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Introduction
Primary intracerebral hemorrhage(ICH), defined as hemorrhage within the brain parenchyma in the absence of readily identifiable causes, occurs with an annual incidence rate of 15 to 19 per 100000,76) and the 30-day case mortality rate is 40% to 50%.14) Indeed, genetic and environmental risk factors likely play a role in the occurrence of ICH. Although conventional risk factors such as lipid profiles, smoking, and hypertension accounted for a considerable part of the stroke events, most subjects with these risk factors do not develop stroke during their lifetime, suggesting that other factors are also involved.35) Recently, ICH has become increasingly accessible to genetic investigation, a result of technologic advances in both clinical diagnosis and molecular genetics.3)34) Several groups of investigators have reported that the biology of candidate genes have given important clues to potential genetic risk factors for primary ICH.2)7)8)17)27)39)53)62)63)72)80) Information generated by these studies has benefited our understanding of the pathophysiology of ICH, pointing to specific genes and alleles with roles in the disease process.
1. General considerations：Homogeneity and heterogeneity of primary ICH
Investigators must decide whether more homogenous phenotypic subtypes should be studied separately to identify genetic risk factors. For example, apolipoprotein E(APOE) genotype appears to be related to risk of cerebral amyloid angiopathy(CAA)-related ICH but unrelated to the risk of other types of hemorrhage.32)53)77) Thus, whereas there will likely be some genetic factors that affects all subtypes of ICH equally, it is reasonable to assume that genetic factors related to specific vascular processes will affect ICH subtypes differently. Fortunately, ICH appears to occur by relatively few major pathophysiologic mechanisms, and these mechanisms often can be distinguished during life.43) The ability to split patients into reliable subtypes may indeed render the genetics of ICH a more tractable problem than the genetics of ischemic stroke. The clinical course followed by ICH patients is also heterogeneous, 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 ICH(typically by case-control analysis), but also for the severity of ICH(as a cohort study). A final complication in the interpretation of stroke genetics is the likely interaction of genetic and environmental risk factors. Particular genetic polymorphisms may alter risk for hypertension or during anticoagulation, for example.
2. Genetic risk factors for ICH
1) Genes associated with cerebral amyloid angiopathy
(1) Mutations at β-amyloid peptide positions 22 and 23
The genetics of CAA have been studied for both familial and sporadic forms. CAA typically entails vascular deposition of the β-amyoid peptide(Aβ), a 39- to 43-amino acid fragment derived from the β-amyloid precursor protein (APP). At least 4 mutations in the APP gene have been implicated in autosomal dominant forms of familial CAA. Interestingly, these CAA-related mutations occur in a cluster from amino acid positions 21 to 23 of APP's Aβ-cording region. Using names assigned according to the residence of the index family, these include the Flemish A21G mutation,36) the Dutch E22Q15,70) and Italian E22K17,57) mutations at amino acid position 22, and the Iowa D23N mutation.29) Each point mutation is associated with prominent CAA and hemorrhagic lesions, though the Iowa and Flemish kindred show substantial Alzheimer's disease pathology as well.29)36) Dutch-type hereditary CAA, the best characterized of these genetic syndromes, is associated with recurrent ICH, relatively little AD pathology, and early mortality.10)74) CAA-associated mutations at Aβ positions 22 and 23 appear to generate an Aβ peptide with heightened fibrillogenic properties and increased toxicity toward components of the vessel wall.19)22)55)57)73) The precise biochemical mechanism for the increased toxicity remains to be determined. Melchor et al55) have implicated the loss of the negatively charged residues as playing an important role.
(2) Several other genes with familial CAA
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 result in Icelandic CAA, characterized by very early deposition of a mutant protein fragment in vessel walls and symptomatic ICH by the third and fourth decade of life.48)65) Familial British dementia caused by mutation in the BRI gene is another form of CAA without Aβ deposition and hemorrhagic stroke.54) Mutations also have been characterized in presenilin 1 and 2, two related genes associated with familial Alzheimer's disease and altered processing APP. A pedigree with mutant presenilin 2 has been reported in which patients show advanced CAA and at least on family member with hemorrhagic stroke.61) 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.79) 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, only one has shown the cystatin C Icelandic mutation.6)30)40)52)59) 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 homozygote for the polymorphism.78)
(3) Polymorphisms of apolipoprotein E
APOE is a polymorphic member of a family of proteins that transport lipids in blood and other body fluids and is also associated with brain amyloid. APOE is comprised of three major allelic forms(ε2, ε3, and ε4) that differ by cysteine/arginine polymorphisms at positions 112 and 158. Studies of APOE and CAA indicate that the APOE ε2 and ε4 alleles increase risk for CAA.32)60) The two APOE alleles appear not only to increase the risk for CAA occurrence, but also to lower the age of first hemorrhage and to shorten the time to recurrent ICH.33)62) The presence of APOE ε2 or ε4 associated with an adjusted odds ratio for lobar ICH of 2.3 in the Greater Cincinnati/Northern Kentucky region, accounting for an attributable risk of 29% of all lobar ICH.77) Different mechanisms have been suggested for the effects of the two APOE allelic risk factor. APOE ε4 appears to act in CAA to promote deposition of Aβ.5)64)68) APOE ε2, conversely, associates not with the deposition of Aβ but with the subsequent destructive changes that occur in the amyloid-laden vessel wall.33) One potential application of APOE polymorphisms would be to predict risk for ICH in patients undergoing anticoagulation. A genetic analysis of 41 elderly patients with warfarin-associated ICH showed a significant overrepresentation of APOE ε2, specifically among those patients with ICH in lobar regions characteristic of CAA. These results highlight the possibility 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.
2) Genes associated with hemostasis
The dependence of ICH risk in anticoagulated patients on the degree of anticoagulation supports the possibility that genetic variation in the hemostasis pathway likewise might affect the likelihood of sporadic ICH.25)38) Relatively few studies have investigated the relationship between ICH and polymorphisms in coagulation factors,46) 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 cross-linking 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 ICH.7) 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.42)44) Some studies found a modestly increased risk(odd ratio 1.7) among carriers of V34L,15)28) whereas another study reported no association.16)18)24) It should be noted that the epidemiologic data suggesting increased risk for ICH and decreased risk for thrombotic events such as myocardial infarction, ischemic stroke, or venous thrombosis associated with V34L,23)26)45) appear to run opposite to the biochemical data predicting enhanced fibrin cross-linking.42)44) Further studies will be required to unravel this important in whom thrombin-induced activation of factor XIII may be substantially altered.
Relatively little data are available regarding ICH and other polymorphisms reportedly with hemostasis. The factor VG-1691A Leiden mutation was examined in a single study of 140 ICH patients and appeared in only one patients(0.4% allele frequency), significantly less than the population frequency.18) 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. Also, a 10-nucleotide insert in the factor VII promoter(323 Ins) was present at slightly higher frequency in 99 ICH patients than 161 controls.18) 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 ICH.80) 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).37)
Platelets play a key role in generating the protective hemostatic role that avoids blood loss at sites of vascular injury. Platelet -platelet aggregation is mediated by both major platelet receptors：glycoprotein(GP) IIb/IIIa and GP Ib-IX-V. The relevance of GP IIb/IIa, GP Ib-IX-V and GP Ia/IIa in hemostasis is demonstrated by the bleeding tendency associated with inherited or acquired deficiency of these proteins. During the last decade, it has been demonstrated that common polymorphisms affecting important platelet GPs determine changes in the structure or level of these adhesive molecules.12) Several reports suggested that polymorphisms affecting the structure or level of the main adhesive platelet glycoproteins(GPs) could behave as genetic risk factors for arterial thrombotic disorders.39)56)
Finally, moderate elevation of plasma homocysteine is a recently established risk factor for cerebrovascular disease.11)31)66) However, its role in stroke remains controversial. Although most case-control studies suggest a positive association between homocysteine and stroke,11)31)66) it has not been established in nested case-control studies.4)71) Methylenetetrahydrofolate reductase(MTHFR) is an important enzyme in modulation of plasma homocysteine by converting it into methionine. Polymorphism of MTHFR C677T leads to a reduction in enzyme activity and subsequent elevation of plasma homocysteine.41) Relatively little data are available regarding ICH and polymorphism of the MTHFR reportedly associated with hyperhomocysteinemia. One study in China resulted that the C677T polymorphism of the MTHFR gene was not associated with increased risk of ICH and total plasma homocysteine was correlated with both ischemic and hemorrhagic stroke.50) This study suggests potential initiation of homocysteine-lowering therapy in ischemic and hemorrhagic stroke.
3) Other genetic pathways
Studies of the transforming growth factor-β(TGF-β) receptor-associated protein endoglin suggest a potential role for the TGF-β pathway in promoting ICH. Genetic knockout of endoglin in mice causes abnormalities of vascular smooth muscle cell development and vascular endothelium remodeling,49) and a naturally occurring loss-of-function mutation is associated with hereditary human telangiectasia type I.51) A possible relationship between endoglin and sporadic ICH 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 ICH.
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