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| REVIEW ARTICLE |
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| Year : 2012 | Volume
: 60
| Issue : 1 | Page : 3-8 |
Genetics of intracerebral hemorrhage: Insights from candidate gene approaches
Baoqiong Liu, Le Zhang, Qidong Yang
Department of Neurology, Xiangya Hospital, Central South University, China
| Date of Submission | 23-Oct-2011 |
| Date of Decision | 16-Nov-2011 |
| Date of Acceptance | 15-Jan-2012 |
| Date of Web Publication | 7-Mar-2012 |
Correspondence Address:
Qidong Yang
Department of Neurology, Xiangya Hospital, Central South University
China
 Source of Support: National Natural Science Foundation of China (Grant Numbers 30600199)., Conflict of Interest: None  | Check |
DOI: 10.4103/0028-3886.93581
Intracerebral hemorrhage (ICH) is a heterogeneous disease with genetic factors playing an important role. Association studies on a wide range of candidate pathways suggest a weak but significant effect for several alleles with ICH risk. Among the most widely investigated genes are those involved in the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme), coagulation pathway (e.g., Factor XIII, Factor VII, platelet-activating factor acetylhydrolase, Factor V Leiden, and beta1-tubulin), lipid metabolism (e.g., apolipoproteins (Apo)E, Apo(a), ApoH), homocysteine metabolism (e.g., methylenetetrahydrofolate reductase), inflammation (e.g., interleukin-6 and tumor necrosis-alpha) and other candidate pathways. To identify the robustness of the above associations with ICH, a search of Pubmed (1988 through December 2011) was performed, with searches limited to English-language studies conducted among adult human subjects. This article presents a review of the examined literature on the genetics of ICH.
Keywords: Candidate genes, intracerebral hemorrhage, polymorphism
How to cite this article:
Liu B, Zhang L, Yang Q. Genetics of intracerebral hemorrhage: Insights from candidate gene approaches. Neurol India 2012;60:3-8 |
| » Introduction | |  |
Stroke is the second leading cause of death and main cause of disability worldwide. [1],[2] Intracerebral hemorrhage (ICH) accounts for 10-55% of all strokes. [3],[4],[5] Etiology of ICH is multifactorial. Studies involving twins and families have detected significant evidence for genetic factors, [6],[7],[8],[9],[10],[11] however, the extent of predisposition remains unknown. We reviewed published articles related to the role of genetic polymorphisms in ICH. Pubmed (1988 through December 2011) was searched to identify studies. Literature searches were limited to English-language research articles conducted among adult human subjects and the results are discussed below.
Renin-angiotensin-aldosterone genes
The renin-angiotensin-aldosterone system (RAAS) is a hormone system that regulates blood pressure and fluid balance. Among the genes related to RASS, the angiotensin-converting enzyme (ACE) gene has been the most studied. The ACE gene has an insertion (I)/deletion (D) polymorphism in Intron 16, which has been associated with variations in ACE activity [12],[13] and ischemic stroke. [14] Genetic studies of this sequence difference in ICH have produced conflicting results. The DD genotype has been associated with ICH in Polish and Indian populations. [15],[16] A meta-analysis of 6,359 cases and 13,805 controls revealed significant associations of homozygosity for the ACE/I allele with hemorrhagic stroke. [17] However, no differences in genotype frequency were observed between controls and subjects with ICH in Chinese, [18] Japanese, [19] or Greek cohorts, [20] or in Leeds. [21]
Fewer studies have addressed the relationship between other RAAS-related genes and ICH. In a study in Japan, it was found that renin gene MboI site m allele was associated with an increased risk of cerebral bleeding. [22] No association has been found between ICH and the angiotensinogen gene or angiotensin II Type I receptor gene. [23],[18],[19]
Blood coagulation system genes
Coagulation involves both a cellular (platelet) and protein (coagulation factor) component. Deficiency or dysfunction of any coagulation factor can lead to bleeding disease.
Factor XIII
Inherited deficiency of the proenzyme Factor XIII is a very rare autosomal-recessive bleeding disorder characterized by a particularly high rate of intracranial hemorrhage. [24] The Val34Leu polymorphism of Factor XIII gene has been associated with high Factor XIII activity. [25],[26] Association studies of this polymorphism with ICH have generated conflicting results. [27],[28],[29],[30],[31],[32] Two other common polymorphisms of the Factor XIII subunit A, Tyr204Phe and Pro564Leu, were examined together with the plasminogen activator inhibitor (PAI)-1 polymorphism 5G/5G in white women with ICH (n=42, age <45 years). Tyr204/Phe204 and Leu564/Leu564 were both associated with an increased risk of hemorrhagic stroke, which was further magnified when either genotype was combined with the PAI-1 5G/5G genotype. [33]
Factor VII
Factor VII initiates the extrinsic pathway of coagulation and plays a key role in various bleeding disorders. Congenital Factor VII deficiency predisposes patients to spontaneous bleeding. [34] A case-control study in 201 patients with ICH and 201 controls found that carriers of the -323Ins allele of Factor VII had a 1.54-fold risk for ICH. [35] Another study showed no significant association between the -401G > T polymorphism and ICH. [36]
Platelet-activating factor acetylhydrolase
Platelet-activating factor (PAF), a phospholipid contained within the platelet granules, is inactivated by PAF acetylhydrolase. Deficiency of this enzyme is caused by a missense mutation (V279F) in Exon 9 of the gene, [37] which is also a genetic risk factor for stroke. [38] A case-control study of 99 ICH patients and 138 hypertension patients in Japan showed an association of the V279F mutation with ICH. [39]
Other hemostatic gene variants
Factor V GI691A Leiden mutation and G/A transition in the 3'-untranslated region of the prothrombin gene were examined in 140 primary ICH patients. Frequency of the prothrombin 20210A/G genotype was lower in patients than in controls, whereas there was no significant difference in the prevalence of the V GI691A Leiden mutation. [35] In a study of 259 patients with ICH and 449 controls, the beta1-tubulin Q43P polymorphism significantly increased ICH risk in men and was associated with an earlier age of ICH occurrence. [40] Two additional studies showed no association between genetic platelet glycoprotein variants and ICH. [41],[42]
Lipid metabolism-related genes
Dyslipidemia is a major risk factor for stroke.
Apolipoprotein E
Apolipoprotein E (ApoE) plays a major role in lipid transport and metabolism. ApoE ∈2 and ∈4 alleles have been established as risk factors for cerebral amyloid angiopathy (CAA), [43],[44] which is the major cause of lobar ICH in the elderly. [45] However, studies have produced conflicting results regarding the influence of ApoE alleles on predisposition to ICH. Several studies have reported an association between the ∈4 allele and ICH risk, [46],[47],[48] with carriers of the ε4 genotype showing poorer outcome and reduced survival. [49],[50] However, a meta-analysis of 31 studies (5961 cases, 17,965 controls) showed that the ∈2+ genotype, but not the ∈4+ genotype, was associated with ICH. Associations were stronger for lobar than for deep hemorrhages. [51] In a prospective study of 5671 subjects, the ∈2 and ∈4 alleles were associated with an increased risk of ICH. Most of the estimated risks were higher in Asians than in Europeans. [52] However, the ApoE genotype was not confirmed as a candidate in an unselected Central European population. [53]
ApoH
ApoH has been implicated in lipid metabolism, hemostasis, and antiphospholipid antibody production. [54],[55],[56] The variation in ApoH plasma levels is thought to be under genetic control. [57],[58] Four polymorphisms of ApoH were examined in 140 ICH patients in a Chinese population. Frequencies of the A allele of G341A were significantly higher in ICH patients than in controls, especially in ICH patients with hypertension and a family history of stroke. No differences in the genotype frequencies of the G817T, G1025C, and C1080T polymorphisms were found. [59]
Apo(a)
Apo(a) is a glycoprotein that comprises lipoprotein(a) [Lp(a)]. Plasma Lp(a) levels have been associated with hemorrhagic stroke [60] and with the pentanucleotide TTTTA repeat (PNTR) polymorphism at the 5' untranslated region of the apo(a) gene. [61] Low-number repeats (sum of both alleles <16) of Apo(a) pentanucleotide TTTTA repeat polymorphism have been associated with both hemorrhagic and atherothrombotic stroke. [61]
Homocysteine metabolism-related genes
Elevated homocysteine levels have been associated with hemorrhagic and ischemic stroke. [62] Remethylation of homocysteine to methionine requires 5-methyltetrahydrofolate, which is generated from dietary folate through the action of methylenetetrahydrofolate reductase (MTHFR). Two polymorphisms in the MTHFR gene, C677T and A1298C, have been shown to reduce enzyme activity and elevate plasma homocysteine levels. [63],[64] These polymorphisms were also found to be genetic risk factors for hemorrhagic and ischemic stroke, respectively, independent of other atherothrombotic risk factors in a Turkish Caucasian population. [65] In a case-control study of Mongolian patients with ICH, the C677T polymorphism TT genotype was more common in patients with ICH and was associated with reduced plasma folate levels. [66] However, no association of the C677T polymorphism with ICH was observed in a Chinese population or in India. [62],[67]
Inflammation-related genes
Interleukin-6 (IL-6) is an inflammatory cytokine that may be pivotal in the pathogenesis of vascular disease. The -572G>C polymorphism of the IL-6 gene was examined in 3151 Japanese individuals. Multivariable logistic regression analysis revealed that the -572G>C polymorphism was significantly associated with ICH. [68] However, the -174G>C polymorphism showed no association with respect to ICH. [69]
Tumor necrosis factor-alpha (TNF-α) is a primary proinflammatory cytokine that plays an important role in initiating and regulating inflammatory responses. Associations of spontaneous deep ICH with four single-nucleotide polymorphisms (T-1031C, C-863A, C-857T, and G-308A) within the TNF-α gene promoter were examined in a Taiwanese population. The ICH risk was positively associated with minor alleles -1031C and -308A in men, but inversely associated with -863A in females, which indicated that the associations were gender-dependent. [70]
Other candidate pathways
In addition to the above systems, other candidate pathways have been associated with ICH, including extracellular matrix (ECM) degradation, estrogen receptor signaling, and antioxidant systems. Tissue inhibitor of metalloproteinase (TIMP)-2 plays a significant role in matrix metalloproteinase-mediated ECM degradation and tissue remodeling. In Caucasians, homozygosity for the A allele of the -261G/A polymorphism in the TIMP-2 gene was associated with an increased risk of ICH. [71] Signaling through estrogen receptor alpha (coded by ESR1) regulates vasodilation and atherogenesis. Variations in the ESR1 gene have been associated with plasma estradiol levels, [72] blood pressure, [73] and lipid levels. [74] A recent case-control study showed an increased risk of first-time ICH in carriers of the c.454-397T/T genotype, particularly in combination with hypertension, even after adjustment for conventional stroke determinants. [75] Glutathione peroxidase 1 (GPX1) is a key enzyme of the antioxidant system. Recently, genotypes containing the T allele of the C593T polymorphism in the GPX1 gene were shown to be related to entire ICH and lobar ICH, but not non-lobar ICH. [76] Alpha-1 antichymotrypsin (ACT) is an acute-phase protein member of the serine proteinase inhibitors. [77] Several studies have examined the ACT gene with respect to ICH, with some studies showing an association [78],[79] and others failing to find an effect. [80],[81],[82] The osteoprotegerin -1181C/C genotype, [69] transforming growth factor beta receptor II (TGFBR2) Asn389Asn genotype, [83] and homozygosity for a six-base insertion in Intron 7 of the endoglin gene [84] also have been associated with ICH. A recent study of 150 polymorphisms in Japanese individuals revealed that the C > T polymorphism (rs1324694) of ERLIN1, C>T polymorphism (rs12679196) of TRAPPC9, and G>T polymorphism (rs16936752) of WNK2 were associated with ICH prevalence. [85] In another large genetic epidemiological study, nine polymorphisms, including those in IL-6, TNF, CD14, FBN1, PECAM1, UCP1, CPB2, LIPC, and CCL5, were related to ICH. [86]
Genetic polymorphisms and recurrence of intracerebral hemorrhage
Genetic variants also play a role in ICH recurrence. The most common pattern of ICH recurrence in Asia is ganglionic-ganglionic, [87],[88],[89] whereas most recurrences in European countries are of the lobar-lobar type. [90],[91] The ApoE ε2/ε4 genotype has been associated with recurrence of lobar ICH. [92] The W allele of the ADD1gene in isolation or in combination with the D allele of the ACE gene has been associated with recurrence of hypertensive ICH. [89]
| » Conclusions | | |
Extensive genetic studies have addressed the relationship between ICH and candidate genes, with conflicting results. It is difficult to know the precise reasons for the observed inconsistencies among different studies. Results may vary with the genetic setting, method of approach, demographic variables, and nonparticipation rate. Candidate genes and ICH have been studied in different ethnic groups, with ethnic heterogeneity in allele frequencies. This heterogeneity may partially explain the differences among the results. Most of the studies in this review did not divide ICH into lobar and deep ICH subtypes. Deep ICH is mainly due to hypertension, whereas lobar ICH is mostly due to cerebral amyloid angiopathy. These two subtypes may have different molecular genetics' bases, because their etiologies are different. Some of the studies in this review were quite small, such that the observed negative associations may be false. Finally, few of the reports on the genetics of ICH provided refusal rates or addressed the factors that may affect refusal. Because of this lack of information about nonparticipation, it is impossible to determine whether a particular study was subject to selection bias. ICH is a multifactorial disease. There are limitations to the use of single-gene approaches. Genes may interact with each other or with environmental factors to contribute to ICH development. More large-scale population genetic association studies with further comprehensive analyses will be required to identify susceptibility genes and to detect the gene-gene or gene-environment interactions.
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