Exome sequencing reveals a novel variant in NFX1 causing intracranial aneurysm in a Chinese family.

BACKGROUND: Genetic risk factors play an important role in the pathogenesis of familial intracranial aneurysms (FIAs); however, the molecular mechanisms remain largely unknown. OBJECTIVE: To investigate potential FIA-causing genetic variants by rare variant interrogation and a family-based genomics approach in a large family with an extensive multigenerational pedigree with FIAs. METHOD: Exome sequencing (ES) was performed in a dominant likely family with intracranial aneurysms (IAs). Variants were analyzed by an in-house developed pipeline and prioritized using various filtering strategies, including population frequency, variant type, and predicted variant pathogenicity. Sanger sequencing was also performed to evaluate the segregation of the variants with the phenotype. RESULTS: Based on the ES data obtained from five individuals from a family with 7/21 living members affected with IAs, a total of 14 variants were prioritized as candidate variants. Familial segregation analysis revealed that NFX1 c.2519T>C (p.Leu840Pro) segregated in accordance with Mendelian expectations with the phenotype within the family-that is, present in all IA-affected cases and absent from all unaffected members of the second generation. This missense variant is absent from public databases (1000genome, ExAC, gnomAD, ESP5400), and has damaging predictions by bioinformatics tools (Gerp ++ score = 5.88, CADD score = 16.43, MutationTaster score = 1, LRT score = 0). In addition, 840Leu in NFX1 is robustly conserved in mammals and maps in a region before the RING-type zinc finger domain. CONCLUSION: NFX1 c.2519T>C (p.Leu840Pro) may contribute to the pathogenetics of a subset of FIAs.

Racial and economic disparities in the access to treatment of unruptured intracranial aneurysms are persistent problems.

BACKGROUND AND PURPOSE: Previous studies have documented disparate access to cerebrovascular neurosurgery for patients of different racial and socioeconomic backgrounds. We further investigated the effect of race and insurance status on access to treatment of unruptured intracranial aneurysms (UIAs) and compared it with data on patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS: Through the use of a national database, admissions for clipping or coiling of an UIA and for aSAH were identified. Demographic characteristics of patients were characterized according to age, sex, race/ethnicity, and insurance status, and comparisons between patients admitted for treatment of an UIA versus aSAH were performed. RESULTS: There were 10 545 admissions for clipping or coiling of an UIA and 33 166 admissions for aSAH between October 2014 and July 2018. White/non-Hispanic patients made up a greater proportion of patients presenting for treatment of an UIA than those presenting with aSAH (64.3% vs 48.2%; P<0.001), whereas black/Hispanic patients presented more frequently with aSAH than for treatment of an UIA (29.3% vs 26.1%; P=0.006). On multivariate linear regression analysis, the proportion of patients admitted for management of an UIA relative to those admitted for aSAH increased with the proportion of patients who were women (P<0.001) and decreased with the proportion of patients with a black/Hispanic background (P=0.010) and those insured with Medicaid or without insurance (P=0.003). CONCLUSION: For patients with UIAs, racial, ethnic, and socioeconomic backgrounds appear to continue to influence access to treatment.

Characteristics of Unruptured Compared to Ruptured Intracranial Aneurysms: A Multicenter Case-Control Study.

BACKGROUND: Only a minority of intracranial aneurysms rupture to cause subarachnoid hemorrhage. OBJECTIVE: To test the hypothesis that unruptured aneurysms have different characteristics and risk factor profiles compared to ruptured aneurysms. METHODS: We recruited patients with unruptured aneurysms or aneurysmal subarachnoid hemorrhages at 22 UK hospitals between 2011 and 2014. Demographic, clinical, and imaging data were collected using standardized case report forms. We compared risk factors using multivariable logistic regression. RESULTS: A total of 2334 patients (1729 with aneurysmal subarachnoid hemorrhage, 605 with unruptured aneurysms) were included (mean age 54.22 yr). In multivariable analyses, the following variables were independently associated with rupture status: black ethnicity (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.29-4.56, compared to white) and aneurysm location (anterior cerebral artery/anterior communicating artery [OR 3.21; 95% CI 2.34-4.40], posterior communicating artery [OR 3.92; 95% CI 2.67-5.74], or posterior circulation [OR 3.12; 95% CI 2.08-4.70], compared to middle cerebral artery). The following variables were inversely associated with rupture status: antihypertensive medication (OR 0.65; 95% CI 0.49-0.84), hypercholesterolemia (0.64 OR; 95% CI 0.48-0.85), aspirin use (OR 0.28; 95% CI 0.20-0.40), internal carotid artery location (OR 0.53; 95% CI 0.38-0.75), and aneurysm size (per mm increase; OR 0.76; 95% CI 0.69-0.84). CONCLUSION: We show substantial differences in patient and aneurysm characteristics between ruptured and unruptured aneurysms. These findings support the hypothesis that different pathological mechanisms are involved in the formation of ruptured aneurysms and incidentally detected unruptured aneurysms. The potential protective effect of aspirin might justify randomized prevention trials in patients with unruptured aneurysms.

Genetic Risk Assessment of Elastin Gene Polymorphisms with Intracranial Aneurysm in Koreans.

Elastin encoded by elastin gene (ELN) is a crucial extracellular matrix protein responsible for arterial resilience. The objective of this study was to identify single nucleotide polymorphisms (SNPs) of ELN gene susceptible to intracranial aneurysm (IA) in Korean population. Two SNPs of ELN gene, rs2071307 (Gly422Ser) and rs2856728 (intron), were genotyped in 90 patients with IA and 90 age and frequency matched controls. Fisher's exact test was conducted to evaluate allelic association with IA. Of the two SNPs in ELN gene, T allele of rs2856728 (intron) showed statistically significant association with increased development of IA (odds ratio [OR]: 2.34, 95% confidence interval [CI]: 1.44-3.81, P = 7.6 × 10-4). However, G allele of rs2071307 (Gly422Ser) had no significant association with the development of IA (OR: 1.27, 95% CI: 1.44-3.81, P = 0.607). Interestingly, the odds of having rs2856728 variant was approximately 2-fold higher in males than that in females (OR: 3.46 vs. 1.88, P < 0.05). However, none of SNPs showed difference between single and multiple IA in this study. This preliminary study implies that the rs2856728 variant in ELN gene polymorphisms might play crucial roles in the development and pathogenesis of IA in Korean population.

Association of SOX17 Gene Polymorphisms and Intracranial Aneurysm: A Case-Control Study and Meta-Analysis.

BACKGROUND: Genome-wide association studies have revealed an association between SRY-box 17 (SOX17) gene and intracranial aneurysm (IA) formation. However, results were mainly derived from European and Japanese populations. We investigated the association between SOX17 gene polymorphisms and IA in a homogeneous Korean population. We performed a meta-analysis to assess these results in East-Asian populations. METHODS: This cross-sectional study included 187 age- and sex-matched patients with IA and 372 control subjects. Genetic association analysis was performed in the generalized linear model to identify associations between 4 single nucleotide polymorphisms and IA, including 95 patients with ruptured aneurysms and 92 with unruptured aneurysms. The East-Asian meta-analysis of 5100 IA cases and 7930 control cases was conducted under an inverse variance model. RESULTS: Among 4 single nucleotide polymorphisms that passed quality control tests, the minor C allele of rs1072737 was significantly associated with IA (odds ratio 0.69, 95% confidence interval 0.49-0.96, P = 0.03). None of the 4 single nucleotide polymorphisms showed a significant association between patients with ruptured and unruptured aneurysms. Meta-analysis revealed that G alleles of rs10958409 and rs9298506 were significantly associated with IA in the East-Asian population after removing study heterogeneity (odds ratio 1.11, 95% confidence interval 1.04-1.19, P = 0.0023 and odds ratio 1.19, 95% confidence interval 1.07-1.32, P = 0.0016). CONCLUSIONS: Identification of genetic variants located near SOX17 is likely to be clinically significant for IA formation. rs10958409 and rs9298506 may increase risk of IA in East-Asian populations. Our findings may help in the identification of IA pathogenesis.

Hyperhomocysteinemia as a Risk Factor for Saccular Intracranial Aneurysm: A Cohort Study in a Chinese Han Population.

BACKGROUND: We evaluated the possible relationships between serum total homocysteine and folate and Vitamin B12 in patients with intracranial aneurysm. METHODS: We enrolled consecutive patients with intracranial aneurysm from the Han population who were admitted to the hospital, as well as control subjects who received medical examination on an outpatient basis. The serum total homocysteine, folate, and Vitamin B12 levels were measured in patients with intracranial aneurysm and the control group, and the associations between those factors were analyzed using multivariate logistic analysis. RESULTS: A total of 140 patients with intracranial aneurysm and 140 control subjects were enrolled from July 2014 to December 2015. The mean serum total homocysteine level in the patient group (19.98 ± 10.84 µmol/L) was significantly higher than that in the control group (15.13 ± 5.55 µmol/L, P < .001). The serum total homocysteine level was negatively correlated with folate and Vitamin B12 levels (r = -.349, P < .001; r = -.531, P < .001, respectively) in the patient group. Homocysteine had an adjusted odds ratio of 2.196 (95% confidence interval: 1.188-4.057, P = .012) for the development of intracranial aneurysm. CONCLUSIONS: The present study provides evidence regarding the association between serum total homocysteine and folate and Vitamin B12 in patients with intracranial aneurysm. Hyperhomocysteinemia is an independent risk factor for intracranial aneurysm, and folate and Vitamin B12 are protective against intracranial aneurysm due to their roles in regulating the metabolism of homocysteine.

Investigating the Role of Ethnicity and Race in Patients Undergoing Treatment for Intracerebral Aneurysms Between 2008 and 2013 from a National Database.

BACKGROUND: The objective of this study is to classify patients using federally mandated categories of ethnicity and race and to determine whether subgroups are associated with patient outcomes and aneurysmal subarachnoid hemorrhage (SAH). METHODS: The American College of Surgeons National Surgical Quality Improvement Program database from 2008 to 2013 was used to identify patients undergoing treatment of an intracerebral aneurysm. Ethnicity and race were combined to create subgroups. A descriptive statistical analysis was performed and a multivariable logistic regression model was tested whether ethnic and racial subgroups were associated with SAH. RESULTS: A total of 686 patients met the study criteria. There were no endovascular cases reported. Four subgroups were identified, which included non-Hispanic Whites (n = 504, 73.47%, NH Whites), Hispanic Whites (n = 38, 5.54%), non-Hispanic Blacks (n = 109, 15.89%, NH Blacks), and non-Hispanic Asians (n = 35, 5.10%, NH Asians). Significant statistical associations were found between subgroups and the following baseline variables: age, female gender, body mass index, smoking, and treated hypertension (all P < 0.01). The NH Whites had the lowest proportion of SAH diagnosis (30.91%), which was statistically significant (P < 0.001). Multivariable logistic regression model adjusted for age, smoking, female gender, hypertension, and multiple comparisons found a statistically significant difference only between NH Asians compared with NH Whites (odds ratio = 1.25, 95% confidence interval 0.25-2.29, P < 0.01). Postoperative outcomes were similar across ethnic and racial subgroups. CONCLUSIONS: There are differences in baseline characteristics and the proportion of SAH. Future studies must take into account risk factors and outcomes not reported in the database.

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.

TGFBR2 mutation and MTHFR-C677T polymorphism in a Mexican mestizo population with cervico-cerebral artery dissection.

Spontaneous cervico-cerebral artery dissection (CCAD) is a common condition found among young patients with ischemic stroke. We examined the possible association between the polymorphism of methylenetetrahydrofolate reductase (MTHFR)-C677T and the gene mutation in transforming growth factor beta receptor II (TGFBR2) in a cohort of CCAD patients. One-hundred CCAD cases (65 males; mean age: 38.08 ± 10.68 years) and 100 matching controls were included. Ancestry informative markers (AIMs) were used to increase internal validity of the genetic analysis. Genotypes of the C677T polymorphism in the MTHFR gene were determined by polymerase chain reaction and restriction fragment length polymorphism; direct sequencing was used for a mutation analysis of the TGFBR2 gene. Associations were evaluated using a multivariate statistics, and Hardy-Weinberg equilibrium was analyzed. We also incorporated our data into a meta-analysis of the MTHFR-C677T. Sixty-three patients presented with vertebral and 37 with carotid artery dissection. Ancestry markers found a call rate on each over 95 %. All AIMs did not deviate from Hardy-Weinberg equilibrium (p > 0.05). The homozygous TT genotype was more frequent in cases (OR 2.04, CI 95 % 1.53-2.72, p = 0.005), whereas no significant difference was found on heterozygous CT genotype. TGFBR2 mutation was not present in our samples. In the meta-analysis of MTHFR/C677T variant, a total 613 cases and 1547 controls were analyzed; we found a moderate association for the recessive model genotype (OR 2.04, CI 95 % 1.53-2.72; p = 0.342; Z = 4.83; I (2) = 11.3). This study supports a positive association between the MTHFR-C677T polymorphism and genetically confirmed Mexican mestizo CCAD patients.

Screening for intracranial aneurysms? Prevalence of unruptured intracranial aneurysms in Hong Kong Chinese.

OBJECT The objective of this study was to generate data on the local prevalence of unruptured intracranial aneurysms (UIAs) in asymptomatic Hong Kong Chinese individuals. First-degree relatives of patients with aneurysmal subarachnoid hemorrhage (aSAH) were recruited as surrogates of the general population and to explore the potential role of screening in this locality. METHODS The authors identified first-degree relatives of consecutive patients with subarachnoid hemorrhage from a ruptured aneurysm who were admitted to a university hospital in Hong Kong from June 2008 to December 2010. Magnetic resonance angiography (MRA) was the imaging modality used to screen the cerebral vasculature of these asymptomatic individuals. If MRA showed abnormal findings, CT angiography was performed to confirm the MRA findings. RESULTS In total, 7 UIAs were identified from the 305 MR angiograms obtained. The prevalence of UIAs in first-degree relatives of patients with aSAH in the Hong Kong Chinese population was 2.30% (95% CI1.02%-4.76%). This percentage was lower than the prevalence rate of 3.2% from a meta-analysis of the literature. The sizes of the UIAs detected ranged from 1.4 mm to 7.5 mm; 85.7% of the UIAs detected in this study were < 5 mm, in contrast to 66% noted in the literature. One of the UIAs identified underwent endovascular stent placement with a flow diverter. None of the UIAs identified ruptured or became symptomatic during a median follow-up period of 3.5 years. CONCLUSIONS The prevalence of UIAs in first-degree relatives of patients with aSAH in the Hong Kong Chinese population was lower than that in Caucasians. At the same time, most of the UIAs detected in this study were small (85.7% were < 5 mm, vs 66% in a meta-analysis). With a similar incidence of aSAH in Hong Kong (7.5 per 100,000 person-years) as compared with data cited in the literature, the hypothesis that UIA rupture risk size threshold is different in Chinese patients should be further investigated.

Intracranial aneurysm risk factor genes: relationship with intracranial aneurysm risk in a Chinese Han population.

Few studies have examined the genes related to risk fac-tors that may contribute to intracranial aneurysms (IAs). This study in Chinese patients aimed to explore the relationship between IA and 28 gene loci, proven to be associated with risk factors for IA. We recruited 119 patients with aneurysms and 257 controls. Single factor and logistic regression models were used to analyze the association of IA and IA rup-ture with risk factors. Twenty-eight single nucleotide polymorphisms (SNPs) in 22 genes were genotyped for the patient and control groups. SNP genotypes and allele frequencies were analyzed by the chi-square test. Logistic regression analysis identified hypertension as a factor that increased IA risk (P = 1.0 x 10(-4); OR, 2.500; 95%CI, 1.573-3.972); IA was associated with two SNPs in the TSLC2A9 gene: rs7660895 (P = 0.007; OR, 1.541; 95%CI, 1.126-2.110); and in the TOX gene: rs11777927 (P = 0.013; OR, 1.511; 95%CI, 1.088-2.098). Subsequent removal of the influence of family relationship identified between 12 of 119 patients enhanced the significant association of these SNPs with IA (P = 0.001; OR, 1.691; 95%CI, 1.226-2.332; and P = 0.006; OR, 1.587; 95%CI, 1.137-2.213 for rs7660895 and rs11777927, respectively). Fur-thermore, the minor allele of rs7660895 (A) was also associated with IA rupture (P = 0.007; OR, 2.196; 95%CI, 1.230-3.921). Therefore, hypertension is an independent risk factor for IA. Importantly, the TSL-C2A9 (rs7660895) and TOX (rs11777927) gene polymorphisms may be associated with formation of IAs, and rs7660895 may be associated with IA rupture.

Association of Kallikrein gene polymorphisms with sporadic intracranial aneurysms in the Chinese population.

OBJECT: Variants of Kallikreins have been shown to be risk factors for intracranial aneurysm (IA) in a Finnish population. In the present study, the authors investigated the correlation between polymorphisms in the Kallikrein gene cluster and IAs in the Chinese population. METHODS: The association of Kallikrein variants (rs1722561 and rs1701946) with sporadic IAs was tested in 308 cases and 443 controls. The differences in allelic frequencies between patients and the control group were evaluated with the chi-square test. RESULTS: The C allele of rs1722561 showed a significant reduction in the risk of sporadic IA (OR 0.71, 95% CI 0.53-0.95; p = 0.023). However, no association of the variant rs1701946 with sporadic IA was found (OR 0.78, 95% CI 0.57-1.06; p = 0.115). CONCLUSIONS: The variant rs1722561 of Kallikreins might reduce the risk of sporadic IAs among individuals of Chinese Han ethnicity. This study confirms the association between Kallikreins and IAs.

Angiotensin-converting enzyme insertion/deletion gene polymorphism and risk of intracranial aneurysm in a Chinese population.

OBJECTIVE: The relationship between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphisms and intracranial aneurysm (IA) has been studied in Caucasian and Japanese populations. The present study aimed to investigate this association in a Chinese population. METHODS: Patients with confirmed IA and age- and sex-matched control subjects without evidence of IA were enrolled. ACE I/D gene polymorphisms were analysed using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: A total of 220 patients with IA and 220 matched controls were enrolled. In the IA group, 64, 106 and 50 patients were of the II, ID and DD genotypes, respectively, compared with 44, 99 and 77 subjects in the control group. The ACE DD genotype and D allele frequencies were significantly lower in the IA group compared with the control group. There were no statistically significant differences in the site, shape, size and Fisher Grade of aneurysms between genotypes in patients with IA. CONCLUSION: The ACE DD genotype may be a protective factor for IA in a Chinese population.

Intracranial aneurysm size responsible for spontaneous subarachnoid haemorrhage.

INTRODUCTION: It has been theorised that the relationship between smaller body size and smaller ruptured intracranial aneurysms in Asians indirectly supports the treatment of small, unruptured intracranial aneurysms. There has also been uncertainty regarding whether the progress that has been made in neuroimaging allows for better detection of smaller ruptured intracranial saccular aneurysms. Therefore, we conducted this systemic review of ruptured intracranial saccular aneurysm sizes according to region and time. MATERIAL AND METHODS: Computerised MEDLINE and PubMed searches of the literature for population-based studies of ruptured intracranial saccular aneurysms were carried out from 1 January 1980 to 1 March 2011. Statistical analyses were generated using SPSS for Windows, Version 15.0 (SPSS Inc., Chicago, IL) and Comprehensive MetaAnalysis 2.0 for Windows (Biostat, Englewood, NJ). The results of the meta-analyses are presented with 95% confidence intervals (CIs). RESULTS: Six eligible population- or hospital-based studies were analysed. The percentage of ruptured intracranial aneurysms measuring less than 5 mm was 28.4% (95% CI: 18.1% to 41.6%, I(2) = 98%). The percentage of ruptured intracranial aneurysms measuring less than 10 mm was 76.7% (95% CI: 69.2% to 82.9%, I2 = 89%). A higher proportion of patients with ruptured intracranial aneurysms of less than 5 mm was found in Asia compared to other regions. Similarly, a higher proportion of patients with ruptured intracranial aneurysms of less than 10 mm was found in Asia compared to other regions. CONCLUSIONS: The present findings suggest that ruptured intracranial aneurysms are smaller in Asians and should be confirmed in future prospective international multi-centre registries to assess ethnicity. Whether these findings support treating smaller unruptured intracranial aneurysms in Asians should be investigated.

Racial and ethnic disparities in the treatment of unruptured intracranial aneurysms: a study of the Nationwide Inpatient Sample 2001-2009.

BACKGROUND AND PURPOSE: Minorities in the United States have less access to healthcare system resources, especially preventative treatments. We sought to determine whether racial and sex disparities existed in the treatment of unruptured intracranial aneurysms. METHODS: Using the Nationwide Inpatient Sample, hospitalizations for clipping and coiling of intracranial aneurysms from 2001 to 2009 were identified by cross-matching International Classification of Diseases, 9th Revision codes for diagnosis of unruptured aneurysm and subarachnoid hemorrhage (SAH) with procedure codes for clipping or coiling of cerebral aneurysms. Demographic information analyzed included age (<50, 50-64, 65-79, and ≥80 years), race (white, black, Hispanic, Asian/Pacific Islander), sex, income quartile, primary payer (Medicare, Medicaid, private insurance, self-pay, no charge, other), and Charlson comorbidity index. RESULTS: When compared with patients treated for SAH, those treated for unruptured intracranial aneurysm were significantly more likely to be women (75.0% versus 69.0%; P<0.0001). In all, 9.7% of patients receiving treatment for SAH were self-payers versus 3.0% of patients being treated for unruptured intracranial aneurysm (P<0.0001). In all, 62.2% of patients receiving treatment for SAH were white compared with 76.4% of patients being treated for unruptured intracranial aneurysm (P<0.0001). There was a higher proportion of black, Hispanic, and Asian patients in the SAH treatment group when compared with the unruptured aneurysm treatment group (P<0.0001 for all groups). CONCLUSIONS: When compared with patients undergoing treatment for SAH, patients undergoing surgical and endovascular treatment for unruptured intracranial aneurysm are generally from higher socioeconomic strata and are more likely to be insured, women, and white. Future studies are needed to determine the underlying causes and solutions for this disparity.

A functional variant of the collagen type III alpha1 gene modify risk of sporadic intracranial aneurysms.

Abnormalities in type III collagen in the arterial walls cause certain familial intracranial aneurysms (IAs); however, it remains unknown whether COL3A1 variants contribute to the risk of sporadic IAs. To study whether COL3A1 variants are associated with sporadic IAs, the association of COL3A1 variants with sporadic IAs was tested in 298 cases and 488 controls, replicated in an independent population of 192 cases and 1,690 controls, and further verified in 633 patients with intra-cerebral hemorrhage, 1,074 hypertensives, and 1,883 controls. We found that allele A of SNP rs1800255 conferred a 1.71-fold increased risk for IAs (adjusted odds ratio: OR = 1.71, 95% confidence interval: CI 1.19-2.45, P = 0.004) and results in an amino acid change of Ala698Thr, which led to a lower thermal stability of the peptide. These results were confirmed in the independent study. The associations were independent of the presence of hemorrhagic stroke and hypertension. These results support the view that the functional variant of COL3A1 is genetic risk factors for IAs in the Chinese population.

The relationships between endothelial nitric oxide synthase polymorphisms and the formation of intracranial aneurysms in the Korean population.

OBJECT: Some genetic factors are known to be associated with the formation of cerebral aneurysms in the Caucasian population. One of these factors is endothelial nitric oxide synthase (eNOS) gene polymorphisms. Endothelial nitric oxide synthase genes encode eNOS, which synthesizes NO from l-arginine. There continues to be controversy about the relationships between eNOS gene polymorphisms and the formation of intracranial aneurysms. In this study, the authors evaluated these relationships in the Korean population. METHODS: Three eNOS polymorphisms (eNOS 27VNTR, T786C, and G894T) were genotyped in 96 patients with ruptured aneurysms, 53 patients with unruptured aneurysms, and in 121 volunteers via polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The mean ages of the patients and healthy volunteers were 52.9 ± 12.3 years and 55.2 ± 9.1 years, respectively. The patient group was composed of 56 men and 93 women, and the healthy volunteer group was composed of 46 men and 75 women. Only the incidence of smoking history was significantly higher in the patient group than in the control group (p = 0.001). The genotypic frequencies for the 3 eNOS gene polymorphisms were in agreement with those predicted by Hardy-Weinberg equilibrium. There were no significant associations between the eNOS recessive models and the formation of an aneurysm. The authors found no genotypic differences between similar races among patients with aneurysms. CONCLUSIONS: The present study shows that eNOS 27VNTR, T786C, and G894T polymorphisms cannot be used as indicators of the formation of intracranial aneurysms in Korean patients. To confirm these findings an additional analyses might need to be performed using a larger sample size. There were no differences in the genotypic distributions and allelic frequencies between similar races among patients with aneurysms, which were the same in previously reported normal populations.

Association of the Jun dimerization protein 2 gene with intracranial aneurysms in Japanese and Korean cohorts as compared to a Dutch cohort.

In a previous study a linkage region for association to IA patients was found on chromosome 14q22. In this study, we report the findings of a positional candidate gene, Jun dimerization Protein 2 (JDP2), and single nucleotide polymorphisms (SNP) of that gene that are associated with intracranial aneurysms in different ethnic populations. We screened the linkage region around chromosome 14q22 and narrowed it down to JDP2. We then genotyped case and control groups of three different ethnic populations: 403 Japanese intracranial aneurysm (IA) cases and 412 controls, 181 Korean IA cases and 181 controls, 379 Dutch cases and 642 Dutch controls. Genotyping was performed using polymerase chain reaction and direct sequencing technology. The allele distribution of three SNPs (two intronic: rs741846; P=0.0041 and rs175646; P=0.0014, and one in the untranslated region: rs8215; P=0.019) and their genotype distribution showed significant association in the Japanese IA patients. The allelic and genotypic frequency of one intronic SNP (rs175646; P=0.0135 and P=0.0137, respectively) and the genotypic frequency for the SNP in the UTR region (rs8215; P=0.049) was also significantly different between cases and controls of the Korean cohort. There was no difference in allelic or genotypic frequencies in the Dutch population. These SNPs in JDP2 are associated with intracranial aneurysms, suggesting that variation in or near JDP2 play a role in susceptibility to IAs in East Asian populations.

Ten-year detection rate of brain arteriovenous malformations in a large, multiethnic, defined population.

BACKGROUND AND PURPOSE: To evaluate whether increased neuroimaging use is associated with increased brain arteriovenous malformation (BAVM) detection, we examined detection rates in the Kaiser Permanente Medical Care Program of northern California between 1995 and 2004. METHODS: We reviewed medical records, radiology reports, and administrative databases to identify BAVMs, intracranial aneurysms (IAs: subarachnoid hemorrhage [SAH] and unruptured aneurysms), and other vascular malformations (OVMs: dural fistulas, cavernous malformations, Vein of Galen malformations, and venous malformations). Poisson regression (with robust standard errors) was used to test for trend. Random-effects meta-analysis generated a pooled measure of BAVM detection rate from 6 studies. RESULTS: We identified 401 BAVMs (197 ruptured, 204 unruptured), 570 OVMs, and 2892 IAs (2079 SAHs and 813 unruptured IAs). Detection rates per 100 000 person-years were 1.4 (95% CI, 1.3 to 1.6) for BAVMs, 2.0 (95% CI, 1.8 to 2.3) for OVMs, and 10.3 (95% CI, 9.9 to 10.7) for IAs. Neuroimaging utilization increased 12% per year during the time period (P<0.001). Overall, rates increased for IAs (P<0.001), remained stable for OVMs (P=0.858), and decreased for BAVMs (P=0.001). Detection rates increased 15% per year for unruptured IAs (P<0.001), with no change in SAHs (P=0.903). However, rates decreased 7% per year for unruptured BAVMs (P=0.016) and 3% per year for ruptured BAVMs (P=0.005). Meta-analysis yielded a pooled BAVM detection rate of 1.3 (95% CI, 1.2 to 1.4) per 100 000 person-years, without heterogeneity between studies (P=0.25). CONCLUSIONS: Rates for BAVMs, OVMs, and IAs in this large, multiethnic population were similar to those in other series. During 1995 to 2004, a period of increasing neuroimaging utilization, we did not observe an increased rate of detection of unruptured BAVMs, despite increased detection of unruptured IAs.

Polymorphism rs4934 of SERPINA3 and sporadic intracranial aneurysms in the Chinese population.

BACKGROUND: Serine protease inhibitor member 3 of clade A (SERPINA3) has been shown as a risk factor for aneurysmal subarachnoid hemorrhage in a Polish population. In the present study, the authors investigated the correlation between the rs4934 polymorphism of SERPINA3 and sporadic intracranial aneurysms in Chinese patients. METHODS: The rs4934 polymorphism of SERPINA3 was identified by PCR and Taqman MGB probe analysis in genomic DNA from 275 patients with sporadic intracranial aneurysms (mean age 50.83 +/- 10.78 years) and 361 control participants (mean age 53.21 +/- 10.81 years). Differences in allelic and genotypic frequencies between the patient and control groups were evaluated with the chi(2) test. RESULTS: No significant difference was found in either the genotype distribution or allelic frequencies of SERPINA3 between patients and controls. CONCLUSIONS: The rs4934 polymorphism of SERPINA3 is not associated with sporadic intracranial aneurysms among individuals of Chinese Han ethnicity.