Common mutations which alone are minor or non-significant risk factors for ischemic stroke can yield, in specific combination patterns, a highly significant, moderate genetic risk of specific stroke subtypes.

Objectives: Ischaemic stroke is a frequent heterogeneous multifactorial disease that is affected by a number of genetic mutations and environmental factors. We hypothesised the clinical importance of the interactions between common, unfavourable genetic mutations and clinical risk factors in the development of ischaemic stroke. Methods: The Factor V Leiden G1691A (Leiden V), the prothrombin G20210A, the methylenetetrahydrofolate reductase C677T (MTHFR C677T) mutations, the angiotensin converting enzyme I/D (ACE I/D), and apolipoprotein allele e4 (APO e4) genotypes were examined by the polymerase chain reaction (PCR) technique in 867 ischaemic stroke patients and 743 healthy controls. Logistic regression models were used to estimate the roles of the co-occurrences of the clinical risk factors and common genetic mutations in ischaemic stroke. Results: The Leiden V mutation in combination with hypertension or diabetes mellitus increased the risk of ischaemic stroke. We found synergistic effects between the ACE D/D and MTHFR 677TT genotypes and drinking or smoking. The presence of the APO e4 greatly facilitated the unfavourable effects of hypertension, diabetes mellitus, smoking, or drinking on the incidence of ischaemic stroke. Conclusion: In certain combinations, pairing of common unfavourable genetic factors, which alone confer only minor or non-significant risk, with clinical risk factors can greatly increase the susceptibility to ischaemic stroke.

The eNOS G894T or eNOS 894TT genotypes in combination with the MTHFR 677TT or ACE D/D genotype increases the risk of ischaemic stroke.

These data indicate that the contributions of the ACE D/D genotype and the homozygous MTHFR C677T mutation to leukoaraiosis should be taken into consideration not as major, but as additive factors. These findings draw attention to the fact that genetic polymorphisms that alone are insignificant can be risk factors for leukoaraiosis if they cluster in the same subjects.

The possible pathogenic role of triglycerides (TG) in the development of ischemic stroke is still under extensive investigation. Recently, apolipoprotein (apo)A5 gene promoter region T-1131C polymorphism has been shown to associate with elevated serum TG levels. In the current work, a total of 302 subjects were classified as being large vessel-associated, small vessel-associated, or belonging to a mixed group of ischemic stroke-affected patients. The level of TG was increased in all groups (p < 0.01). The apoA5-1131C allele frequency was approximately twofold in all groups of stroke patients compared with the controls (5 vs 10-12%; p < 0.05); and the apoA5-1131C allele itself was also found to associate with increased TG levels in all groups. In a multivariate logistic regression analysis model adjusted for differences in age, gender, serum cholesterol, hypertension, presence of diabetes mellitus, smoking and drinking habits, and ischemic heart disease, a significantly increased risk of developing stroke disease was found in patients carrying the apoA5-1131C allele (p < 0.05; odds ratio OR = 2.1 [1.3-4.7]); this association was also proven for all subtypes of the stroke. The results presented here suggest that the apoA5-1131C allele is an independent risk factor for the development of stroke. Being that apoA5 gene is under the control of the peroxisome proliferator-activated receptor alpha, theoretically, the current observations also can have long-term therapeutic consequences.