held T, Stoegerer E, Tomás M, Rabionet R, Estivill X, Brown D, Silliman S, Selim M, Worrall B, Meschia J, Montaner J, Lindgren A, Roquer J, Schmidt R, Greenberg S, Slowik A, Broderick J, Woo D and Rosand J (2010) Variants at APOE influence risk of deep and lobar intracerebral hemorrhage, Annals of Neurology, 10.1002/ana.22134, 68:6, (934-943), Online publication date: 1-Dec-2010. Freeman W and Aguilar M (2010) Anticoagulation therapy for cardioembolic stroke prevention in the elderly: defining benefits and risks, Aging Health, 10.2217/ahe.10.45, 6:4, (439-450), Online publication date: 1-Aug-2010. March 2009Vol 40, Issue 3_suppl_1 Advertisement Article InformationMetrics https://doi.org/10.1161/STROKEAHA.108.533190 Manuscript acceptedJuly 30, 2008Originally publishedJanuary 15, 2009 KeywordsanticoagulationPDF download Advertisement
Referência(s)