Signature and function of plasma exosome-derived circular RNAs in patients with hypertensive intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is one of the major causes of death and disability, and hypertensive ICH (HICH) is the most common type of ICH. Currently, the outcomes of HICH patients remain poor after treatment, and early prognosis prediction of HICH is important. However, there are limited effective clinical treatments and biomarkers for HICH patients. Although circRNA has been widely studied in diseases, the role of plasma exosomal circRNAs in HICH remains unknown. The present study was conducted to investigate the characteristics and function of plasma exosomal circRNAs in six HICH patients using circRNA microarray and bioinformatics analysis. The results showed that there were 499 differentially expressed exosomal circRNAs between the HICH patients and control subjects. According to GO annotation and KEGG pathway analyses, the targets regulated by differentially expressed exosomal circRNAs were tightly related to the development of HICH via nerve/neuronal growth, neuroinflammation and endothelial homeostasis. And the differentially expressed exosomal circRNAs could mainly bind to four RNA-binding proteins (EIF4A3, FMRP, AGO2 and HUR). Moreover, of differentially expressed exosomal circRNAs, hsa_circ_00054843, hsa_circ_0010493 and hsa_circ_00090516 were significantly associated with bleeding volume and Glasgow Coma Scale score of the subjects. Our findings firstly revealed that the plasma exosomal circRNAs are significantly involved in the progression of HICH, and could be potent biomarkers for HICH. This provides the basis for further research to pinpoint the best biomarkers and illustrate the mechanism of exosomal circRNAs in HICH.

Correlations of endothelin-1 gene polymorphisms and hypertensive intracerebral hemorrhage.

OBJECTIVE: The aim of this study was to investigate the correlations of endothelin-1 (ET-1) gene polymorphisms with the occurrence of hypertensive intracerebral hemorrhage (HICH). PATIENTS AND METHODS: In this case-control study, 100 HICH patients and 100 controls with matched race, age and gender were enrolled as research subjects. Single nucleotide polymorphisms (rs1920453, rs1022436 and rs1035627) in the promoter region of ET-1 gene were typed via conformational difference gel electrophoresis. Whether the distribution frequency of ET-1 genotypes conformed to Hardy-Weinberg equilibrium was evaluated by chi-square test. The correlations of different gene polymorphisms and alleles in the promoter region of ET-1 gene with the occurrence of HICH were analyzed. Furthermore, the associations of rs1920453 polymorphism in the promoter region of ET-1 gene with neurological deficit scores and laboratory parameters of HICH patients were explored. RESULTS: It was found that ET-1 gene polymorphisms (rs1920453, rs1022436 and rs1035627) conformed to Hardy-Weinberg equilibrium (p>0.05). Gene-based association analysis indicated that only rs1920453 polymorphism and alleles were correlated with the occurrence of HICH (p<0.05). However, rs1022436 and rs1035627 polymorphisms and alleles had no association with HICH (p>0.05). Additionally, NIHSS score and high-density lipoprotein cholesterol level were prominently higher in HICH patients with CG and GG genotypes of ET-1 gene polymorphism rs1920453 than those in patients with CC genotype (p<0.05). CONCLUSIONS: Rs1920453 in the promoter region of ET-1 gene is correlated with the occurrence of HICH.

TIMP-2 Polymorphisms Define Subtypes of Hypertensive Intracerebral Hemorrhage with Distinct Perihematomal Edema Development Patterns.

BACKGROUND: Perihematomal edema (PHE) is a major threat leading to poor functional outcomes after intracerebral hemorrhage (ICH). TIMP-2 is considered to participate in the formation of PHE after ICH by antagonizing the damaging effects of MMP-2. In the early study, the polymorphisms of TIMP-2 rs8179090 have shown to influence the expression of TIMP-2. OBJECTIVE: To prove that the severity of PHE was different in ICH patients with different TIMP-2 rs8179090 genotypes. METHODS: In this prospective study, 130 hypertensive ICH patients were enrolled. The poly phisms of rs8179090 in TIMP-2 were determined. The hematoma volume and PHE volume were measured by computed tomography (CT) scan immediately after the onset of ICH, and were measured again one week and two weeks after the onset. Then, the comparison of TIMP-2 rs8179090 genotypes was made. RESULTS: TIMP-2-418 position (rs8179090) had two genotypes in the studied population, GC and GG. Patients with the GC genotype developed more severe PHE, with a higher incidence of delayed cerebral edema in cerebral hemorrhage than those with the GG genotype. CONCLUSION: We have found that the GC genotype group may develop more severe PHE, with an increased incidence of delayed cerebral edema in cerebral hemorrhage.

Common variants of ROCKs and the risk of hypertension, and stroke: Two case-control studies and a follow-up study in Chinese Han population.

The Rho kinases (ROCKs) are recognized as a critical regulator of vascular functions in cardiovascular disorders. It is crucial to illustrate the association of ROCKs genetic variation and hypertension and/or stroke events. Herein we aimed at investigating the association of ROCK1 and ROCK2 with hypertension and stroke in Chinese Han population. Seven tagSNPs at ROCK1 and ROCK2 were genotyped in a community-based case-control study consisting of 2012 hypertension cases and 2210 normotensive controls and 4128 subjects were further followed up. In stroke case-control study, 1471 ischemic stroke (IS) inpatients and 607 hemorrhagic stroke (HS) inpatients were collected, and 2443 age-matched controls were selected from the follow-up population. Risks were estimated as odds ratio (OR) and hazard ratio (HR) by logistic and Cox regression. The community-based case-control study didn't identify any significant tagSNPs associated with hypertension even after adjustment for covariates. The follow-up analysis showed that rs1481280 of ROCK1 significantly associated with incident hypertension (HR=1.130, P=0.048) after adjusting for covariates. rs7589629 and rs978906 of ROCK2 were significantly associated with incident IS (HR=1.373, P=0.004; HR=1.284, P=0.026) respectively. In stroke case-control study, rs288980, rs1481280 and rs7237677 were significantly associated with IS and the adjusted ORs (P values) of additive model were 0.879 (0.010), 0.895 (0.036) and 0.857 (0.002) respectively. Furthermore, rs288980, rs7237677 and rs978906 were significantly associated with HS and the adjusted ORs (P values) of additive model were 0.857 (0.025), 0.848 (0.018) and 0.856 (0.027) respectively. Our findings suggest that ROCK1 and ROCK2 contribute to the genetic susceptibility of hypertension and stroke.

Joint Effects of GWAS SNPs in Coagulation System Confer Risk to Hypertensive Intracerebral Hemorrhage.

Recent genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with coagulation system, including hemostatic factors and hematological phenotypes. However, few articles described the relationships between these SNPs and the risk of hemorrhagic stroke. The aim of our study was to evaluate the roles of these SNPs as risk factors and survival predictors for hemorrhagic stroke. Thirteen SNPs from GWAS in coagulation system were genotyped in a Chinese Han population including 1000 patients with hemorrhagic stroke (intracerebral hemorrhage, ICH = 743; subarachnoid hemorrhage, SAH = 257) and 1044 population-based controls. The associations between the genetics risk score (GRS) and risk of hemorrhagic stroke as well as post-stroke adverse outcomes were determined. No individual SNP was associated with the risk of hemorrhagic stroke. The GRS was calculated by summing the number of risk alleles of each SNP, and a total of 13 SNPs were included. Meanwhile, the GRS cutoffs values were defined to be close to quartiles or tertiles in control subjects. For quartiles, individuals with GRS about 8-9, 10-11, ≥12 had 1.28 (OR 1.28, 95% CI 0.98-1.68, p = 0.067)-, 1.36 (OR 1.36, 95% CI 1.04-1.79, p = 0.026)-, 1.53 (OR 1.53, 95% CI 1.13-2.07, p = 0.006)-fold increase in ICH risk compared to those with GRS ≤7, respectively; for tertiles, individuals with GRS about GRS 9-10, ≥11 had 0.98 (OR 0.98, 95% CI 0.78-1.23, p = 0.067)- and 1.26 (OR 1.26, 95% CI 1.00-1.59, p = 0.048)-fold increase in ICH risk compared to those with GRS ≤8, respectively. Further stratification analyses indicated that this association was only found in hypertensive ICH subjects. However, no statistical difference was found in the volume of hematoma, activities of daily living scale as well as hospital death in the ICH patients based on GRS values. Joint effects of SNPs associated with low coagulation factor levels might confer risk to ICH patients with hypertension. However, the clinical value on risk stratification and survival prediction was limited.

Influence of COL1A2 gene variants on the incidence of hypertensive intracerebral hemorrhage in a Chinese population.

Type I collagen (transcribed by COL1A1 and COL1A2 genes) is important for maintaining vessel wall elasticity and is a critical part of the extracellular matrix. We conducted a case-control study to investigate the role of the COL1A2 rs42524 polymorphism in the development of hypertensive intracerebral hemorrhage. Between January 2012 and December 2014, a total of 227 patients with hypertensive intracerebral hemorrhage and 227 controls were selected from the Affiliated Hospital of Yanan University (China). Genotyping of the COL1A2 rs42524 polymorphism was performed using polymerase chain reaction coupled with restriction fragment length polymorphism. By logistic regression analysis, we found that the CC genotype was associated with increased risk of hypertensive intracerebral hemorrhage as compared to the GG genotype (OR = 12.67, 95%CI = 3.03-112.11). In a dominant model, the GC + CC genotype of the COL1A2 rs42524 polymorphism was associated with a 2.57-fold increased risk of hypertensive intracerebral hemorrhage as compared to the GG genotype. In a recessive model, the CC genotype of the COL1A2 rs42524 polymorphism was correlated with a higher risk of hypertensive intracerebral hemorrhage as compared to the GG + GC genotype (OR = 12.07, 95%CI = 2.89-106.75). The GC and CC genotypes of the COL1A2 rs42524 polymorphism were associated with a substantial risk of hypertensive intracerebral hemorrhage among patients who consumed alcohol and used tobacco. In conclusion, our study suggests that the COL1A2 rs42524 polymorphism is associated with the development of hypertensive intracerebral hemorrhage, particularly in conjunction with tobacco use and alcohol consumption.

HindIII polymorphism in the lipoprotein lipase gene and hypertensive intracerebral hemorrhage in the Chinese Han population.

BACKGROUND: To investigate the relationship between the HindIII polymorphism and hypertensive intracerebral hemorrhage (HIH) and lipid metabolism. METHODS: A polymerase chain reaction-restriction fragment length polymorphism assay and the chain termination DNA sequencing method were used to determine the HindIII genotypes of 267 subjects, which included 120 cerebral hemorrhagic patients and 147 controls. The fasting levels of lipids and glucose in the plasma were used to measure the effect of genotype on HIH risk factors. RESULTS: The frequency of the T allele of the HindIII polymorphism in the HIH group was 90.8%. The frequency of the G allele was 9.2%. In the control group, the frequencies were 82.3% T and 17.7% G, which indicated that the proportion of the G allele in the HIH patient group was significantly lower than in the control group (P<.05). The frequency of GG+GT genotypes in HIH patients (P<.05) and the plasma triglyceride (TG) levels in these patients (P<.05) were also lower than in the control group. The levels of plasma TG, low-density lipoprotein cholesterol, glucose, systolic blood pressure, and diastolic blood pressure in the HIH group were higher than in the controls (P<.05). After controlling for risk factors related to HIH, the HindIII G allele was negatively correlated with the incidence of HIH (odds ratio=.417, 95% confidence interval: .193-.901). CONCLUSIONS: The HindIII G allele may be a protective factor against the development of HIH among the Han Chinese population.

Recurrent intracerebral hemorrhage in patients with hypertension is associated with APOE gene polymorphism: a preliminary study.

BACKGROUND: Recurrent intracerebral hemorrhage (ICH) in patients with hypertension has been reported in Asia and is attributed to poor control of blood pressure, but there may be a genetic basis. This study evaluates the roles of apolipoprotein E (APOE) and α-1 antichymotrypsin (ACT) genes in patients with recurrent hypertensive ICH and compares patients with nonrecurring hypertensive ICH and normal controls. METHODS: Thirty-three recurrent and 101 nonrecurrent patients with hypertension and ICH were included. The demographic, stroke risk factors, and computed tomographic or magnetic resonance imaging findings were recorded. Magnetic resonance angiography or digital subtraction angiography and vasculitic profile were done in recurrent group to exclude secondary causes of ICH. APOE and ACT gene polymorphisms were assessed with polymerase chain reaction studies in patients with ICH and 188 healthy controls. RESULTS: The demographic and clinical variables were similar in patients with recurrent and nonrecurrent ICH, but patients with recurrent ICH were older (61.1 vs 57.2 years). In the recurrent ICH group, only 7 (10%) out of 69 episodes were lobar; the remaining were deep-seated hematomas. In the nonrecurrent group, 7 (6.9%) patients had lobar ICH. The E2 (odds ratio 4.32; 95% confidence interval 1.65-11.28; P = .003) and E4 alleles of APOE (odds ratio 11.33; 95% confidence interval 5.37-23.02; P < .0001) were significantly related to recurrent ICH compared to healthy controls. The E4 allele was also independently related to recurrent compared to nonrecurrent ICH, even after adjustment for stroke risk factors (odds ratio 25.99; 95% confidence interval 11.65-57.97; P < .0001). ACT gene polymorphism, however, was not related to recurrent ICH compared to controls and nonrecurrent ICH. CONCLUSIONS: APOE polymorphism may contribute to the recurrence of hypertensive ICH.

Burden of risk alleles for hypertension increases risk of intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms [SNPs]) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. METHODS: We conducted a prospective multicenter case-control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. RESULTS: No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02-1.21; P=0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07-1.30; P=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04-1.31; P=0.009) and ICH cases (OR, 1.15; 95% CI, 1.01-1.31; P=0.04). Similar results were obtained when using a weighted score. CONCLUSIONS: Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN.

Do ACE (rs4646994) and αADDUCIN (rs4961) gene polymorphisms predict the recurrence of hypertensive intracerebral hemorrhage?

This study was undertaken to evaluate the role of ACE and αADDUCIN polymorphisms in patients with recurrent and nonrecurrent hypertensive intracerebral hemorrhage (ICH). A total of 101 nonrecurrent and 33 recurrent hypertensive ICH patients underwent an ACE (rs4646994) and αADDUCIN (rs4961) gene polymorphism study. The risk factors, clinical findings, CT scan abnormalities and functional outcome of recurrent and nonrecurrent ICH were compared. ACE (rs4646994) and αADDUCIN (rs4961) gene polymorphisms were also compared in the two groups and with 198 controls. The patients with recurrent ICH were older compared to those with nonrecurrent ICH and the other stroke risk factors were found in the two groups. Ganglionic-ganglionic pattern of recurrence was the commonest (75.6%) and all had at least one ICH in the location of hypertensive ICH. ACE DD genotype (OR6.18, 95%CI 2.93-13.02) and D allele (OR 2.43, 95%CI 1.70-3.47) were associated with nonrecurrent ICH compared to controls. In patients with recurrent ICH, DD genotype (OR 7.46, 95%CI 2.8-19.4) and D allele (OR 3.16, 95%CI 1.83-5.46) of ACE, and GW (OR 3.49, 95%CI 1.47-8.28), WW (OR 2.9, 95%CI 1.40-4.30) genotypes and W allele (OR 7.46, 95%CI 2.80-19.40) of αADDUCIN were more frequent compared to controls. Recurrent ICH also had higher frequency of WW genotype (OR 9.43, 95%CI 1.49-59.50) and W allele (OR 2.19, 95%CI 1.11-4.03) compared to nonrecurrent ICH. The frequency of DD + WW (P = 0.008) and DD/WW + ID/GW (P = 0.0001) genotypes in the recurrent ICH was higher than in the nonrecurrent ICH and the controls. Variant genotype combinations of ACE and αADDUCIN render the hypertensive patient more vulnerable to recurrent ICH.

Decreased expression of transient receptor potential channels in cerebral vascular tissue from patients after hypertensive intracerebral hemorrhage.

Recent data indicate that transient receptor potential (TRP) cation channels play an important role in hypertension. Now, we tested the hypothesis that TRP expression is altered in human cerebral vascular tissue in patients who had experienced hypertensive intracerebral hemorrhage. TRPC1, TRPC3, TRPC5, TRPC6, TRPM4, TRPM6, and TRPM7 channels were detected in cerebral vascular tissue by quantitative real-time RT-PCR. Control cerebral vascular tissue was obtained from normotensive patients who underwent neurosurgical operation because of brain tumor. To examine a possible relation between the expression of TRP expression and hypoxic conditions caused by the intracerebral bleeding, we examined the expression of hypoxia inducible factor 1a (HIF1a). Transcripts of TRPC3, TRPC5, TRPM6, and HIF1a were significantly reduced in cerebral vascular tissue from patients after hypertensive intracerebral hemorrhage compared to controls. TRPC3 mRNA correlated well with the expression of HIF1a mRNA (r(2) = 0.59; p = 0.01). TRPC3 expression is associated with hypertension and hypoxic conditions in human cerebral vascular tissue.

[Correlation of ABO groups to hypertensive intracerebral hemorrhage].

OBJECTIVE: To study the relationship between ABO blood groups and hypertensive intracerebral hemorrhage (HICH). METHODS: The clinical data of 425 patients with HICH admitted to Nanfang Hospital were collected to analyze the relationship between the ABO blood groups and the occurrence of HICH, with normal Han Chinese subjects serving as the controls. RESULTS: Compared to the officially documented distribution of ABO groups in Chinese population (O 34.11%, B 28.98%, A 28.29%, AB 8.69%) and in Guangzhou residents (O 46.00%, B 25.00%, A 23.00%, AB 6.00%), a significant difference was noted in the blood group distribution in this cohort (O 45.10%, A 26.00%, B 24.00%, AB 4.90%). O blood type individuals with HICH showed a higher morbidity than others. Th ABO blood type distribution in this cohort showed no significant difference from that in the control group (P>0.05), but differed significantly from the Chinese norm (P<0.05). CONCLUSION: The ABO blood group is a factor contributing to the occurrence of HICH. O blood type is related to cerebral hemorrhage, and may serve as a risk factor for HICH.

Familial hypertensive intracerebral hemorrhage and autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a generalized disease known to be associated with intracranial aneurysms. Non-aneurysmal intracerebral hemorrhage (ICH) has also been reported in ADPKD. We report a familial clustering of ICH and symptomatic ADPKD. This pedigree had at least six affected family members who suffered from ADPKD, hypertension and non-aneurysmal ICH. The proband demonstrated ADPKD, hypertension and cerebral hemorrhage. To our knowledge, this is the first report of familial ICH in ADPKD, which may have underlying genetic and environmental etiologies.

Family history of stroke in stroke types and subtypes.

Many studies have provided data showing that family history of stroke (FHS) is associated with an increased risk of stroke. The association of the FHS with the various stroke subtypes has not been adequately studied. The purpose of this study was to assess the association of the FHS with the two major stroke types (cerebral haematomas and ischaemic strokes) and the four stroke subtypes (cardioembolic, large artery disease, small artery disease, and undetermined) in a Greek population. The FHS was obtained from 421 consecutive acute stroke patients and from 239 matched control subjects. Positive FHS was observed in 49% of all stroke patients compared with 28% of the control subjects [adjusted OR=2.06 (95% confidence intervals (CI) 1.42-3.00)]. Haematomas, ischaemic strokes, and from the ischaemic strokes, both large and small artery disease strokes were strongly associated with positive FHS compared with the control subjects [adjusted OR=2.06 (95% CI 9-3.04), 2.07 (95% CI 1.09-3.91), 2.05 (95% CI 1.24-3.38), and 2.76 (95% CI 1.55-4.91), respectively]. There was no difference between maternal and paternal heritable contribution.In conclusion, FHS was found in this study to be an independent risk factor for all strokes combined, for each stroke type, and for the large and small-artery disease stroke subtypes, but not for the cardioembolic and undetermined stroke subtypes.

Cerebral hemorrhage and apoE.

The epsilon4 allele of apolipoprotein E (apoE) is found more commonly among patients with Alzheimer's disease (AD) than in the normal population. ApoE is associated with brain amyloid, a component of cerebral amyloid angiopathy (CAA), which is both a pathological feature of AD and a frequent cause of lobar intracerebral hemorrhage (ICH). We hypothesized that the frequency of epsilon4 allele is higher in patients with CAA-related ICH than in hypertensive ICH and in the normal population. To test this hypothesis we compared the frequency of apoE alleles in four populations: 24 patients with lobar ICH, 24 matched patients with hypertensive ICH, 24 matched normal controls, and 173 population controls. Although there was a tendency to a higher frequency of apoE epsilon4 in lobar ICH patients, we found no significant differences in the frequency of this allele between the four studied populations. In addition we did not confirm the finding of some authors of a higher frequency of apoE epsilon2 in patients with lobar ICH than in the normal population. Previous studies on the subject are discussed. The relationship between apoE polymorphism and lobar CAA-related ICH remains to be clearly defined.