The genetics of sporadic ruptured and unruptured intracranial aneurysms: a genetic meta-analysis of 8 genes and 13 polymorphisms in approximately 20,000 individuals

Clinical article

Restricted access

Object

Intracranial aneurysms (IAs) are thought to have a multifactorial origin. The authors undertook a comprehensive meta-analysis on all genes investigated using a case-control model in ruptured (subarachnoid hemorrhage) and unruptured aneurysms.

Methods

Electronic databases were searched until and including July 2008 for any candidate gene studied in IA or subarachnoid hemorrhage using a case-control model. The ORs and 95% CIs were determined for each gene-disease association using fixed and random effect models.

Results

Thirty studies of 8 genes and 13 polymorphisms were analyzed among 19,961 individuals (6622 cases and 13,339 controls). Two genes and 3 polymorphisms were associated with IA. The eNOS gene T786C polymorphism (OR 1.24, 95% CI 1.0–1.54; p = 0.05) and IL-6 gene G572C polymorphism (OR 7.08, 95% CI 2.85–17.57; p < 0.0001) both showed a significant association with ruptured/unruptured IA. The IL-6/G174C polymorphism exerted a significant protective effect against IA (OR 0.49, 95% CI 0.25–0.95; p = 0.04). The other candidate genes investigated (ACE, endoglin, APOE, elastin, MMP-3, and SERPINA3) showed no significant associations.

Conclusions

There is a likely genetic basis to sporadic IAs. However, the evidence base is small when compared against other complex disorders.

Abbreviations used in this paper: eNOS = endothelial nitric oxide synthase; IA = intracranial aneurysm; IL-6 = interleukin-6; NO = nitric oxide; PAR = population-attributable risk; pHet = probability test for heterogeneity; SAH = subarachnoid hemorrhage; SNP = single nucleotide polymorphism.

Article Information

Address correspondence to: Pankaj Sharma, M.D., Ph.D., F.R.C.P. email: pankaj.sharma@imperial.ac.uk.

Please include this information when citing this paper: published online September 25, 2009; DOI: 10.3171/2009.8.JNS092.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Flowchart illustrating number of studies included in the meta-analyses.

  • View in gallery

    Forest plot of pooled OR of eNOS 786C in IAs. The 95% CIs are drawn with the size of the box reflecting the weighting given to each study. M-H = Mantel-Haenszel.

References

  • 1

    Akagawa HKasuya HOnda HYoneyama TSasahara AKim CJ: Influence of endothelial nitric oxide synthase T-786C single nucleotide polymorphism on aneurysm size. J Neurosurg 102:68712005

  • 2

    Ariyaratnam RCasas JPWhittaker JSmeeth LHingorani ADSharma P: Genetics of ischaemic stroke among persons of non-European descent: a meta-analysis of eight genes involving approximately 32,500 individuals. PLoS Med 4:e1312007

  • 3

    Broderick JPBrott TTomsick THuster GMiller R: The risk of subarachnoid and intracerebral hemorrhages in blacks as compared with whites. N Engl J Med 326:7337361992

  • 4

    Bromberg JERinkel GJAlgra AGreebe Pvan Duyn CMHasan D: Subarachnoid haemorrhage in first and second degree relatives of patients with subarachnoid haemorrhage. BMJ 311:2882891995

  • 5

    Brull DJMontgomery HESanders JDhamrait SLuong LRumley A: Interleukin-6 gene −174g>c and −572g>c promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery. Arterioscler Thromb Vasc Biol 21:145814632001

  • 6

    Casas JPHingorani ADBautista LESharma P: Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol 61:165216612004

  • 7

    Deeks JJ: Systematic reviews in health care: systematic reviews of evaluations of diagnostic and screening tests. BMJ 323:1571622001

  • 8

    DerSimonian RLaird N: Meta-analysis in clinical trials. Control Clin Trials 7:1771881986

  • 9

    Egger MDavey Smith GSchneider MMinder C: Bias in meta-analysis detected by a simple, graphical test. BMJ 315:6296341997

  • 10

    Faraci FMBrian JE Jr: Nitric oxide and the cerebral circulation. Stroke 25:6927031994

  • 11

    Fishman DFaulds GJeffery RMohammed-Ali VYudkin JSHumphries S: The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 102:136913761998

  • 12

    Fontanella MRainero IGallone SRubino EFenoglio PValfre W: Interleukin 6 gene polymorphisms are not associated with aneurysmal subarachnoid haemorrhage in an Italian population. J Neurol Neurosurg Psychiatry 79:4714732008

  • 13

    Fontanella MRainero IGallone SRubino ERivoiro CValfre W: Lack of association between the apolipoprotein E gene and aneurysmal subarachnoid hemorrhage in an Italian population. J Neurosurg 106:2452492007

  • 14

    Georges JLLoukaci VPoirier OEvans ALuc GArveiler D: Interleukin-6 gene polymorphisms and susceptibility to myocardial infarction: the ECTIM study. Etude Cas-Témoin de l'Infarctus du Myocarde. J Mol Med 79:3003052001

  • 15

    Guzik TJWest NEPillai RTaggart DPChannon KM: Nitric oxide modulates superoxide release and peroxynitrite formation in human blood vessels. Hypertension 39:108810942002

  • 16

    Hofer AHermans MKubassek NSitzer MFunke HStogbauer F: Elastin polymorphism haplotype and intracranial aneurysms are not associated in Central Europe. Stroke 34:120712112003

  • 17

    Hoggart CJParra EJShriver MDBonilla CKittles RAClayton DG: Control of confounding of genetic associations in stratified populations. Am J Hum Genet 72:149215042003

  • 18

    Hop JWRinkel GJAlgra Avan Gijn J: Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 28:6606641997

  • 19

    Humphries SELuong LAOgg MSHawe EMiller GJ: The interleukin-6 −174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men. Eur Heart J 22:224322522001

  • 20

    Inagawa TTokuda YOhbayashi NTakaya MMoritake K: Study of aneurysmal subarachnoid hemorrhage in Izumo City, Japan. Stroke 26:7617661995

  • 21

    Johanning JMArmstrong PJFranklin DPHan DCCarey DJElmore JR: Nitric oxide in experimental aneurysm formation: early events and consequences of nitric oxide inhibition. Ann Vasc Surg 16:65722002

  • 22

    Joo SPLee JKKim TSKim MKLee IKSeo BR: A polymorphic variant of the endoglin gene is associated with increased risk for intracranial aneurysms in a Korean population. Surg Neurol 70:39442008

  • 23

    Juvela SPorras MPoussa K: Natural history of unruptured intracranial aneurysms: probability of and risk factors for aneurysm rupture. J Neurosurg 93:3793872000

  • 24

    Kamitani ARakugi HHigaki JOhishi MShi SJTakami S: Enhanced predictability of myocardial infarction in Japanese by combined genotype analysis. Hypertension 25:9509531995

  • 25

    Kaushal RWoo DPal PHaverbusch MXi HMoomaw C: Subarachnoid hemorrhage: tests of association with apolipoprotein E and elastin genes. BMC Med Genet 8:492007

  • 26

    Keramatipour MMcConnell RSKirkpatrick PTebbs SFurlong RARubinsztein DC: The ACE I allele is associated with increased risk for ruptured intracranial aneurysms. J Med Genet 37:4985002000

  • 27

    Khurana VGSohni YRMangrum WIMcCelland RLO'Kane DJMeyer FB: Endothelial nitric oxide synthase gene polymorphisms predict susceptibility to aneurysmal subarachnoid hemorrhage and cerebral vasospasm. J Cereb Blood Flow Metab 24:2912972004

  • 28

    Kirkpatrick PJ: Subarachnoid haemorrhage and intracranial aneurysms: what neurologists need to know. J Neurol Neurosurg Psychiatry 73:Suppl 1i28i332002

  • 29

    Kokubo YChowdhury AHDate CYokoyama TSobue HTanaka H: Age-dependent association of apolipoprotein E genotypes with stroke subtypes in a Japanese rural population. Stroke 31:129913062000

  • 30

    Krex DFortun SKuhlisch ESchackert HKSchackert G: The role of endothelial nitric oxide synthase (eNOS) genetic variants in European patients with intracranial aneurysms. J Cereb Blood Flow Metab 26:125012552006

  • 31

    Krex DSchackert HKSchackert G: Genesis of cerebral aneurysms—an update. Acta Neurochir (Wien) 143:4294482001

  • 32

    Krex DZiegler ASchackert HKSchackert G: Lack of association between endoglin intron 7 insertion polymorphism and intracranial aneurysms in a white population: evidence of racial/ethnic differences. Stroke 32:268926942001

  • 33

    Krischek BAkagawa HTajima ANarita AKasuya HHori T: The alanine/threonine polymorphism of the alpha-1-antichymotrypsin (SERPINA3) gene and ruptured intracranial aneurysms in the Japanese population. Cerebrovasc Dis 23:46492007

  • 34

    Krischek BKasuya HAkagawa HTajima ANarita AOnda H: Using endothelial nitric oxide synthase gene polymorphisms to identify intracranial aneurysms more prone to rupture in Japanese patients. J Neurosurg 105:7177222006

  • 35

    Kuhlencordt PJGyurko RHan FScherrer-Crosbie MAretz THHajjar R: Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice. Circulation 104:4484542001

  • 36

    Longstreth WT JrNelson LMKoepsell TDvan Belle G: Clinical course of spontaneous subarachnoid hemorrhage: a population-based study in King County, Washington. Neurology 43:7127181993

  • 37

    Mantel NHaenszel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:7197481959

  • 38

    McCarron MONicoll JA: High frequency of apolipoprotein E epsilon 2 allele is specific for patients with cerebral amyloid angiopathy-related haemorrhage. Neurosci Lett 247:45481998

  • 39

    Moncada SPalmer RMHiggs EA: Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:1091421991

  • 40

    Morgan LCooper JMontgomery HKitchen NHumphries SE: The interleukin-6 gene −174G>C and −572G>C promoter polymorphisms are related to cerebral aneurysms. J Neurol Neurosurg Psychiatry 77:9159172006

  • 41

    Nahed BVBydon MOzturk AKBilguvar KBayrakli FGunel M: Genetics of intracranial aneurysms. Neurosurgery 60:2132262007

  • 42

    Onda HKasuya HYoneyama THori TNakajima TInoue I: Endoglin is not a major susceptibility gene for intracranial aneurysm among Japanese. Stroke 34:164016442003

  • 43

    Ozum UBolat NGul EOzdemir O: Endothelial nitric oxide synthase gene [G894T] polymorphism as a possible risk factor in aneurysmal subarachnoid haemorrhage. Acta Neurochir (Wien) 150:57612008

  • 44

    Pannu HKim DHSeaman CRvan Ginhoven GShete SMilewicz DM: Lack of an association between the angiotensin-converting enzyme insertion/deletion polymorphism and intracranial aneurysms in a Caucasian population in the United States. J Neurosurg 103:92962005

  • 45

    Peck GSmeeth LWhittaker JCasas JPHingorani ASharma P: The genetics of primary haemorrhagic stroke, subarachnoid haemorrhage and ruptured intracranial aneurysms in adults. PLoS One 3:e36912008

  • 46

    Pera JSlowik ADziedzic TBorratynska ARog TMBetlej M: Endoglin gene insertion polymorphism not associated with aneurysmal subarachnoid hemorrhage. J Neurosurg 102:8798812005

  • 47

    Peters DGKassam ABChang YF: A DNA sequence polymorphism in the endoglin gene is not associated with intracranial aneurysm or aneurysmal subarachnoid hemorrhage. Cerebrovasc Dis 20:961002005

  • 48

    Qureshi AISuri MASafdar KOttenlips JRJanssen RSFrankel MR: Intracerebral hemorrhage in blacks. Risk factors, subtypes, and outcome. Stroke 28:9619641997

  • 49

    Rinkel GJDjibuti MAlgra Avan Gijn J: Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke 29:2512561998

  • 50

    Robins JGreenland SBreslow NE: A general estimator for the variance of the Mantel-Haenszel odds ratio. Am J Epidemiol 124:7197231986

  • 51

    Ruigrok YMRinkel GJWijmenga C: Genetics of intracranial aneurysms. Lancet Neurol 4:1791892005

  • 52

    Ruigrok YMSeitz UWolterink SRinkel GJWijmenga CUrban Z: Association of polymorphisms and haplotypes in the elastin gene in Dutch patients with sporadic aneurysmal subarachnoid hemorrhage. Stroke 35:206420682004

  • 53

    Sablotzki AEbel HMuhling JDehne MGNopens HGiesselmann H: Dysregulation of immune response following neurosurgical operations. Acta Anaesthesiol Scand 44:82872000

  • 54

    Sadamitsu DKuroda YNagamitsu TTsuruta RInoue TUeda T: Cerebrospinal fluid and plasma concentrations of nitric oxide metabolites in postoperative patients with subarachnoid hemorrhage. Crit Care Med 29:77792001

  • 55

    Slowik ABorratynska APera JBetlej MDziedzic TKrzyszkowski T: II genotype of the angiotensin-converting enzyme gene increases the risk for subarachnoid hemorrhage from ruptured aneurysm. Stroke 35:159415972004

  • 56

    Slowik ABorratynska ATuraj WPera JDziedzic TFiglewicz DA: Alpha1-antichymotrypsin gene (SERPINA3) A/T polymorphism as a risk factor for aneurysmal subarachnoid hemorrhage. Stroke 36:7377402005

  • 57

    Song JYoon YPark KUPark JHong YJHong SH: Genotype-specific influence on nitric oxide synthase gene expression, protein concentrations, and enzyme activity in cultured human endothelial cells. Clin Chem 49:8478522003

  • 58

    Song MKKim MKKim TSJoo SPPark MSKim BC: Endothelial nitric oxide gene T-786C polymorphism and subarachnoid hemorrhage in Korean population. J Korean Med Sci 21:9229262006

  • 59

    Sun HZhang DZhao J: The interleukin-6 gene −572G>C promoter polymorphism is related to intracranial aneurysms in Chinese Han nationality. Neurosci Lett 440:132008

  • 60

    Takenaka KSakai HYamakawa HYoshimura SKumagai MYamakawa H: Polymorphism of the endoglin gene in patients with intracranial saccular aneurysms. J Neurosurg 90:9359381999

  • 61

    Tang JZhao JZhao YWang SChen BZeng W: Apolipoprotein E epsilon4 and the risk of unfavorable outcome after aneurysmal subarachnoid hemorrhage. Surg Neurol 60:3913962003

  • 62

    Wang XLSim ASWang MXMurrell GATrudinger BWang J: Genotype dependent and cigarette specific effects on endothelial nitric oxide synthase gene expression and enzyme activity. FEBS Lett 471:45502000

  • 63

    Weir BMacDonald L: Cerebral vasospasm. Clin Neurosurg 40:40551993

  • 64

    Yoon STromp GVongpunsawad SRonkainen AJuvonen TKuivaniemi H: Genetic analysis of MMP3, MMP9, and PAI-1 in Finnish patients with abdominal aortic or intracranial aneurysms. Biochem Biophys Res Commun 265:5635681999

  • 65

    Zhang BDhillon SGeary IHowell WMIannotti FDay IN: Polymorphisms in matrix metalloproteinase-1, -3, -9, and -12 genes in relation to subarachnoid hemorrhage. Stroke 32:219822022001

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 106 106 13
Full Text Views 149 149 0
PDF Downloads 98 98 0
EPUB Downloads 0 0 0

PubMed

Google Scholar