There is evidence for a role of genetic factors in the development of ICH. Studies investigating the association between genetic polymorphisms and ICH risk are being reported with rapidly increasing frequency. Endoglin gene polymorphism was a risk factor for sporadic ICH . A comparative study that angiotensin converting enzyme (ACE) gene DD homozygosity of the I/D polymorphism in intron 16 is an independent risk factor for ICH in a Polish population . A case–control study suggested that the beta1-tubulin Q43P polymorphism could be associated with ICH in men from southern Spain . A population-based prospective nested case–control study found that estrogen receptor alpha gene polymorphisms were associated with first-ever ICH, particularly in combination with hypertension . A case–control study found that glutathione peroxidase 1 C593T polymorphism was associated with lobar ICH in a Polish population . A case–control study suggested that the rs2228048 of TGFBR2 gene may be associated with development of ICH in Korean population . A study suggested that the rs17222919 of ALOX5AP may be associated with the development of ICH in Korean population .
The APOE gene polymorphisms are associated with many other diseases. A meta-analysis showed that APOE ϵ4 allele appeared to be associated with a higher prevalence of dementia in Parkinson disease . A meta-analysis suggested that the APOE ϵ4 isoform was a genetic factor that might influence the age at onset of temporal lobe epilepsy . A meta-analysis showed that the APOE ϵ4 allele was associated with an increased risk of developing hypertension . A meta-analysis found that the APOE ϵ4 allele was associated with a moderately increased risk for progression from mild cognitive impairment to Alzheimer's disease-type dementia . Prevalence of APOE ϵ4 alleles was significantly higher in patients with coronary artery disease than controls .
The exact mechanism of the association between APOE polymorphism and the risk of ICH remains unclear. APOE plays a critical role in redistributing lipids among central nervous system cells for normal lipid homeostasis , repairing injured neurons , maintaining synaptodendritic connections , neurite outgrowth , synaptic plasticity , mitochondrial resistance to oxidative stress , and glucose use by neurons and glial cells . Compared with ϵ3/ϵ3, ϵ4 allele-containing genotypes are associated with increased total cholesterol levels . It appears that the ϵ4 allele enhances amyloid deposition in blood vessels . Thus, one might expect ϵ4 carriers to have increased susceptibility to ICH, especially in a lobar location. Furthermore, APOE ϵ4 allele was also associated with an increased risk of developing hypertension , which may be the reason that APOE ϵ4 allele was associated with a higher risk of ICH.
Several limitations of our meta-analysis should be noted. First of all, meta-analysis is powerful but also controversial-controversial because several conditions are critical to a sound meta-analysis, and small violations of those conditions can lead to misleading results . Second, relatively small sample size of studies in overall comparisons was observed in this meta-analysis. The results of small meta-analyses should be regarded with caution, even if the P value shows extreme statistical significance . Thirdly, because of the lack of individual patient data, we could not perform an adjustment estimate. In spite of these limitations, our meta-analysis also had some advantages. First, the major strengths of the meta-analysis are that we used a comprehensive searching strategy based on computer-assisted and manual searching which allowed the eligible studies to be included as far as possible. Second, no heterogeneity or publication bias was found, which leads to a possibly robust result.
In conclusion, our meta-analysis suggested that APOE ϵ4 allele was associated with a higher risk of ICH. Future studies will be required to clarify the biological implications of our findings.