- Email: [email protected]
Genetics of primary intracerebral hemorrhage
Genetics of Primary Intracerebral Hemorrhage Steven M. Greenberg
Genetic studies of primary intracerebral hemorrhage (PICH) have begun to yield important biologic insights into the pathogenesis of this disorder. This review of candidate genes for PICH emphasizes the value of focusing on individual pathogenic phenotypes. One type of PICH in particular, cerebral amyloid angiopathy, is known to have specific genetic factors regulating both its familial and sporadic forms. Another promising research method is to focus on pathways involved in hemostasis that may be etiologically relevant to all types of PICH. Genetic studies will improve our understanding of the biology of PICH, and may eventually be incorporated into clinical decision making regarding anticoagulation. Key Words: Intracerebral hemorrhage— cerebral amyloid angiopathy— hemostasis.
This article focuses on recent findings in the genetics of primary intracerebral hemorrhage (PICH), defined as hemorrhage within the brain parenchyma in the absence of readily identifiable causes, such as head trauma, ruptured vascular malformation or tumor. PICH is not a random event, but rather the result of a specific underlying vascular process such as hypertensive vasculopathy (HTN) or the increasingly recognized entity of cerebral amyloid angiopathy (CAA). Indeed, the biology of these pathologic processes (particularly CAA) have given important clues to potential genetic risk factors for PICH. PICH, like other diseases of the central nervous system, has become increasingly accessible to genetic investigation, a result of technologic advances in both clinical diagnosis and molecular genetics.1,2 Information generated by these studies has benefited our understanding of the pathophysiology of intracerebral hemorrhage (ICH), pointing to specific genes and alleles with roles in the disease process. Whether genetic information can also
From the Neurology Clinical Trials Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA. Supported in part by the National Institute of Health (AG00725). Address reprint requests to Steven M. Greenberg, MD, PhD, Massachusetts General Hospital, Wang ACC 836, Boston, MA 02114. E-mail: [email protected] Reprinted from Seminars in Cerebrovascular Diseases and Stroke 2002;2(1), copyright 2002 by Elsevier Science (USA). All rights reserved. 1052-3057/02/1105-0009$35.00/0 doi:10.1053/jscd.2002.129615
routinely benefit clinical practice in this area remains to be determined, but it is plausible that genetic factors might influence clinical decisions such as whether to treat particular individuals with anticoagulants or thrombolytics.3 Another area in which genetic information is likely to prove useful is in the design and analysis of clinical drug trials for PICH, potentially allowing patients to be stratified according to their predicted clinical course.4
General Considerations: Homogeneity and Heterogeneity of PICH An issue that arises in the genetics of stroke is the lumping-versus-splitting problem. Investigators must decide whether more homogeneous phenotypic subtypes should be studied separately to identify genetic risk factors. The experience in PICH suggests that the answer is often yes. Apolipoprotein E (APOE) genotype, for example, appears to be related to risk of CAA-related ICH but unrelated to the risk of other types of hemorrhage.5-7 Thus, whereas there will likely be some genetic factors that affect all subtypes of PICH equally, it is reasonable to assume that genetic factors related to specific vascular processes will affect PICH subtypes differently. Fortunately, PICH appears to occur by relatively few major pathophysiologic mechanisms, and these mechanisms often can be distinguished during life.8 The ability to split patients into reliable subtypes may indeed render the genetics of PICH a more tractable problem than the genetics of ischemic stroke.
Journal of Stroke and Cerebrovascular Diseases, Vol. 11, No. 5 (August-October), 2002: pp 265-271
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The clinical course followed by PICH patients is also heterogenous, with multiple distinguishing features such as age of onset, size, location, poststroke morbidity and mortality, and long-term risk of recurrence or clinical deterioration. These features make it possible to study genetic risk factors for not only the occurrence of PICH (typically by case-control analysis), but also for the severity of PICH (as a cohort study). An example discussed below is the finding that APOE genotype affects both the odds for occurrence of lobar hemorrhage as well as the time to recurrent hemorrhage.7,9-12 In these instances, the confluence of multiple, independent lines of evidence can provide strong support for a true biologic relationship between variations in a gene and disease. A final complication in the interpretation of stroke genetics is the likely intraction of genetic and environmental risk factors. Particular genetic polymorphisms may alter risk for hemorrhagic stroke only in the setting of chronic hypertension or during anticoagulation, for example. CAA may again prove an advantageous model system in this regard, as occurrence of CAA appears to be independent of traditional risk factors for stroke, such as hypertension.13 The discussion below begins with consideration of the genetics of CAA-related hemorrhagic stroke.
Genetic Risk Factors for PICH Genes Associated With CAA The genetics of CAA have been studied for both familial and sporadic forms. CAA typically entails vascular deposition of the -amyloid peptide (A), a 39 – to 43– amino acid fragment derived from the -amyloid precursor protein (APP). At least 4 mutations in the APP gene have been implicated in autosomal dominant forms of familial CAA (Fig 1). Interestingly, these CAA-related mutations occur in a cluster from amino acid positions 21 to 23 of APP’s A-coding region. Using names assigned according to the residence of the index family, these include the Flemish A21G mutation,14 the Dutch E22Q15,16 and Italian E22K17,18 mutations at amino acid position 22, and the Iowa D23N mutation.19 Each point mutation is associated with prominent CAA and hemorrhagic lesions, though the Iowa19 and Flemish14,20 kindreds show substantial Alzheimer’s disease (AD) pathology as well. Dutch-type hereditary CAA, the best characterized of these genetic syndromes, is associated with recurrent ICH, relatively little AD pathology, and early mortality.21,22 CAA-associated mutations at A positions 22 and 23 appear to generate an A peptide with heightened fibrillogenic properties and increased toxicity toward components of the vessel wall.18,23-30 The precise biochemical mechanism for the increased toxicity remains to be determined. Studies by Van Nostrand et al27 have impli-
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cated the loss of the negatively charged residues as playing an important role. These mutations contrast with the AD-associated mutations that occur outside the A-coding segment of APP (Fig 1), which appear to affect APP processing rather than A toxicity.31 The Flemish mutation at A position 21 also may act primarily through altered APP processing rather than increased peptide toxicity.29,30,32 Several other genes are associated with familial CAA, most notably that encoding cystatin C, a protease inhibitor unrelated to APP. An L68Q substitution in cystatin C results in Icelandic CAA, characterized by very early deposition of a mutant protein fragment in vessel walls and symptomatic ICH by the third or fourth decade of life.33,34 Familial British dementia is another form of CAA without A deposition. The disorder is caused by mutation in the BRI gene.35 A single nucleotide substitution in the BRI stop codon causes deposition of an abnormal carboxyl-terminus peptide fragment in vessel walls and a clinical syndrome of dementia and ataxia without hemorrhagic stroke.36 Mutations also have been characterized in presenilin 1 and 2, two related genes associated with familial AD and altered processing of APP. A pedigree with mutant presenilin 2 has been reported in which patients show advanced CAA and at least one family member with hemorrhagic stroke.37 Hemorrhagic strokes have not been reported in families with the more common presenilin 1 mutations, though some of these families also have shown pathologically advanced CAA.38,39 Most studies suggest that the genes associated with familial CAA do not play a major role as risk factors for sporadic disease. Among 55 sporadic CAA patients reported in the literature,40-44 only one has shown the cystatin C Icelandic mutation.40 The significance of this one instance of cystatin C mutation is unclear, as the patient pathologically appeared to have sporadic rather than Icelandic CAA. Similar searches for APP mutations at AS positions 22 or 23 have yielded no instances in 111 reported sporadic CAA patients.19,40-43 A weak protective effect of an intronic polymorphism in presenilin 1 toward pathologic extent of CAA has been reported in a single series and only in homozygotes for the polymorphism.45 Among examined candidate genes, it is APOE that has emerged as the strongest predictor of risk for sporadic CAA-related ICH. APOE is comprised of three major allelic forms (⑀2, ⑀3, and ⑀4) that differ by cysteine/ arginine polymorphisms at positions 112 and 158. Studies of APOE and CAA indicate that the APOE ⑀4 allele increases risk for CAA as it does in AD.9,10 They have also yielded the unexpected finding that APOE ⑀2, generally found to protect from AD, instead acts as an additional risk factor for CAA.11,46 The two APOE alleles appear not only to increase the risk for CAA occurrence, but also to lower the age of first hemorrhage46 and to shorten the time to recurrent ICH.12 In the latter study of
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Figure 1. APP mutations associated with familial CAA. (A) Schematic centered on the region of APP that contains the 42-amino acid species of A (boxed amino acid residues). Mutations at A positions 21-23 associated with familial CAA are shown in boxes. Representative AD-associated mutations are also shown. (B) An anti-A immunostain of a section of frontal cortex (200⫻) from a 68-year-old man with the APP Iowa mutation.19 Cortical vessels are severely affected with CAA, whereas parenchymal deposition of A as diffuse plaques (arrow) is mild.
70 consecutive survivors of an initial lobar ICH, carriers of APOE ⑀2 or ⑀4 rebled at a 2-year rate of 28% compared with only 10% for patients with the common APOE ⑀3/⑀3 genotype. Although the relationship between APOE and lobar ICH has been studied primarily in hospitalized patients, its applicability was recently extended to a population-based sample drawn from the Greater Cincinnati/Northern Kentucky region.7 The presence of APOE ⑀2 or ⑀4 associated with an adjusted odds ratio for lobar ICH of 2.3 in this population, accounting for an attributable risk of 29% of all lobar ICH. Different mechanisms have been suggested for the effects of the two APOE allelic risk factors. APOE ⑀4 appears to act in CAA, as it does in AD, to promote deposition of A.47-49 APOE ⑀2, conversely, associates
not with the deposition of A but with the subsequent destructive changes that occur in the amyloid-laden vessel wall.46,50 APOE ⑀2 and ⑀4 thus appear to have complementary roles in CAA progression, a model supported by the observation that the rare APOE ⑀2/⑀4 genotype associates with a particularly severe disease course.12,46 One potential application of CAA genetics would be to predict risk for ICH in patients undergoing anticoagulation. A genetic analysis of 41 elderly patients with warfarin-associated ICH3 showed a significant overrepresentation of APOE ⑀2, specifically among those patients with ICH in lobar regions characteristic of CAA. Limited pathologic data from these series support the interpretation that ⑀2 promotes warfarin-related ICH through its association with CAA. These results highlight the possi-
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bility that a panel of genetic tests ultimately might be useful for distinguishing between patients at high and low risk for ICH when treated with anticoagulants.
Genes Associated With Hemostasis The dependence of ICH risk in anticoagulated patients on the degree of anticoagulation51,52 supports the possibility that genetic variation in the hemostasis pathway likewise might affect the likelihood of sporadic ICH. Relatively few studies have investigated the relationship between ICH and polymorphisms in coagulation factors,53 and to date no robust relationships have been fully established. The most extensively investigated coagulation factor in ICH has been factor XIII, a transglutaminase with an important role in clot formation related to the crosslinking of fibrin and other plasma proteins. Genetic deficiency of either the catalytic (a) or regulatory (b) subunit of factor XIII results in a clinical bleeding disorder with prominent and severe intracranial hemorrhages.54 Studies in sporadic ICH have focused on a relatively common polymorphism involving substitution of leucine for valine at position 34 (V34L) of the a-subunit. This polymorphism appears to confer functional changes on factor XIII, affecting both its thrombin-induced activation as well as its intrinsic enzymatic activity.55-58 Two casecontrol studies of 62 and 130 PICH patients found a modestly increased risk (odds ratio 1.7 for both studies) among carriers of V34L,59,60 whereas another study of 141 PICH and 60 subarachnoid hemorrhage patients reported no association.61 It should be noted that the epidemiologic data suggesting increased risk for PICH and decreased risk for thrombotic events such as myocardial infarction, ischemic stroke, or venous thrombosis associated with V34L59,62-65 appear to run opposite to the biochemical data predicting enhanced fibrin cross-linking.55-58 Further studies will be required to unravel this important question, including analysis of anticoagulated patients in whom thrombin-induced activation of factor XIII may be substantially altered. Relatively little data are available regarding PICH and other polymorphisms reportedly associated with hemostasis. The factor VG1691A Leiden mutation was examined in a single study of 140 PICH patients and appeared in only one patient (0.4% allele frequency), significantly less than the population frequency.61 The same study examined the G/A transition in the untranslated region of the prothrombin gene 3 and found no association with risk of ICH. Finally, a 10-nucleotide insert in the factor VII promoter (323 Ins) was present at slightly higher frequency in 99 PICH patients than 161 controls.61 Like all studies that involve the testing of multiple genes and polymorphisms, these interesting observations will require confirmation in independent data sets to rule out the possibility of spurious association. A polymorphism
(V279F) in the platelet-activating factor (PAF) acetylhydrolase gene found primarily in Asian populations has been reported at increased frequency in a study of Japanese patients with PICH.66 This finding again appears at odds with earlier biochemical data, which had found V279F to associate with decreased PAF inactivation (as well as increased risk for thrombotic strokes).67
Other Genetic Pathways Studies of the transforming growth factor- (TGF-) receptor-associated protein endoglin suggest a potential role for the TGF- pathway in promoting ICH. Genetic knockout of endoglin in mice causes abnormalities of vascular smooth muscle cell development and vascular endothelium remodeling,68 and a naturally occurring loss-of-function mutation is associated with hereditary human telangiectasia type I.69 A possible relationship between endoglin and sporadic PICH was suggested by the finding that homozygosity for a 6-base insertion in intron 7 of the endoglin gene was associated with a 4.8-fold increase in PICH.70 Another study found a similar association of the homozygous ⫹insert/⫹insert genotype with intracranial sacular aneurysms.71 Although no biochemical effects have been ascribed to this intronic polymorphism, the data suggest that it might be linked to a functional site in endoglin. The presence of polymorphisms in CYP2C9, the cytochrome P450 enzyme primarily responsible for hydroxylation of the potent S-isomer of warfarin, raises the possibility that genetic factors may affect a patient’s ability to remain in a therapeutic range of anticoagulation. Carriers of single amino acid substitutions in this enzyme (designated CYP2C9*2 and CYP2C9*3) appear to have decreased dosing requirements for warfarin and increased tendencies to reach supratherapeutic levels of anticoagulation during induction.72,73 These polymorphisms have not been analyzed in PICH, but highlight the possibility of exploring such a pharmacogenetic approach to identifying patients at highest risk for anticoagulation. Conspicuously absent from the list of genes discussed here are candidate risk factors specific for pathways involved in hypertensive hemorrhage. A recent study by Alberts et al74 suggests that such factors likely exist. The authors found 14 of 144 prospectively assessed PICH patients (9.8%) to have a family history positive for ICH, including 9 of 75 patients (12.0%) with ICH in the basal ganglionic or thalamic locations typical of hypertensive hemorrhage. Similarly, the population-based Greater Cincinnati/Northern Kentucky study found a positive history in a first degree relative to confer an adjusted odds ratio for ICH of 6.3, with significant effects in both the lobar and the nonlobar ICH subgroups.7 These results agree with the clinical observation that patients who develop HTN hemorrhage are not necessarily those with the most severe or poorly controlled hypertension, sug-
GENETICS OF PRIMARY INTRACEREBRAL HEMORRHAGE
gesting possible host susceptibility genes. Families with clusters of hypertensive ICH represent a promising resource for identification of candidate genes for this vascular disorder. Another approach will be molecular investigations into the pathology of hypertensive vasculopathy, a process that has gone relatively unexplored since the seminal studies of Fisher.75 Acknowledgement: I wish to thank Drs Mark J. Alberts, Daniel Woo, and Joseph P. Broderick for sharing data prior to publication; Dr Jonathan Rosand for critically reviewing this manuscript; and my research colleagues and collaborators who participated in studies described here.
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270 31. Selkoe DJ: Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399:A23-A31, 1999 (suppl) 32. De Jonghe C, Zehr C, Yager D, et al: Flemish and Dutch mutations in amyloid beta precursor protein have different effects on amyloid beta secretion. Neurobiol Dis 5:281-286, 1998 33. Palsdottir A, Abrahamson M, Thorsteinsson L, et al: Mutation in cystatin C gene causes hereditary brain haemorrhage. Lancet 2:603-604, 1988 34. Levy E, Lopez-Otin C, Ghiso J, et al: Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases. J Exp Med 169:1771-1778, 1989 35. Vidal R, Frangione B, Rostagno A, et al: A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 399:776-781, 1999 36. Mead S, James-Galton M, Revesz T, et al: Familial British dementia with amyloid angiopathy: Early clinical, neuropsychological and imaging findings. Brain 123:975-991, 2000 37. Nochlin D, Bird TD, Nemens EJ, et al: Amyloid angiopathy in a Volga German family with Alzheimer’s disease and a presenilin-2 mutation (N141I). Ann Neurol 43:131135, 1998 38. Yasuda M, Maeda S, Kawamata T, et al: Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy. J Neurol Neurosurg Psychiatry 68:220-223, 2000 39. Mann DM, Pickering-Brown SM, Takeuchi A, et al: Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1linked Alzheimer’s disease. Am J Pathol 158:2165-2175, 2001 40. Graffagnino C, Herbstreith MH, Schmechel DE, et al: Cystatin C mutation in an elderly man with sporadic amyloid angiopathy and intracerebral hemorrhage. Stroke 26:2190-2193, 1995 41. Anders KH, Wang ZZ, Kornfeld M, et al: Giant cell arteritis in association with cerebral amyloid angiopathy: Immunohistochemical and molecular studies. Hum Pathol 28:1237-1246, 1997 42. Itoh Y, Yamada M: Cerebral amyloid angiopathy in the elderly: The clinicopathological features, pathogenesis, and risk factors. J Med Dent Sci 44:11-19, 1997 43. Nagai A, Kobayashi S, Shimode K, et al: No mutations in cystatin C gene in cerebral amyloid angiopathy with cystatin C deposition. Mol Chem Neuropathol 33:63-78, 1998 44. McCarron MO, Nicoll JA, Stewart J, et al: Absence of cystatin C mutation in sporadic cerebral amyloid angiopathy-related hemorrhage. Neurology 54:242-244, 2000 45. Yamada M, Sodeyama N, Itoh Y, et al: Association of presenilin-1 polymorphism with cerebral amyloid angiopathy in the elderly. Stroke 28:2219-2221, 1997 46. Greenberg SM, Vonsattel JP, Segal AZ, et al: Association of apolipoprotein E epsilon2 and vasculopathy in cerebral amyloid angiopathy. Neurology 50:961-965, 1998 47. Schmechel DE, Saunders AM, Strittmatter WJ, et al: Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci U S A 90:9649-9653, 1993 48. Olichney JM, Hansen LA, Galasko D, et al: The apolipoprotein E epsilon 4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in
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271 71. Takenaka K, Sakai H, Yamakawa H, et al: Polymorphism of the endoglin gene in patients with intracranial saccular aneurysms. J Neurosurg 90:935-938, 1999 72. Steward DJ, Haining RL, Henne KR, et al: Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 7:361-367, 1997 73. Aithal GP, Day CP, Kesteven PJ, et al: Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353:717-719, 1999 74. Alberts MJ, McCarron MO, Hoffmann KL, et al: Familial clustering of intracerebral hemorrhage: A prospective study in North Carolina. Neuroepidemiology 21:18-21, 2002 75. Fisher CM: Pathological observations in hypertensive cerebral hemorrhage. J Neuropathol Exp Neurol 30:536550, 1971
Genetic studies of primary intracerebral hemorrhage (PICH) have begun to yield important biologic insights into the pathogenesis of this disorder. This review of candidate genes for PICH emphasizes the value of focusing on individual pathogenic phenotypes. One type of PICH in particular, cerebral amyloid angiopathy, is known to have specific genetic factors regulating both its familial and sporadic forms. Another promising research method is to focus on pathways involved in hemostasis that may be etiologically relevant to all types of PICH. Genetic studies will improve our understanding of the biology of PICH, and may eventually be incorporated into clinical decision making regarding anticoagulation. Key Words: Intracerebral hemorrhage— cerebral amyloid angiopathy— hemostasis.
This article focuses on recent findings in the genetics of primary intracerebral hemorrhage (PICH), defined as hemorrhage within the brain parenchyma in the absence of readily identifiable causes, such as head trauma, ruptured vascular malformation or tumor. PICH is not a random event, but rather the result of a specific underlying vascular process such as hypertensive vasculopathy (HTN) or the increasingly recognized entity of cerebral amyloid angiopathy (CAA). Indeed, the biology of these pathologic processes (particularly CAA) have given important clues to potential genetic risk factors for PICH. PICH, like other diseases of the central nervous system, has become increasingly accessible to genetic investigation, a result of technologic advances in both clinical diagnosis and molecular genetics.1,2 Information generated by these studies has benefited our understanding of the pathophysiology of intracerebral hemorrhage (ICH), pointing to specific genes and alleles with roles in the disease process. Whether genetic information can also
From the Neurology Clinical Trials Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA. Supported in part by the National Institute of Health (AG00725). Address reprint requests to Steven M. Greenberg, MD, PhD, Massachusetts General Hospital, Wang ACC 836, Boston, MA 02114. E-mail: [email protected] Reprinted from Seminars in Cerebrovascular Diseases and Stroke 2002;2(1), copyright 2002 by Elsevier Science (USA). All rights reserved. 1052-3057/02/1105-0009$35.00/0 doi:10.1053/jscd.2002.129615
routinely benefit clinical practice in this area remains to be determined, but it is plausible that genetic factors might influence clinical decisions such as whether to treat particular individuals with anticoagulants or thrombolytics.3 Another area in which genetic information is likely to prove useful is in the design and analysis of clinical drug trials for PICH, potentially allowing patients to be stratified according to their predicted clinical course.4
General Considerations: Homogeneity and Heterogeneity of PICH An issue that arises in the genetics of stroke is the lumping-versus-splitting problem. Investigators must decide whether more homogeneous phenotypic subtypes should be studied separately to identify genetic risk factors. The experience in PICH suggests that the answer is often yes. Apolipoprotein E (APOE) genotype, for example, appears to be related to risk of CAA-related ICH but unrelated to the risk of other types of hemorrhage.5-7 Thus, whereas there will likely be some genetic factors that affect all subtypes of PICH equally, it is reasonable to assume that genetic factors related to specific vascular processes will affect PICH subtypes differently. Fortunately, PICH appears to occur by relatively few major pathophysiologic mechanisms, and these mechanisms often can be distinguished during life.8 The ability to split patients into reliable subtypes may indeed render the genetics of PICH a more tractable problem than the genetics of ischemic stroke.
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The clinical course followed by PICH patients is also heterogenous, with multiple distinguishing features such as age of onset, size, location, poststroke morbidity and mortality, and long-term risk of recurrence or clinical deterioration. These features make it possible to study genetic risk factors for not only the occurrence of PICH (typically by case-control analysis), but also for the severity of PICH (as a cohort study). An example discussed below is the finding that APOE genotype affects both the odds for occurrence of lobar hemorrhage as well as the time to recurrent hemorrhage.7,9-12 In these instances, the confluence of multiple, independent lines of evidence can provide strong support for a true biologic relationship between variations in a gene and disease. A final complication in the interpretation of stroke genetics is the likely intraction of genetic and environmental risk factors. Particular genetic polymorphisms may alter risk for hemorrhagic stroke only in the setting of chronic hypertension or during anticoagulation, for example. CAA may again prove an advantageous model system in this regard, as occurrence of CAA appears to be independent of traditional risk factors for stroke, such as hypertension.13 The discussion below begins with consideration of the genetics of CAA-related hemorrhagic stroke.
Genetic Risk Factors for PICH Genes Associated With CAA The genetics of CAA have been studied for both familial and sporadic forms. CAA typically entails vascular deposition of the -amyloid peptide (A), a 39 – to 43– amino acid fragment derived from the -amyloid precursor protein (APP). At least 4 mutations in the APP gene have been implicated in autosomal dominant forms of familial CAA (Fig 1). Interestingly, these CAA-related mutations occur in a cluster from amino acid positions 21 to 23 of APP’s A-coding region. Using names assigned according to the residence of the index family, these include the Flemish A21G mutation,14 the Dutch E22Q15,16 and Italian E22K17,18 mutations at amino acid position 22, and the Iowa D23N mutation.19 Each point mutation is associated with prominent CAA and hemorrhagic lesions, though the Iowa19 and Flemish14,20 kindreds show substantial Alzheimer’s disease (AD) pathology as well. Dutch-type hereditary CAA, the best characterized of these genetic syndromes, is associated with recurrent ICH, relatively little AD pathology, and early mortality.21,22 CAA-associated mutations at A positions 22 and 23 appear to generate an A peptide with heightened fibrillogenic properties and increased toxicity toward components of the vessel wall.18,23-30 The precise biochemical mechanism for the increased toxicity remains to be determined. Studies by Van Nostrand et al27 have impli-
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cated the loss of the negatively charged residues as playing an important role. These mutations contrast with the AD-associated mutations that occur outside the A-coding segment of APP (Fig 1), which appear to affect APP processing rather than A toxicity.31 The Flemish mutation at A position 21 also may act primarily through altered APP processing rather than increased peptide toxicity.29,30,32 Several other genes are associated with familial CAA, most notably that encoding cystatin C, a protease inhibitor unrelated to APP. An L68Q substitution in cystatin C results in Icelandic CAA, characterized by very early deposition of a mutant protein fragment in vessel walls and symptomatic ICH by the third or fourth decade of life.33,34 Familial British dementia is another form of CAA without A deposition. The disorder is caused by mutation in the BRI gene.35 A single nucleotide substitution in the BRI stop codon causes deposition of an abnormal carboxyl-terminus peptide fragment in vessel walls and a clinical syndrome of dementia and ataxia without hemorrhagic stroke.36 Mutations also have been characterized in presenilin 1 and 2, two related genes associated with familial AD and altered processing of APP. A pedigree with mutant presenilin 2 has been reported in which patients show advanced CAA and at least one family member with hemorrhagic stroke.37 Hemorrhagic strokes have not been reported in families with the more common presenilin 1 mutations, though some of these families also have shown pathologically advanced CAA.38,39 Most studies suggest that the genes associated with familial CAA do not play a major role as risk factors for sporadic disease. Among 55 sporadic CAA patients reported in the literature,40-44 only one has shown the cystatin C Icelandic mutation.40 The significance of this one instance of cystatin C mutation is unclear, as the patient pathologically appeared to have sporadic rather than Icelandic CAA. Similar searches for APP mutations at AS positions 22 or 23 have yielded no instances in 111 reported sporadic CAA patients.19,40-43 A weak protective effect of an intronic polymorphism in presenilin 1 toward pathologic extent of CAA has been reported in a single series and only in homozygotes for the polymorphism.45 Among examined candidate genes, it is APOE that has emerged as the strongest predictor of risk for sporadic CAA-related ICH. APOE is comprised of three major allelic forms (⑀2, ⑀3, and ⑀4) that differ by cysteine/ arginine polymorphisms at positions 112 and 158. Studies of APOE and CAA indicate that the APOE ⑀4 allele increases risk for CAA as it does in AD.9,10 They have also yielded the unexpected finding that APOE ⑀2, generally found to protect from AD, instead acts as an additional risk factor for CAA.11,46 The two APOE alleles appear not only to increase the risk for CAA occurrence, but also to lower the age of first hemorrhage46 and to shorten the time to recurrent ICH.12 In the latter study of
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Figure 1. APP mutations associated with familial CAA. (A) Schematic centered on the region of APP that contains the 42-amino acid species of A (boxed amino acid residues). Mutations at A positions 21-23 associated with familial CAA are shown in boxes. Representative AD-associated mutations are also shown. (B) An anti-A immunostain of a section of frontal cortex (200⫻) from a 68-year-old man with the APP Iowa mutation.19 Cortical vessels are severely affected with CAA, whereas parenchymal deposition of A as diffuse plaques (arrow) is mild.
70 consecutive survivors of an initial lobar ICH, carriers of APOE ⑀2 or ⑀4 rebled at a 2-year rate of 28% compared with only 10% for patients with the common APOE ⑀3/⑀3 genotype. Although the relationship between APOE and lobar ICH has been studied primarily in hospitalized patients, its applicability was recently extended to a population-based sample drawn from the Greater Cincinnati/Northern Kentucky region.7 The presence of APOE ⑀2 or ⑀4 associated with an adjusted odds ratio for lobar ICH of 2.3 in this population, accounting for an attributable risk of 29% of all lobar ICH. Different mechanisms have been suggested for the effects of the two APOE allelic risk factors. APOE ⑀4 appears to act in CAA, as it does in AD, to promote deposition of A.47-49 APOE ⑀2, conversely, associates
not with the deposition of A but with the subsequent destructive changes that occur in the amyloid-laden vessel wall.46,50 APOE ⑀2 and ⑀4 thus appear to have complementary roles in CAA progression, a model supported by the observation that the rare APOE ⑀2/⑀4 genotype associates with a particularly severe disease course.12,46 One potential application of CAA genetics would be to predict risk for ICH in patients undergoing anticoagulation. A genetic analysis of 41 elderly patients with warfarin-associated ICH3 showed a significant overrepresentation of APOE ⑀2, specifically among those patients with ICH in lobar regions characteristic of CAA. Limited pathologic data from these series support the interpretation that ⑀2 promotes warfarin-related ICH through its association with CAA. These results highlight the possi-
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bility that a panel of genetic tests ultimately might be useful for distinguishing between patients at high and low risk for ICH when treated with anticoagulants.
Genes Associated With Hemostasis The dependence of ICH risk in anticoagulated patients on the degree of anticoagulation51,52 supports the possibility that genetic variation in the hemostasis pathway likewise might affect the likelihood of sporadic ICH. Relatively few studies have investigated the relationship between ICH and polymorphisms in coagulation factors,53 and to date no robust relationships have been fully established. The most extensively investigated coagulation factor in ICH has been factor XIII, a transglutaminase with an important role in clot formation related to the crosslinking of fibrin and other plasma proteins. Genetic deficiency of either the catalytic (a) or regulatory (b) subunit of factor XIII results in a clinical bleeding disorder with prominent and severe intracranial hemorrhages.54 Studies in sporadic ICH have focused on a relatively common polymorphism involving substitution of leucine for valine at position 34 (V34L) of the a-subunit. This polymorphism appears to confer functional changes on factor XIII, affecting both its thrombin-induced activation as well as its intrinsic enzymatic activity.55-58 Two casecontrol studies of 62 and 130 PICH patients found a modestly increased risk (odds ratio 1.7 for both studies) among carriers of V34L,59,60 whereas another study of 141 PICH and 60 subarachnoid hemorrhage patients reported no association.61 It should be noted that the epidemiologic data suggesting increased risk for PICH and decreased risk for thrombotic events such as myocardial infarction, ischemic stroke, or venous thrombosis associated with V34L59,62-65 appear to run opposite to the biochemical data predicting enhanced fibrin cross-linking.55-58 Further studies will be required to unravel this important question, including analysis of anticoagulated patients in whom thrombin-induced activation of factor XIII may be substantially altered. Relatively little data are available regarding PICH and other polymorphisms reportedly associated with hemostasis. The factor VG1691A Leiden mutation was examined in a single study of 140 PICH patients and appeared in only one patient (0.4% allele frequency), significantly less than the population frequency.61 The same study examined the G/A transition in the untranslated region of the prothrombin gene 3 and found no association with risk of ICH. Finally, a 10-nucleotide insert in the factor VII promoter (323 Ins) was present at slightly higher frequency in 99 PICH patients than 161 controls.61 Like all studies that involve the testing of multiple genes and polymorphisms, these interesting observations will require confirmation in independent data sets to rule out the possibility of spurious association. A polymorphism
(V279F) in the platelet-activating factor (PAF) acetylhydrolase gene found primarily in Asian populations has been reported at increased frequency in a study of Japanese patients with PICH.66 This finding again appears at odds with earlier biochemical data, which had found V279F to associate with decreased PAF inactivation (as well as increased risk for thrombotic strokes).67
Other Genetic Pathways Studies of the transforming growth factor- (TGF-) receptor-associated protein endoglin suggest a potential role for the TGF- pathway in promoting ICH. Genetic knockout of endoglin in mice causes abnormalities of vascular smooth muscle cell development and vascular endothelium remodeling,68 and a naturally occurring loss-of-function mutation is associated with hereditary human telangiectasia type I.69 A possible relationship between endoglin and sporadic PICH was suggested by the finding that homozygosity for a 6-base insertion in intron 7 of the endoglin gene was associated with a 4.8-fold increase in PICH.70 Another study found a similar association of the homozygous ⫹insert/⫹insert genotype with intracranial sacular aneurysms.71 Although no biochemical effects have been ascribed to this intronic polymorphism, the data suggest that it might be linked to a functional site in endoglin. The presence of polymorphisms in CYP2C9, the cytochrome P450 enzyme primarily responsible for hydroxylation of the potent S-isomer of warfarin, raises the possibility that genetic factors may affect a patient’s ability to remain in a therapeutic range of anticoagulation. Carriers of single amino acid substitutions in this enzyme (designated CYP2C9*2 and CYP2C9*3) appear to have decreased dosing requirements for warfarin and increased tendencies to reach supratherapeutic levels of anticoagulation during induction.72,73 These polymorphisms have not been analyzed in PICH, but highlight the possibility of exploring such a pharmacogenetic approach to identifying patients at highest risk for anticoagulation. Conspicuously absent from the list of genes discussed here are candidate risk factors specific for pathways involved in hypertensive hemorrhage. A recent study by Alberts et al74 suggests that such factors likely exist. The authors found 14 of 144 prospectively assessed PICH patients (9.8%) to have a family history positive for ICH, including 9 of 75 patients (12.0%) with ICH in the basal ganglionic or thalamic locations typical of hypertensive hemorrhage. Similarly, the population-based Greater Cincinnati/Northern Kentucky study found a positive history in a first degree relative to confer an adjusted odds ratio for ICH of 6.3, with significant effects in both the lobar and the nonlobar ICH subgroups.7 These results agree with the clinical observation that patients who develop HTN hemorrhage are not necessarily those with the most severe or poorly controlled hypertension, sug-
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gesting possible host susceptibility genes. Families with clusters of hypertensive ICH represent a promising resource for identification of candidate genes for this vascular disorder. Another approach will be molecular investigations into the pathology of hypertensive vasculopathy, a process that has gone relatively unexplored since the seminal studies of Fisher.75 Acknowledgement: I wish to thank Drs Mark J. Alberts, Daniel Woo, and Joseph P. Broderick for sharing data prior to publication; Dr Jonathan Rosand for critically reviewing this manuscript; and my research colleagues and collaborators who participated in studies described here.
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