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Meta-Analysis
. 2008;3(11):e3691.
doi: 10.1371/journal.pone.0003691. Epub 2008 Nov 14.

The genetics of primary haemorrhagic stroke, subarachnoid haemorrhage and ruptured intracranial aneurysms in adults

George Peck  1 , Liam Smeeth, John Whittaker, Juan Pablo Casas, Aroon Hingorani, Pankaj Sharma
Affiliations
Meta-Analysis

The genetics of primary haemorrhagic stroke, subarachnoid haemorrhage and ruptured intracranial aneurysms in adults

George Peck et al. PLoS One. 2008.

Abstract

Background: The genetic basis of haemorrhagic stroke has proved difficult to unravel, partly hampered by the small numbers of subjects in any single study. A meta-analysis of all candidate gene association studies of haemorrhagic stroke (including ruptured subarachnoid haemorrhage and amyloid angiopathy-related haemorrhage) was performed, allowing more reliable estimates of risk.

Methods: A systematic review and meta-analysis of all genetic studies in haemorrhagic stroke was conducted. Electronic databases were searched until and including March 2007 for any candidate gene in haemorrhagic stroke. Odds ratio (OR) and 95% confidence intervals (CI) were determined for each gene disease association using fixed and random effect models.

Results: Our meta-analyses included 6,359 cases and 13,805 controls derived from 55 case-control studies, which included 12 genes (13 polymorphisms). Statistically significant associations with haemorrhagic stroke were identified for those homozygous for the ACE/I allele (OR, 1.48; 95% CI, 1.20-1.83; p = 0.0003) and for the 5G allele in the SERPINE1 4G/5G polymorphism (OR, 1.42; 95% CI, 1.03-1.96; p = 0.03). In addition, both epsilon2 and epsilon4 alleles of APOE were significantly associated with lobar haemorrhage (OR, 1.81; 95% CI, 1.26-2.62; p = 0.002 and OR, 1.49; 95% 1.08-2.05; p = 0.01 respectively). Furthermore, a significant protective association against haemorrhagic stroke was found for the factor V Leiden mutation (OR, 0.30; 95% CI, 0.10-0.87; p = 0.03).

Conclusion: Our data suggests a genetic contribution to some types of haemorrhagic stroke, with no overall responsible single gene but rather supporting a polygenic aetiology . However, the evidence base is smaller compared to ischaemic stroke. Importantly, for several alleles previously found to be associated with protection from ischaemic stroke, there was a trend towards an increased risk of haemorrhagic stroke.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Flow chart illustrating number of studies included in the meta-analyses.
Figure 2
Figure 2
2a. Results for apolipoprotein &b.epsi;2 allele and intracerebral haemorrhage comparing carriers of the &b.epsi;2 allele with those with the &b.epsi;3 and &b.epsi;4 alleles. 2b. Results for apolipoprotein &b.epsi;4 allele and intracerebral haemorrhage comparing carriers of the &b.epsi;4 allele with those with the &b.epsi;2 and &b.epsi;3 alleles. 2c. Results for apolipoprotein &b.epsi;2 allele and subarachnoid haemorrhage comparing carriers of the &b.epsi;2 allele with those with the &b.epsi;3 and &b.epsi;4 alleles. 2d. Results for apolipoprotein &b.epsi;4 allele and subarachnoid haemorrhage comparing carriers of the &b.epsi;4 allele with those with the &b.epsi;2 and &b.epsi;3 alleles. 2e. Results for apolipoprotein &b.epsi;2 allele and cerebral amyloid angiopathy-related haemorrhage comparing carriers of the &b.epsi;2 allele with those with the &b.epsi;3 and &b.epsi;4 alleles. 2f. Results for apolipoprotein &b.epsi;4 allele and cerebral amyloid angiopathy-related haemorrhage comparing carriers of the &b.epsi;4 allele with those with the &b.epsi;2 and &b.epsi;3 alleles. 2g. Results for apolipoprotein &b.epsi;2 allele and lobar or non-lobar haemorrhage comparing carriers of the &b.epsi;2 allele with those with the &b.epsi;3 and &b.epsi;4 alleles. 2h. Results for apolipoprotein &b.epsi;4 allele and lobar or non-lobar haemorrhage comparing carriers of the &b.epsi;4 allele with those with the &b.epsi;2 and &b.epsi;3 alleles.
Figure 3
Figure 3. Results for SERPINE1 4G/5G and intracerebral haemorrhage of 5G allele homozygous (5G/5G) genotype.
Figure 4
Figure 4. Results for ACE/II gene and haemorrhagic stroke.
Figure 5
Figure 5
5a. Results for Factor V Leiden mutation and haemorrhagic stroke. 5b. Results for Factor V Leiden mutation and ICH. 5c. Results for Factor V Leiden mutation and SAH.
Figure 6
Figure 6. Results for SERPINA3/TT in haemorrhagic stroke.
Figure 7
Figure 7. Results for eNOS/786C polymorphism and subarachnoid haemorrhage.
Figure 8
Figure 8. Results for MTHFR/677TT gene and intracerebral haemorrhage.
See this image and copyright information in PMC

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