Chloroplast translation factor EF-Tu of Arabidopsis thaliana can be inactivated via oxidation of a specific cysteine residue.

Translational elongation factor EF-Tu, which delivers aminoacyl-tRNA to the ribosome, is susceptible to inactivation by reactive oxygen species (ROS) in the cyanobacterium Synechocystis sp. PCC 6803. However, the sensitivity to ROS of chloroplast-localized EF-Tu (cpEF-Tu) of plants remains to be elucidated. In the present study, we generated a recombinant cpEF-Tu protein of Arabidopsis thaliana and examined its sensitivity to ROS in vitro. In cpEF-Tu that lacked a bound nucleotide, one of the two cysteine residues, Cys149 and Cys451, in the mature protein was sensitive to oxidation by H2O2, with the resultant formation of sulfenic acid. The translational activity of cpEF-Tu, as determined with an in vitro translation system, derived from Escherichia coli, that had been reconstituted without EF-Tu, decreased with the oxidation of a cysteine residue. Replacement of Cys149 with an alanine residue rendered cpEF-Tu insensitive to inactivation by H2O2, indicating that Cys149 might be the target of oxidation. In contrast, cpEF-Tu that had bound either GDP or GTP was less sensitive to oxidation by H2O2 than nucleotide-free cpEF-Tu. The addition of thioredoxin f1, a major thioredoxin in the Arabidopsis chloroplast, to oxidized cpEF-Tu allowed the reduction of Cys149 and the reactivation of cpEF-Tu, suggesting that the oxidation of cpEF-Tu might be a reversible regulatory mechanism that suppresses the chloroplast translation system in a redox-dependent manner.

A case of idiopathic extracranial carotid artery pseudoaneurysm with a rare clinical course and pathological features.

Extracranial carotid artery aneurysms (ECAAs) are rare, with the etiology mainly classified as degeneration or dissection. Pseudoaneurysms in the region are even rarer and are seen following trauma, iatrogenic injury, or infection. We report a case of extracranial carotid artery pseudoaneurysm (pseudo-ECAA) with a rare clinical course and pathological features. A 58-year-old man presented with swelling and purpura on the left side of his neck after sneezing. Radiological examinations suggested a ruptured left common carotid artery aneurysm. The operative findings were consistent with a pseudoaneurysm. Pathological examination revealed disarrangement and degeneration of smooth muscle fibers in the media, in addition to scattered foci of mucoid accumulation and irregular-shaped cavitation in the medial extracellular matrix, raising the possibility of an intrinsic dysfunction of the vascular wall in the pathological process of pseudoaneurysm formation.

[A Case of Segmental Arterial Mediolysis:Subarachnoid Hemorrhage Followed by Abdominal Bleeding].

We describe a case involving subarachnoid and intraperitoneal hemorrhage due to segmental arterial mediolysis(SAM). A 77-year-old female patient with sudden subarachnoid hemorrhage was immediately transferred to our institution. The hemorrhage was classified as grade 2 according to the World Federation of Neurosurgical Societies system. The patient was a non-smoker and did not drink alcohol regularly. A right internal carotid aneurysm was detected using CT angiography and was clipped during frontotemporal craniotomy. Bleeding was observed from the anterior wall of the internal carotid artery, and the tear was clipped. The patient had an uneventful postoperative course until sudden cardiopulmonary arrest eight days after craniotomy. She died of massive intraperitoneal hemorrhage. Autopsy revealed that the hemorrhage was due to dissection of the celiac artery. Tunica media denaturation was observed not only in the celiac artery, but also in the splenic and internal carotid arteries, which exhibited ruptured aneurysms, and the patient was diagnosed with segmental arterial mediolysis(SAM). SAM is an arterial degenerative disease affecting the medial layer of the arterial and dissecting walls. Multiple lesions are sometimes found. Radiographic imaging findings of SAM are similar to those of dissecting aneurysms, which are characterized by a single continuous dissection of the medial layer. As observed in this case, abdominal bleeding caused by SAM can occur after intracranial bleeding. When surgeons encounter unusual intracranial dissecting aneurysms, SAM should be considered as a differential diagnosis.

Exome Sequencing Identified CCER2 as a Novel Candidate Gene for Moyamoya Disease.

The etiology of Moyamoya disease (MMD) is still largely unclear, despite identification of RNF213 as the most significant susceptibility gene in East Asian patients. Following up our previous study confirming genetic heterogeneity in Japanese patients with MMD, we extensively surveyed novel candidate genes for a new perspective on the etiology of this disease. Two characteristic pedigrees without susceptibility variants in RNF213 were selected for whole-exome sequencing; 1 harbored 3 affected members, and the other included discordant monozygotic twins. In the former pedigree, 12 rare mutations in 12 genes were co-segregated with MMD. One of the most deleterious amino acid changes among these was p.T76_G80delinsPS in CCER2, which was also mutated in the latter pedigree (p.E242K), although the unaffected twin sister shared the same mutation reflecting reduced penetrance. These CCER2 mutations were predicted to promote aggregation or oligomerization of their protein product, using in silico functional analysis. Subsequent CCER2 re-sequencing in an additional 135 MMD probands identified 1 recurrent and an additional 2 in-frame insertion-deletion mutations, recurrent p.T76_G80delinsPS, p.H218_H220del, and p.E299del. Although CCER2 molecular function is not well characterized, it is a secretory protein expressed in the brain; therefore, it constitutes a potential biomarker of MMD.

Association of Rare Nonsynonymous Variants in PKD1 and PKD2 with Familial Intracranial Aneurysms in a Japanese Population.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) caused by deleterious mutations in PKD1 (16p13.3) and PKD2 (4q21) often coexists with intracranial aneurysms (IAs). In this study, we investigated whether IAs without obvious renal diseases were also associated with these ADPKD genes. METHODS: We performed next-generation sequencing of the ADPKD genes in 150 Japanese familial IA patients and age- and sex-matched 150 non-IA controls without obvious renal diseases. Rare coding variants for the following association analysis were defined according to allelic frequencies of less than .5% either in our controls or in the 1000 genomes database. Association with IA was evaluated using burden and variance component methods: the weighted-sum statistic (WSS) and the sequence kernel association test (SKAT), respectively. RESULTS: A total of 44 rare candidate variants were confirmed by Sanger sequencing; 26 were identified from 33 patients, whereas 21 were identified from 20 controls. The candidate variants were all missense variants, except for 1 patient's nonsense variant (p.Q924X) in PKD2, and showed consistent association with IA in both burden and variance component tests (odds ratio [OR] = 1.80; WSS, P = .026; SKAT, P = .044). This association was largely derived from the variants found in the extracellular structural domains of PKD1 (OR = 2.06; WSS, P = .030; SKAT, P = .029). CONCLUSION: ADPKD genes are susceptibility genes for IA even in patients without ADPKD.

Gene expression profiling reveals distinct molecular signatures associated with the rupture of intracranial aneurysm.

BACKGROUND AND PURPOSE: The rupture of intracranial aneurysm (IA) causes subarachnoid hemorrhage associated with high morbidity and mortality. We compared gene expression profiles in aneurysmal domes between unruptured IAs and ruptured IAs (RIAs) to elucidate biological mechanisms predisposing to the rupture of IA. METHODS: We determined gene expression levels of 8 RIAs, 5 unruptured IAs, and 10 superficial temporal arteries with the Agilent microarrays. To explore biological heterogeneity of IAs, we classified the samples into subgroups showing similar gene expression patterns, using clustering methods. RESULTS: The clustering analysis identified 4 groups: superficial temporal arteries and unruptured IAs were aggregated into their own clusters, whereas RIAs segregated into 2 distinct subgroups (early and late RIAs). Comparing gene expression levels between early RIAs and unruptured IAs, we identified 430 upregulated and 617 downregulated genes in early RIAs. The upregulated genes were associated with inflammatory and immune responses and phagocytosis including S100/calgranulin genes (S100A8, S100A9, and S100A12). The downregulated genes suggest mechanical weakness of aneurysm walls. The expressions of Krüppel-like family of transcription factors (KLF2, KLF12, and KLF15), which were anti-inflammatory regulators, and CDKN2A, which was located on chromosome 9p21 that was the most consistently replicated locus in genome-wide association studies of IA, were also downregulated. CONCLUSIONS: We demonstrate that gene expression patterns of RIAs were different according to the age of patients. The results suggest that macrophage-mediated inflammation is a key biological pathway for IA rupture. The identified genes can be good candidates for molecular markers of rupture-prone IAs and therapeutic targets.

Hemodynamics and changes after STA-MCA anastomosis in moyamoya disease and atherosclerotic cerebrovascular disease measured by micro-Doppler ultrasonography.

Moyamoya disease (MMD) and atherosclerotic cerebrovascular disease (ACVD) differ in angiographic appearance and probably hemodynamics. Pediatric MMD (PMMD) usually presents with cerebral ischemia, while intracranial hemorrhage is more common in adult MMD (AMMD), suggesting differences in cerebral hemodynamics. We analyzed the cortical flow velocity and direction of recipient arteries using micro-Doppler ultrasonography to evaluate the cortical circulation before and after anastomosis in MMD and ACVD. Twenty-eight patients with adult MMD (AMMD), 7 with pediatric MMD (PMMD), 16 with ACVD, and 12 control patients were studied. A micro-Doppler probe was applied on the cortical recipient artery (A4 or M4) before and after anastomosis. Systolic maximum flow velocity (V max) and blood flow direction were investigated at proximal and distal parts of anastomosed sites in recipient arteries. Pre- and postoperative regional cerebral blood flow was measured by cold xenon-computed tomography (Xe-CT). Before anastomosis, retrograde cortical flow was significantly more common in PMMD patients, and V max in cortical artery was significantly lower in AMMD patients. Bypass surgery changed the direction of blood flow from the anastomosis site to proximal and distal sites of the recipient artery in most patients, but pre-anastomosis flow direction was preserved more frequently in PMMD patients. The rate of V max increase after anastomosis was significantly higher in AMMD than in PMMD (11.6 ± 9.8 vs. 3.9 ± 1.8; P = 0.01). Micro-Doppler ultrasonography identified differences in cortical circulation among AMMD, PMMD, and ACVD. In AMMD, significantly low velocity in the cortical artery was observed before anastomosis, and bypass surgery reversed the flow and significantly increased flow velocity. The data of PMMD showed unique hemodynamics of the cortical artery before anastomosis, characterized by a higher frequency of retrograde flow and preserved velocity. The V max increase rate was significantly higher in patients with postoperative cerebral hyperperfusion on Xe-CT, and further study is warranted to validate the clinical use of intraoperative micro-Doppler monitoring to predict postoperative hyperperfusion.

[Neuromyelitis optica spectrum disorder: a case report].

Neuromyelitis optica (NMO) is a relapsing inflammatory disease of the central nervous system, usually affecting the optic nerves and the spinal cord. It is presumed to be an antibody-mediated disorder and the target antigen is the water channel aquaporin-4 (AQP4) on astrocyte cell membranes. NMO is a disease caused by astrocyte disorder and is distinct from multiple sclerosis (MS), which is a primarily demyelinating disease caused by oligodendrocyte disorder. In NMO, spinal MRI shows a T2-hyperintense, longitudinally extensive (≥ 3 vertebral segments) spinal cord lesion. The case, which has optic neuritis or transverse myelitis with the presence of AQP4 antibody, is called as NMO spectrum disorder. A 68 year-old woman with a history of hypertension and diabetes mellitus was brought to the former hospital by ambulance with acute onset of tetraparesis. She denied visual acuity disturbance. MRI revealed a T2-hyperintense lesion from C5 to T2 level. Laboratory examination showed the presence of AQP4 antibody and the absence of oligoclonal bands. Low-dose steroid treatment was started after establishing a diagnosis of NMO. She incompletely recovered from disability, although the T2-hyperintense lesion on MRI had almost disappeared six months after the onset. It is important to maintain a high index of suspicion for NMO in cases with a longitudinally extensive spinal cord lesion, because untreated NMO leads to severe disability.

[Two cases of iatrogenic vertebral arteriovenous fistulas successfully treated by surgery].

Cervical vertebral arteriovenous fistulas (AVFs) are very rare. The most frequent cause is trauma including iatrogenesis which result from vertebral artery penetration during central venous catheterization. Some endovascular techniques have been reported for this type of lesion. However, several potential problems exist, such as possibility of recurrence of AVFs and VA occlusion with endovascular treatment. In this article, we review two cases with iatrogenic vertebral AVFs which were successfully treated surgically and report the advantages of surgical treatment.

Optimal timing and safety of the external ventricular drainage in patients with high-grade aneurysmal subarachnoid hemorrhage treated with endovascular coiling.

The presented retrospective analysis has evaluated the optimal timing and safety of external ventricular drainage (EVD) for acute hydrocephalus after aneurysmal subarachnoid hemorrhage (aSAH). The study cohort comprised 102 patients, 49 of whom underwent EVD at 3-120 h (mean, 16 h) after the clinical onset of aSAH, either before (N = 27) or after (N = 22) ruptured aneurysm coiling. Among those treated with EVD, favorable and fair outcomes at discharge (modified Rankin Scale [mRS] scores 0-3) were noted in 14 (29%) and unfavorable (mRS scores 4-6) in 35 (71%). The former was more common among women (P = 0.019) and patients without chronic arterial hypertension (P = 0.028). The cut-off value for optimal timing of EVD was defined at 13 h after the onset of aSAH. Favorable and fair outcomes were more frequent after early (≤13 h; N = 30) than late (>13 h; N = 19) EVD (40% vs. 11%; P = 0.026), whereas did not differ significantly between those in whom such procedure was done before or after ruptured aneurysm coiling (19% vs. 41%; P = 0.083). In the entire study cohort, 2 patients had re-rupture of the aneurysm, and while both of them were treated with EVD, neither case of complication was directly associated with the procedure and, in fact, preceded it. In conclusion, EVD for management of acute hydrocephalus in patients with high-grade aSAH should be preferably applied within 13 h after the clinical onset of stroke, which may be considered sufficiently safe regardless whether it is performed before or after ruptured aneurysm coiling.

Novel and recurrent RNF213 variants in Japanese pediatric patients with moyamoya disease.

Moyamoya disease is a progressive steno-occlusive condition of the main intracranial arteries that results in the compensatory formation of fragile moyamoya vessels at the base of the brain. RNF213 is the most significant susceptibility gene and is often found with the p.Arg4810Lys founder variant in East Asian patients. We identified three putatively deleterious variants of this gene from three pediatric patients: two were novel, and one was a recurrent missense variant previously reported in other pediatric patients.

In vivo semi-automatic segmentation of multicontrast cardiovascular magnetic resonance for prospective cohort studies on plaque tissue composition: initial experience.

Automatic in vivo segmentation of multicontrast (multisequence) carotid magnetic resonance for plaque composition has been proposed as a substitute for manual review to save time and reduce inter-reader variability in large-scale or multicenter studies. Using serial images from a prospective longitudinal study, we sought to compare a semi-automatic approach versus expert human reading in analyzing carotid atherosclerosis progression. Baseline and 6-month follow-up multicontrast carotid images from 59 asymptomatic subjects with 16-79 % carotid stenosis were reviewed by both trained radiologists with 2-4 years of specialized experience in carotid plaque characterization with MRI and a previously reported automatic atherosclerotic plaque segmentation algorithm, referred to as morphology-enhanced probabilistic plaque segmentation (MEPPS). Agreement on measurements from individual time points, as well as on compositional changes, was assessed using the intraclass correlation coefficient (ICC). There was good agreement between manual and MEPPS reviews on individual time points for calcification (CA) (area: ICC; 0.85-0.91; volume: ICC; 0.92-0.95) and lipid-rich necrotic core (LRNC) (area: ICC; 0.78-0.82; volume: ICC; 0.84-0.86). For compositional changes, agreement was good for CA volume change (ICC; 0.78) and moderate for LRNC volume change (ICC; 0.49). Factors associated with LRNC progression as detected by MEPPS review included intraplaque hemorrhage (positive association) and reduction in low-density lipoprotein cholesterol (negative association), which were consistent with previous findings from manual review. Automatic classifier for plaque composition produced results similar to expert manual review in a prospective serial MRI study of carotid atherosclerosis progression. Such automatic classification tools may be beneficial in large-scale multicenter studies by reducing image analysis time and avoiding bias between human reviewers.

Influence of endothelial nitric oxide synthase T-786C single nucleotide polymorphism on aneurysm size.

OBJECT: Among patients with aneurysms, those with heterozygous (T/C) endothelial nitric oxide synthase (eNOS) T-786C single nucleotide polymorphism (SNP), a mutation reducing endothelial nitric oxide synthesis, are reported to have larger ruptured intracranial aneurysms (IAs) than those with homozygous (C/C or T/T) genotype. The authors tested patients harboring aneurysms for eNOS T-786C SNP in two populations--Japanese and Korean. METHODS: The eNOS T-786C SNP was genotyped through direct sequencing in genomic DNA obtained from 336 Japanese and 191 Korean patients with lAs and 214 Japanese and 191 Korean control volunteers. Differences in genotype frequencies among the various aneurysm sizes were evaluated using the Fisher exact test. There was no significant difference in heterozygous (T/C) eNOS T-786C SNP between aneurysms 5 mm or smaller and those from 6 to 9 mm, and between lesions 5 mm or smaller and those 10 mm or larger in 336 Japanese patients harboring aneurysms--220 with ruptured and 116 with unruptured lesions--and in 191 Korean patients with ruptured aneurysms. CONCLUSION: The eNOS T-786C SNP genotype does not influence the size of aneurysms.

Omnidirectional retractor-supporting ring as a new device for carotid endarterectomy.

In carotid endarterectomy (CEA), the traditional retractors are often difficult to use because they tend to obstruct surgical manipulations, especially in the deep operative field on the rostral side. The authors have invented a new omnidirectional retractor-supporting ring (OD ring) to solve the problems of traditional retractors. The OD ring has an ellipsoid-shaped frame (major axis: 275 mm, minor axis: 192 mm) with 22 equally spaced outward protrusions. Rubber bands from which blunt mini-hooks are hung are twisted around the protrusions. The OD ring was placed on the operative area, and the skin edges were retracted by mini-hooks placed symmetrically. The hooks were moved gradually from the shallow to the deep operative field as surgical dissection continued to expose the carotid bifurcation and distal internal carotid artery (ICA). The OD ring was used in 158 consecutive CEAs in the authors' institute between July 2010 and October 2013. The OD ring provided a flatter surgical field and was less obstructive than traditional retractors, thereby facilitating surgical manipulation in the deep operative field such as at the distal ICA. Furthermore, because of its simpler shape, angiorrhaphy could be conducted more smoothly, with less tangled thread during closure of the arteriotomy. There were no technical complications related to the OD ring. As a new retractor system for CEA, the OD ring is less obstructive and provides a flatter surgical field than traditional retractors, thereby facilitating surgical manipulations in the deep operative field around the distal ICA.

Perioperative and Long-term Outcomes of Carotid Endarterectomy for Japanese Asymptomatic Cervical Carotid Artery Stenosis: A Single Institution Study.

As the recently developed medical treatments for asymptomatic cervical carotid artery stenosis (ACCAS) have shown excellent stroke prevention, carotid endarterectomy (CEA) should be carried out for more selected patients and with lower complication rates and better long-term outcomes. We have performed CEA for Japanese ACCAS patients with a uniform surgical technique and strict perioperative management. In this study, we retrospectively investigated the perioperative complications and long-term outcomes of our CEA series. A total of 147 CEAs were carried out in 139 Japanese ACCAS patients. All patients were routinely checked for their cardiac function and high risk coronary lesions were preferentially treated before CEA. All CEAs were performed under general anesthesia using a shunt system. The postoperative cerebral blood flow was routinely measured under continued sedation to prevent postoperative hyperperfusion. The 30-day perioperative morbidity rate was 2.04%, including a perioperative stroke rate of 0.68%. There were no perioperative deaths. With regard to the long-term outcomes of the 134 followed-up patients, 9 patients were dead and 5 patients suffered from strokes, including 2 patients with ipsilateral hemispheric ischemia. The annual rates of death, all stroke and ipsilateral ischemic stroke were 1.15%, 0.64%, and 0.25%, respectively. These results showed that the perioperative morbidity and mortality rates of our CEAs were lower than those in the previous large trials. Furthermore, the long-term outcomes of this series were favorable to those reported in the latest medical treatment trials for ACCAS patients. CEA may be useful for preventing ischemic stroke in Japanese ACCAS patients.

Systematic Validation of RNF213 Coding Variants in Japanese Patients With Moyamoya Disease.

BACKGROUND: A founder variant of RNF213, p.R4810K (c.14429G>A, rs112735431), was recently identified as a major genetic risk factor for moyamoya disease (MMD) in Japan. Although the association of p.R4810K was reported to be highly significant and reproducible, the disease susceptibility of other RNF213 variants remains largely unknown. In the present study, we systematically evaluated the coding variants detected in Japanese patients and controls for associations with MMD. METHODS AND RESULTS: To detect variants of RNF213, all coding exons were sequenced in 27 Japanese MMD patients without p.R4810K. We also validated all previously reported variants in our case-control samples and tested for associations in combination with previous Japanese study cohorts, including the 1000 Genomes Project data set, as population-based controls. Forty-six missense variants other than p.R4810K were identified among 370 combined patients and 279 combined controls in Japan. Sixteen of 46 variants were polymorphisms with minor allele frequency >1%, and, after conditioning on the p.R4810K genotype, were not associated with MMD. We conducted a variable threshold test using Combined Annotation-Dependent Depletion on the remaining 30 rare variants (minor allele frequency <1%), and the results showed that the frequency of potentially functional variants was significantly higher in patients than in controls (permutation, minimum P=0.045). CONCLUSIONS: Not only p.4810K but also other functional missense variants of RNF213 conferred susceptibility to MMD. Our analysis also revealed that ≈20% of Japanese MMD patients did not harbor susceptibility variants of RNF213, indicating the presence of other susceptibility genes for MMD.

Bedside monitoring of circulating blood volume after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Maintenance of an adequate intravascular volume is important in the management of patients with subarachnoid hemorrhage (SAH). The purpose of this study was to investigate the circulating blood volume (CBV) after SAH with the use of indocyanine green pulse spectrophotometry. METHODS: CBV and plasma hormones related to stress and fluid regulation were measured 4 times: day 2 to 3, day 4 to 5, day 7 to 8, and day 14 in 50 consecutive patients with SAH surgically treated within 48 hours. RESULTS: The mean value of CBV was 64 mL/kg on day 2 to 3, which gradually increased to 69 mL/kg on day 4 to 5, 71 mL/kg on day 7 to 8, and 70 mL/kg on day 14 (P=0.005) (control, 72 mL/kg). The clinical grades and plasma corticotropin levels were higher in patients with <60 mL/kg of CBV on day 2 to 3 (P<0.05 for both). There were no significant differences in other physiological and laboratory parameters such as time for surgery, estimated blood loss, levels of plasma noradrenaline, brain natriuretic peptide, serum sodium, and hematocrit. When CBV was decreased >10% of the former level, there were decreases in hematocrit (P<0.05), serum sodium (P<0.01), and serum albumin (P<0.05) and an increase in urinary sodium (P<0.05). CONCLUSIONS: A significant reduction of CBV, especially in patients with poor clinical grades, was noted after SAH and early surgery, which could not be detected by routine examinations. Anemia, central salt wasting, and hypoalbuminemia may be related to a decrease in CBV from the former level. Indocyanine green pulse spectrophotometry may be a powerful tool for the management of patients with SAH.

Collagen type I alpha2 (COL1A2) is the susceptible gene for intracranial aneurysms.

BACKGROUND AND PURPOSE: The collagen alpha2(I) gene (COL1A2) on chromosome 7q22.1, a positional and functional candidate for intracranial aneurysm (IA), was extensively screened for susceptibility in Japanese IA patients. METHODS: Twenty-one single nucleotide polymorphisms (SNPs) of COL1A2 were genotyped in genomic DNA from 260 IA patients (including 115 familial cases) (mean age, 59.9 years) and 293 controls (mean age, 61.6 years). Differences in allelic and genotypic frequencies between the patients and controls were evaluated with the chi(2) test. Circular dichroism spectrometry was monitored with collagen-related peptides that mimic triple-helical models of type I collagen with Ala-459 and Pro-459 to estimate the conformation and stability of alterations. RESULTS: Significant genotypic association in the dominant model was observed between an exonic SNP of COL1A2 and familial IA patients (chi(2)=11.08; df=1; P=0.00087; odds ratio=3.19; 95% CI, 2.22 to 6.50). This SNP induces Ala to Pro substitution at amino acid 459, located on a triple-helical domain. Circular dichroism spectra showed that the Pro-459 peptide had a higher thermal stability than the Ala-459 peptide. CONCLUSIONS: The variant of COL1A2 could be a genetic risk factor for IA patients with family history.

Endoglin is not a major susceptibility gene for intracranial aneurysm among Japanese.

BACKGROUND AND PURPOSE: A 6-base insertion (6bINS) polymorphism in intron 7 of the endoglin gene (ENG), which codes for a component of the transforming growth factor-beta receptor complex, was reported to be associated with intracranial aneurysm (IA) in a Japanese population. A recent report using a white population could not replicate the association. We tested for this association with high statistical power in our independent Japanese subjects and evaluated the linkage between markers on chromosome 9, which contains ENG, and IA. METHODS: The sample for the linkage study comprised 179 individuals with IA in 85 nuclear families, with 104 possible affected sibpairs. For the association study of the 6bINS polymorphism and 4 single nucleotide polymorphisms (SNPs) in ENG, 172 Japanese patients with IA and 192 control subjects were examined. RESULTS: There was no evidence of linkage in the vicinity of ENG by analysis of affected sibpairs. The allele frequency of the 6bINS polymorphism was 104 of 344 (30.2%) in the total IA group and 122 of 382 (31.9%) in the control group. The statistical difference in allele frequency between the 2 groups was not significant (chi2=0.245, df=1, P=0.620). The power of the present association study was 98.3% at a significance level of 0.05 on the basis of the allele frequencies in the previous study. In addition, no associations between the 4 SNPs in ENG and IA were detected. CONCLUSIONS: We provide evidence that there is no association between the 6bINS polymorphism or 4 SNPs in ENG and IA and that there is no linkage between the ENG locus and IA, indicating that ENG is not a major susceptibility gene for IA in Japanese.

Absence of alpha-1 antitrypsin deficiency alleles (S and Z) in Japanese and Korean patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: A possible association has been proposed for the formation of intracranial aneurysm (IA) and deficiency alleles (S and Z) of the alpha1-antitrypsin (AAT) gene. We extensively screened this gene in Japanese and Korean patients with aneurysmal subarachnoid hemorrhage. METHODS: Seven allelic variants, including S and Z alleles, were genotyped by direct sequencing of genomic DNA obtained from 195 and 189 ruptured IA patients and 195 and 94 controls in Japanese and Koreans, respectively. The haplotype in phase-unknown samples was constructed with the expectation-maximization method. Differences in allelic frequencies between patients and controls were evaluated by Fisher exact test. RESULTS: No significant differences in allelic frequencies were observed at all 7 variants between ruptured IA patients and controls. We could not detect the S and Z alleles of the AAT gene in Japanese and Korean populations. CONCLUSIONS: AAT deficiency may not be a common genetic risk factor for aneurysmal subarachnoid hemorrhage in Japanese and Koreans.