engleski

Candidate genes in the development of cerebrovascular disease

Numerous epidemiologic studies have documented that cerebrovascular disease leading to transient ischemic attacks and stroke has significant genetic components. Many studies investigating different candidate genes in relation to ischemic stroke have revealed conflicting results. The reasons for such a discrepancy might be explained by the complex etiology of ischemic stroke, genetic factors underlying different stroke subtypes, and population-specific genetic inheritance that may lead to divergent results among patients from different countries, thus potentially producing significant positive associations in some but not in other populations and studies. A large meta-analysis of stroke genetics revealed that 4 of 32 genes studied in 18, 000 stroke subjects and 58, 000 controls were significantly associated with stroke, showing the odds ratios for Factor V Leiden of 1.33 (95% CI, 1.12-1.58), MTHFR 1.2 (95% CI 1.08-1.42) ; prothrombin 1.44 (95% CI, 1.11-1.86) ; and ACE 1.21 (95% CI 1.08-1.35). Recent studies suggest some other genes to have a significant stroke risk, i.e. polymorphism in the atrial natriuretic protein gene, PAI-1, PON-1, LDL-receptor, glycoprotein IIIa, phosphodiesterase 4D (PDE4D), 5 lipoxygenase activating protein (ALOX5AP) and MMP3 genes. Another meta-analysis documented that ACE, APOE and MTHFR genes were associated with higher intimalmedia wall thickness (IMT), which is an independent predictor of stroke. Our results in 144 stroke patients indicated higher MM2 level and MM2/TIMP2 ratio in patients with total anterior circulation infarct (TACI) than in patients with other stroke subtypes according to OCSP classification (p=0.0019 and p=0.065, respectively). The level of MM9 and MM9/TIMP-1 ratio were higher in patients with large artery disease than in patients with small artery disease (TOAST classification, p=0.005 and p=0.31, respectively). A negative correlation between MMP2 and MMP9 level and MMP/TIMP-1 ratio was found in all stroke subtypes except for TACI. ROC analysis indicated significant association of high MMP9/TIMP1 ratio and TACI (odds 3.26), as well as a similar discriminating power for MMP9 levels and Barthel index in differential diagnosis of TACI. Many studies found different likelihood ratios between IMT, stroke and genes associated with atherosclerosis, hemostasis impairment and remodeling. Since these genes may be inherited independently, three, four or even five of these high-risk genes might be inherited. So, it is very important to characterize and confirm genetic markers that will help, along with their circulatory product, identify the people at a high risk of stroke and to advise a more tight control of other modifiable risk factors to reduce risk of stroke. To increase the likelihood of valid and replicable study, the recommended standard criteria for stroke studies should be followed to ensure their quality and reproducibility in order to facilitate their meta-analysis, as proposed by Dichmans and Markus in 2005.

genetic polymorphism; stroke

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