Peripheral Blood Gene Expression Profiling Reveals Molecular Pathways Associated with Cervical Artery Dissection.

Cervical artery dissection (CeAD) is the primary cause of ischemic stroke in young adults. Monogenic heritable connective tissue diseases account for fewer than 5% of cases of CeAD. The remaining sporadic cases have known risk factors. The clinical, radiological, and histological characteristics of systemic vasculopathy and undifferentiated connective tissue dysplasia are present in up to 70% of individuals with sporadic CeAD. Genome-wide association studies identified CeAD-associated genetic variants in the non-coding genomic regions that may impact the gene transcription and RNA processing. However, global gene expression profile analysis has not yet been carried out for CeAD patients. We conducted bulk RNA sequencing and differential gene expression analysis to investigate the expression profile of protein-coding genes in the peripheral blood of 19 CeAD patients and 18 healthy volunteers. This was followed by functional annotation, heatmap clustering, reports on gene-disease associations and protein-protein interactions, as well as gene set enrichment analysis. We found potential correlations between CeAD and the dysregulation of genes linked to nucleolar stress, senescence-associated secretory phenotype, mitochondrial malfunction, and epithelial-mesenchymal plasticity.

Genetic analysis of ring finger protein 213 (RNF213) c.14576G>A polymorphism in patients with vertebral artery dissection: a comparative study with moyamoya disease.

Background: Intracranial vertebral artery dissection (VAD) and moyamoya disease (MMD) are rare cerebrovascular diseases, both of which have an ethnic predominance in the East Asian population. Disruption of the internal elastic lamina and subsequent rupture of the medial layer result in intracranial VAD. MMD is a chronic occlusive cerebrovascular disease of unknown etiology, in which the medial layer and internal elastic lamina of the intracranial arteries are significantly compromised. Recent genetic studies found ring finger protein 213 (RNF213) to be an important susceptibility gene for MMD in East Asian patients, but the association between VAD and RNF213 has not been investigated. . Methods: We investigated polymorphism of the RNF213 gene (c.14576G>A) in genomic DNA of 24 patients with intracranial VAD in comparison with 58 patients with definitive MMD and 48 healthy controls. Results: Although RNF213 gene polymorphism (c.14576G>A) was evident in 69% of the MMD patients (40/58), none of the patients with intracranial VAD had this characteristic polymorphism (0/24, p < 0.001). The incidence of RNF213 c.14576G>A polymorphism was 4.2% in healthy controls (2/48). After adjustment by age and sex, the incidence of RNF213 c.14576G>A was significantly lower in intracranial VAD patients (p = 0.021) than that in MMD patients. Conclusions: In contrast to MMD patients, the prevalence of RNF213 c.14576G>A polymorphism was significantly lower in patients with intracranial VAD. The RNF213 gene polymorphism may preferentially affect the cerebrovascular lesion in the anterior circulation, which is originated from the primitive internal carotid arteries. The genetic background underlying intracranial VAD should be elucidated in future studies. Abbreviations: VAD: vertebral artery dissection; MMD: moyamoya disease; RNF213: ring finger protein 213; CAD: carotid artery dissection.

Pathophysiology and risk factors of cervical artery dissection: what have we learnt from large hospital-based cohorts?

PURPOSE OF REVIEW: Cervical artery dissection (CeAD) is a major cause of ischemic stroke in young and middle-aged adults, although relatively uncommon in the community. Recent large collaborative projects have provided new insights into mechanisms and risk factors of CeAD. RECENT FINDINGS: Pathologic changes observed at the media-adventitia border in temporal arteries of CeAD patients suggest a predisposing arterial wall weakness. In large multicenter series of CeAD patients, compared to age-matched healthy controls and patients with an ischemic stroke of another cause, hypertension and migraine, especially without aura, were confirmed as risk factors for CeAD, in addition to cervical trauma and recent infection. Hypercholesterolemia and being overweight were shown to be inversely associated with CeAD. Differences in risk factor profile and structural features between carotid and vertebral dissection suggest that their pathophysiology may partly differ. An association of CeAD with fibromuscular dysplasia and reversible cerebral vasoconstriction syndrome was described. Genetic risk factors of CeAD are still poorly understood. SUMMARY: Large cohorts of CeAD patients have refined our understanding of the pathophysiology and risk factors of CeAD, but the molecular mechanisms are still poorly understood. Ongoing high-throughput genetic projects will hopefully provide novel insight into the biological substrate of CeAD.

Protease inhibitors in spontaneous cervical artery dissections.

BACKGROUND AND PURPOSE: Observations in patients with arterial aneurysms, fibromuscular dysplasia, and spontaneous cervical artery dissection (sCAD) indicate that protease inhibitor deficiency might boost the enzymatic destruction of arterial tissue and increase the risk of these arterial wall diseases. Here we present the first large investigation of the protease inhibitor hypothesis in patients with sCAD. METHODS: Eighty patients with sCAD were compared with 80 age- and sex-matched healthy individuals. Alpha1-antitrypsin (alpha1-AT) and alpha2-macroglobulin (alpha2-MG) levels, and alpha1-AT genotypes were assessed and compared between groups. RESULTS: alpha1-AT and alpha2-MG levels as well as alpha1-AT genotypes did not differ significantly between patients and controls. The frequency of Z alleles in the patient group was higher than in the control group and than in other cohorts from Europe; however, the difference remained nonsignificant. All patients with Z alleles had internal carotid artery dissections. CONCLUSIONS: Overall, this data does not support the hypothesis that protease inhibitor levels or alpha1-AT genotypes play an important role in the etiology of sCAD. The present data does not exclude that the Pi-Z allele might have an influence on subgroups of sCAD, such as internal carotid artery dissections.

Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections.

Mild hyperhomocysteinemia is a probable risk factor for atherosclerotic diseases and stroke. Recently, associations of elevated plasma homocysteine concentrations in the acute phase and of MTHFR 677 TT genotype with spontaneous cervical artery dissections (sCAD) have been reported. The purpose of this study was to test this hypothesis in the currently largest sample of patients with sCAD, taking into account known factors influencing plasma homocysteine levels. Ninety-five patients with past sCAD were compared with 95 age- and sex-matched healthy individuals. Homocysteine, vitamin B6, B12, folate, and polymorphisms of methylenetetrahydrofolate reductase (MTHFR C677T), cystathionine beta-synthase (CBS 844ins68bp) and methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1 G1958A) were assessed and any associations were analysed using multivariate statistics. The occurrence of sCAD was associated with elevated homocysteine levels with an odds ratio of 1.327 per 20 % percentile. Homocysteine levels were influenced by gender, smoking status, occurrence of hypertension, vitamin B12 and folate levels, and by the MTHFR TT genotype. MTHFR, CBS 844ins68bp, and MTHFD1 G1958A genotype were not independently associated with the occurrence of sCAD. These data suggest that elevated homocysteine is associated with the occurrence of sCAD. The MTHFR C677T polymorphism is associated with the homocysteine level.

Alpha-1-antitrypsin deficiency alleles are not associated with cervical artery dissections.

The authors searched for the presence of alpha-1-antitrypsin (AAT) deficiency alleles PiZ and PiS in 74 patients with spontaneous cervical artery dissections (sCADs) and in 74 healthy control subjects. In both groups, the authors found four carriers of deficiency alleles. The connective tissue morphology of one additional patient with sCAD with PiZM genotype and her relatives was studied in skin biopsies. The PiZ allele did not segregate with morphologic alterations of the dermal connective tissue in the family. Therefore, AAT deficiency alleles may not play a role in the etiology of sCAD.