Polymorphism of Apoprotein E (APOE), Methylenetetrahydrofolate Reductase (MTHFR) and Paraoxonase (PON1) Genes in Patients with Cerebrovascular Disease

Abstract

Although controversial, data on the genetic polymorphism of apoprotein E (APOE), methylenetetrahydrofolate (MTHFR) and paraoxonase (PON1) genes implicate their role in the development of cerebrovascular disease. The aim of this study was to assess the association of polymorphism of APOE, MTHFR and PON1 genes in 56 stroke and 36 carotid stenosis patients, and in 124 control subjects by PCR-restriction fragment length polymorphism analysis. In the stroke group a significantly different MTHFR genotype distribution (p=0.004, odds ratio for T/T of 17.571), but no significant difference in APOE and PON1 allele and genotype distribution compared to the control was found. The carotid stenosis group exhibited a significantly different APOE allele and genotype distribution (p=0.023, odds ratio APOEepsilon3epsilon4 of 4.24), but no significant difference in the MTHFR and PON1 allele and genotype distribution from the control group. The preliminary results obtained in this study revealed an association of the MTHFR and APOE gene polymorphism with cerebrovascular disease, suggesting a significant risk for stroke in subjects who are homozygous for the T allele and for carotid stenosis in subjects having APOEepsilon3epsilon4 genotype. Additional studies in larger patient groups are needed to confirm these observations.

Evaluation of the Paraoxonases as Candidate Genes for Stroke

“…11,12 In a small study from Croatia that examined 56 stroke cases and 124 controls, there was no significant difference in the frequency of the Arg192 allele between the 2 groups. 10 There was no evidence of heterogeneity of odds ratios across the 4 studies ( 2 3df ϭ4.76, Pϭ0. 19), however, and the combined odds ratio for the Arg192 allele versus Gln192 allele was 1.64 (95% CI, 1.39 to 1.94).…”

“…However, in a fourth study, the difference in frequency of the high-risk Arg192 allele between stroke cases and controls was not significant. 10 This lack of association could be the result of differences in diagnostic criteria for stroke or population differences.…”

TagSNP analyses of the PON gene cluster: effects on PON1 activity, LDL oxidative susceptibility, and vascular disease

“…Meta-analyses suggest that the PON1 Q192R and PON1 M55L (and in one study, PON1 -108C/T ) genotypes do not predict cardiovascular disease (CVD) (26)(27)(28). Interestingly, a study of severity of CVD did show a PON1 Q192R effect (29), and the studies for prediction of stroke or CAAD (22,(30)(31)(32)(33)(34) have been more consistently positive for a PON1 locus effect, although negatives occur (35) and the studies tend to be small. Of note, the polymorphisms previously studied represent only a small fraction of PON1 genetic variation: reported studies have examined only a handful of the more than 150 known PON1 region polymorphisms.…”

Genetics of Ischemic Stroke: Emphasis on Candidate-Gene Association Studies

“…In the next decade, five metaanalyses [17-19, 21,23] confirmed that ε4 allele carriers have a higher risk of IS compared with pooled ε2 and ε3 allele carriers in European populations, persons of non-European descent, Asians, Han Chinese and persons with early-onset IS. Performing large-scale meta-analysis (10674 cases/33430 controls) consisted of four meta-analysis [19,[21][22][23] and 9 case-control studies [33,35,36,54,59,65,66,84,88], Hamzi et al [24] calculated OR for the apo4 allele to be 0.95 (95%CI 0.77-1.14, P=0.002).…”

“…According the literature data there are three metaanalysis [18,174,175] and 26 casecontrol studies [28,30,34,35, explored the association of PON1 polymorphisms and IS risk. A positive association of Gln192Arg PON1 polymorphism and IS was described in the metaanalyses and in five case-control studies [177,178,184,185,188], but this association was negative in all other reports.…”