The Genetics of Primary Haemorrhagic Stroke, Subarachnoid Haemorrhage and Ruptured Intracranial Aneurysms in Adults

Abstract

BackgroundThe 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.MethodsA 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.ResultsOur 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 &b.epsi;2 and &b.epsi;4 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).ConclusionOur 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.

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing

“…[45][46][47][48][49][50][51][52] The c.1286A→C variant has been studied less, but current evidence suggests that it is milder than the "thermolabile" variant. [53][54][55][56] Preliminary findings in combined genotypes have found that they are not significantly different from controls.…”

Risk factors for intracerebral hemorrhage differ according to hemorrhage location

“…20,21 Most studies have found APOE alleles e2, e4, or both more frequently in lobar ICH cases, although other studies have found no association. 10,12,[22][23][24][25] The largest and most detailed analysis of APOE genotype and ICH was a meta-analysis that included our cases as well as those from 6 other studies. That study found that alleles e2 and e4 were both associated with lobar ICH in white subjects, most strongly in subjects with a high probability of cerebral amyloid angiopathy.…”

Impact of LIMK1, MMP2 and TNF-α variations for intracranial aneurysm in Japanese population

“…Although several common variants were identified to be associated with the increased risk of IA development through candidate gene approaches [12][13][14][15][16] and genome-wide association studies, 17,18 only few associations were consistently replicated. 19,20 These might be because of the lack of statistical power of the study or differences in the allele frequencies across different populations.…”