The aim of the present study was to investigate the correlation between the −1562C/T polymorphism in an intron of the matrix metalloproteinase-9 (MMP-9) gene and hemorrhagic transformation of ischemic stroke (IS). Using polymerase chain reaction-restriction fragment length polymorphism, the −1562C/T polymorphisms in 222 patients with IS were detected. The patients were divided into hemorrhagic transformation (HT; 84 cases) and non-hemorrhagic transformation (NHT) groups (138 cases) depending on the results from the susceptibility-weighted magnetic resonance imaging, which was performed between one and two weeks following stroke onset. The allele frequencies were subsequently compared. Baseline data of the two groups were comparable. The HT group exhibited a significantly lower frequency of the CT+TT genotype compared with the NHT group (17.86 vs. 30.43%, P<0.05). In addition, the frequency of T allele was significantly lower in the HT group compared with the NHT group (8.93 vs. 15.94%, P<0.05). Therefore, the results indicated that the −1562C/T polymorphism in the MMP-9 gene is correlated with hemorrhagic transformation of IS in the population studied. Furthermore, the T allele may be a protective factor for hemorrhagic transformation of IS in this population.
No coding sequence variants of the gene encoding 5-lipoxygenase-activating protein (ALOX5AP) leading to amino acid substitutions have been identified. Therefore, variants in the ALOX5AP promoter region have received attention recently. The purpose of this study was to explore whether the promoter polymorphism rs17222919 is involved in the etiology of ischemic stroke (IS) in the Chinese Han population. We investigated the rs17222919 polymorphism by TaqMan genotyping in two independent Chinese Han samples: the first comprised 910 IS patients and 925 healthy inhabitants from the northern Henan Province, while the second included 1003 IS patients and 889 healthy controls from the southern Henan Province. Functional characterization of rs17222919 was performed by an in vitro luciferase assay. After adjusting for conventional risk factors, the G allele frequencies in the IS groups were significantly lower than that in the control groups of the two independent Chinese cohorts (19.0% vs. 22.9%, P = 0.004, odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.675–0.929; 18.8% vs. 22.9%, P = 0.002, OR = 0.782, 95% CI = 0.668–0.915, respectively). This was also observed in the large-artery atherosclerosis (LAA) and stroke of other undetermined etiology (SUE) subtypes (P = 0.019, OR = 0.815, 95% CI = 0.687–0.967; P = 0.021, OR = 0.815, 95% CI = 0.685–0.970, respectively). Additionally, the TG genotype and G allele frequencies were significantly lower in the IS compared with the control group in two female cohorts (P<0.05). Finally, the in vitro luciferase assay demonstrated that the G allele has a significantly lower transcription activity than the T allele (P = 0.031). Our study provides evidence that the promoter single nucleotide polymorphism (SNP) rs17222919 is a potential genetic protective factor for IS in the Chinese Han population.
The mtDNA copy number can affect the function of mitochondria and play an important role in the development of diseases. However, there are few studies on the mechanism of mtDNA copy number variation and its effects in IS. The specific mechanism of mtDNA copy number variation is still unclear. In this study, mtDNA copy number of 101 IS patients and 101 normal controls were detected by qRT‐PCR, the effect of D‐loop variation on mtDNA copy number of IS patients was explored. Then, a TFAM gene KD‐OE PC12 cell model was constructed to explore the effect of mtDNA copy number variation on mitochondrial function. The results showed that the mtDNA copy number level of the IS group was significantly lower than that of the normal control group ( p < 0.05). The relative expression of TFAM gene mRNA in the cells of the OGD/R treatment group was significantly lower than that of the control group ( p < 0.05). In addition, after TFAM gene knockdown and over‐expression plasmids were transfected into HEK 293T cells, mtDNA copy number and ATP production level of Sh‐TFAM transfection group was significantly decreased ( p < 0.05), while mtDNA copy number and ATP production level of OE‐TFAM transfected group were significantly higher than that of blank control group and OE‐ctrl negative control group ( p < 0.01). Our study demonstrated that mitochondrial D‐loop mutation and TFAM gene dysfunction can cause the decrease of mtDNA copy number, thus affecting the mitochondrial metabolism and function of nerve cells, participating in the pathological damage mechanism of IS.
Previous studies have shown that CpG-SNPs might have influence on gene function via allele-specific DNA methylation (ASM). However, association study between DNA methylation and the promoter CpG-SNPs in ALOX5AP gene with IS has not been reported. The present study aims to explore the relationship among CpG-SNPs, methylation levels, and messenger RNA (mRNA) expression levels of ALOX5AP gene. Firstly, we made a two-stage association study to identify a potential associated CpG-SNP (rs4073259) by SNaPshot genotyping approach (P = 0.015, OR = 0.672, 95% CI 0.487-0.927; P = 0.035, OR = 0.809, 95% CI 0.664-0.985, respectively). In addition, the methylation levels of 17 CpG sites located in the promoter of ALOX5AP were tested by MethylTarget sequencing. The methylation level of GG genotype carriers is significantly higher than those with the AG and AA genotypes (P < 0.05). And the GG genotype carriers with higher DNA methylation levels have a decreased mRNA expression levels of ALOX5AP (P < 0.05). Finally, we found that the G allele with higher methylation level has got a lower transcription activity than the A allele by luciferase assay (P = 0.000).The study provided evidence that IS-associated CpG-SNP rs4073259 may affect the expression level of ALOX5AP through allele-specific methylation and consequently the phenotype of the disease.
Background and Purpose: Studies have shown that matrix metalloproteinase (MMP-2,3,9) plays an important role in the pathologic process of ischemic stroke (IS). The aim of this study was to investigate the relationship between C1306T, 1612-5A/6A, C-1562T polymorphisms of MMP-2,3,9 genes and IS in Chinese Han population. Methods: The polymorphisms of MMP-2(C1306T), −3(1612-5A/6A), −9(C-1562T) gene were detected by PCR-RFLP and SNaPshot sequencing. Then, stratified analysis was used to study the relationship between IS subtypes and MMP-2,3,9 polymorphisms. Results: For the MMP-2 gene C1306T polymorphism, TT genotype and T allele were significantly associated with a reduced risk of IS (P = 0.015, P = 0.003, respectively). T allele was significantly associated with a reduced risk of small artery occlusion (SAO) subtype compared with the control group (P = 0.012, OR = 0.550, 95% CI = 0.065-1.291). For the MMP-3 gene-1612 (5A/6A) polymorphism, 5A/5A genotype was significantly increased in the IS group (P = 0.011, OR = 0.370, 95% CI = 0.168-0.814), especially in the large-artery atherosclerosis (LAA) subtype (P = 0.001, OR = 2.345) as compared to the control group. Conclusion: Our study suggested that the T allele of MMP-2 may be a protective factor of IS, especially in SAO subtype, while the 5A/5A gene of MMP-3 may increase the risk of IS, especially in LAA subtype in Chinese Han population.
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