A Preliminary Study of the Association between SOX17 Gene Variants and Intracranial Aneurysms Using Exome Sequencing
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ABSTRACT:
SUBMITTER: Park J
PROVIDER: S-EPMC7477156 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTo investigate to what extent low-frequency genetic variants (with minor allele frequencies <5%) affect the risk of intracranial aneurysms (IAs).MethodsOne thousand fifty-six patients with IA and 2,097 population-based controls from the Netherlands were genotyped with the Illumina HumanExome BeadChip. After quality control (QC) of samples and single nucleotide variants (SNVs), we conducted a single variant analysis using the Fisher exact test. We also performed the variable threshold (VT) test and the sequence kernel association test (SKAT) at different minor allele count (MAC) thresholds of >5 and >0 to test the hypothesis that multiple variants within the same gene are associated with IA risk. Significant results were tested in a replication cohort of 425 patients with IA and 311 controls, and results of the 2 cohorts were combined in a meta-analysis.ResultsAfter QC, 995 patients with IA and 2,080 controls remained for further analysis. The single variant analysis comprising 46,534 SNVs did not identify significant loci at the genome-wide level. The gene-based tests showed a statistically significant association for fibulin 2 (FBLN2) (best p = 1 × 10-6 for the VT test, MAC >5). Associations were not statistically significant in the independent but smaller replication cohort (p > 0.57) but became slightly stronger in a meta-analysis of the 2 cohorts (best p = 4.8 × 10-7 for the SKAT, MAC ≥1).ConclusionGene-based tests indicated an association for FBLN2, a gene encoding an extracellular matrix protein implicated in vascular wall remodeling, but independent validation in larger cohorts is warranted. We did not identify any significant associations for single low-frequency genetic variants.
| S-EPMC7080288 | biostudies-literature
Project description:ObjectiveGenetic risk factors for unruptured intracranial aneurysms (UIA) and aneurysmal subarachnoid hemorrhage (aSAH) are poorly understood. We aimed to verify recently reported risk genes and to identify novel sequence variants involved in the etiology of UIA/aSAH.MethodsWe performed exome sequencing (ES) in 35 unrelated individuals and 3 family members, each with a history of UIA and/or aSAH. We searched for sequence variants with minor allele frequency (MAF) ≤ 5% in the reported risk genes ADAMTS15, ANGPTL6, ARHGEF17, LOXL2, PCNT, RNF213, THSD1 and TMEM132B. To identify novel putative risk genes we looked for unknown (MAF = 0) variants shared by the three relatives.ResultsWe identified 20 variants with MAF ≤ 5% in 18 individuals: 9 variants in PCNT (9 patients), 4 in RNF213 (3 patients), 3 in THSD1 (6 patients), 2 in ANGPTL6 (3 patients), 1 in ADAMTS15 (1 patient) and 1 in TMEM132B (1 patient). In the affected family, prioritization of shared sequence variants yielded five novel putative risk genes. Based on predicted pathogenicity of identified variants, population genetics data and a high functional relevance for vascular biology, EDIL3 was selected as top candidate and screened in additional 37 individuals with UIA and/or aSAH: a further very rare EDIL3 sequence variant in two unrelated sporadic patients was identified.ConclusionsOur data support a role of sequence variants in PCNT, RNF213 and THSD1 as susceptibility factors for cerebrovascular disease. The documented function in vascular wall integrity, the crucial localization of affected amino acids and gene/variant association tests suggest EDIL3 as a further valid candidate disease gene for UIA/aSAH.
| S-EPMC7419486 | biostudies-literature
Project description:BackgroundGenomewide association studies have identified novel genetic factors that contribute to intracranial aneurysm (IA) susceptibility. We sought to confirm previously reported loci, to identify novel risk factors, and to evaluate the contribution of these factors to familial and sporadic IA.MethodWe utilized 2 complementary samples, one recruited on the basis of a dense family history of IA (discovery sample 1: 388 IA cases and 397 controls) and the other without regard to family history (discovery sample 2: 1095 IA cases and 1286 controls). Imputation was used to generate a common set of single nucleotide polymorphisms (SNP) across samples, and a logistic regression model was used to test for association in each sample. Results from each sample were then combined in a metaanalysis.ResultsThere was only modest overlap in the association results obtained in the 2 samples. In neither sample did results reach genomewide significance. However, the metaanalysis yielded genomewide significance for SNP on chromosome 9p (CDKN2BAS; rs6475606; P=3.6×10(-8)) and provided further evidence to support the previously reported association of IA with SNP in SOX17 on chromosome 8q (rs1072737; P=8.7×10(-5)). Analyses suggest that the effect of smoking acts multiplicatively with the SNP genotype, and smoking has a greater effect on risk than SNP genotype.ConclusionsIn addition to replicating several previously reported loci, we provide further evidence that the association on chromosome 9p is attributable to variants in CDKN2BAS (also known as ANRIL, an antisense noncoding RNA).
| S-EPMC3752852 | biostudies-literature
Project description:Background Both meteorological factors and morphological factors are important factors to predict intracranial aneurysm rupture. This study investigated the relationship between meteorological factors and aneurysmal subarachnoid hemorrhage (aSAH). Additionally, the morphological differences between ruptured and unruptured aneurysms under these high-risk meteorological conditions were assessed. Methods and Results The records of 1751 patients with aSAH with 2124 intracranial aneurysms were retrospectively analyzed. Spearman rank correlation analysis was used to assess the risks of incident aSAH on the basis of daily meteorological data. Morphological parameters were analyzed using 1-way ANOVA tests, and significant parameters (P<0.05) were further examined using a multivariable logistic regression analysis. Daily aSAH incidence had significant negative correlations with daily mean, maximum, and minimum temperature (P<0.001) and a significant positive correlation with daily mean atmospheric pressure (P<0.001). Additionally, 58 patients with multiple aneurysms were assessed to determine morphological differences. There were significant differences in the mean values for aneurysm size, neck width, length, height, width, parent artery diameter, shape of the aneurysm, aspect ratio, size ratio, and bottleneck factor (P<0.05). The multivariable logistic regression analysis showed that aspect ratio (β=1.277, odds ratio=3.585, 95% CI, 1.588-8.090; P=0.002) was an independent risk factor for aneurysm rupture. Receiver operating characteristic curve analysis indicated that the ruptured aneurysm threshold of size was 3.45 mm and aspect ratio was 1.05. Conclusions Lower daily mean, maximum, and minimum temperatures and a higher daily mean atmospheric pressure were associated with an increased rate of aSAH. Additionally, under these meteorological conditions, the aneurysm size and aspect ratio thresholds for predicting rupture of an aneurysm may be lower.
| S-EPMC6755857 | biostudies-other
Project description:Noninvasive imaging identifying a predictive biomarker of the bleeding risk of unruptured intracranial aneurysms (UIAs) is needed. We investigated a potential biomarker of UIA instability, myeloperoxidase, in human aneurysm tissue.Human brain aneurysms were harvested after clipping and were histologically and biochemically evaluated for the presence of myeloperoxidase. Of the tissue collected, 3 were from ruptured aneurysms and 20 were from UIAs. For each UIA, its 5-year aneurysm rupture risk was determined using the Population, Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm and Site of Aneurysm (PHASES) model.All ruptured aneurysms were myeloperoxidase positive. Of the UIAs, half were myeloperoxidase positive. The median 5-year aneurysm rupture risk was higher for myeloperoxidase-positive UIA (2.28%) than myeloperoxidase-negative UIA (0.69%), and the distributions were statistically different (P<0.005, Wilcoxon-Mann-Whitney test). The likelihood for myeloperoxidase-positive UIA was significantly associated (P=0.031) with aneurysm rupture risk (odds ratio, 4.79; 95% confidence limits, 1.15-19.96).Myeloperoxidase is associated with PHASES estimated risk of aneurysm rupture and may potentially be used as an imaging biomarker of aneurysm instability.
| S-EPMC4021042 | biostudies-literature
Project description:BackgroundIntracranial aneurysms (IAs) cause subarachnoid hemorrhage, which has high rates of mortality and morbidity when ruptured. Recently, the role of rare variants in the genetic background of complex diseases has been increasingly recognized. The aim of this study was to identify rare variants for susceptibility to IA.MethodsWhole-exome sequencing was performed on seven members of a Japanese pedigree with highly aggregated IA. Candidate genes harboring co-segregating rare variants with IA were re-sequenced and tested for association with IA using additional 500 probands and 323 non-IA controls. Functional analysis of rare variants detected in the pedigree was also conducted.ResultsWe identified two gene variants shared among all four affected participants in the pedigree. One was the splicing donor c.1515+1G>A variant in NPNT (Nephronectin), which was confirmed to cause aberrant splicing by a minigene assay. The other was the missense p.P83T variant in CBY2 (Chibby family member 2). Overexpression of p.P83T CBY2 fused with red fluorescent protein tended to aggregate in the cytoplasm. Although Nephronectin has been previously reported to be involved in endothelial angiogenic functions, CBY2 is a novel molecule in terms of vascular pathophysiology. We confirmed that CBY2 was expressed in cerebrovascular smooth muscle cells in an isoform2-specific manner. Targeted CBY2 re-sequencing in additional case-control samples identified three deleterious rare variants (p.R46H, p.P83T, and p.L183R) in seven probands, showing a significant enrichment in the overall probands (8/501) compared to the controls (0/323) (p = 0.026, Fisher's extract test).ConclusionsNPNT and CBY2 were identified as novel susceptibility genes for IA. The highly heterogeneous and polygenic architecture of IA susceptibility can be uncovered by accumulating extensive analyses that focus on each pedigree with a high incidence of IA.
| S-EPMC8929693 | biostudies-literature
Project description:Endothelial nitric oxide synthase (eNOS) is the catalyst of endothelial nitric oxide (NO) synthesis. Polymorphisms in the eNOS gene may influence the risk of intracranial aneurysm (IA), but the results of existing researches are still inconsistent. Thus, we performed the present meta-analysis to derive a more precise estimation between eNOS polymorphisms (T786C, G894T, 27-bp-variable number of tandem repeat [VNTR]) and IA risk. Case-control studies evaluating the association between the eNOS polymorphisms and IA risk were searched in PubMed, Ovid & Embase, Web of Science, and Chinese Wanfang datasets with the last search up to July 15, 2014. The pooled odds ratios (ORs) for the association between eNOS polymorphisms and IA and their corresponding 95% confidence intervals (CIs) were estimated using the random or fixed-effects model. Finally, 10 studies for T786C polymorphism (1819 cases and 1893 controls), 9 studies for G894T polymorphism (1393 cases and 1508 controls), and 7 studies for 27-bp-VNTR polymorphism (1281 cases and 1406 controls) were included in the meta-analyses. In the overall analysis, no evidence of association between eNOS polymorphisms and susceptibility of IA was found. When subgrouped by race descent, significantly increased risk was detected among Asians for T786C polymorphism (heterozygous comparison of codominant model: OR?=?1.294, 95% CI?=?1.025-1.634; dominant model: OR?=?1.277, 95% CI?=?1.019-1.600), but not in Caucasians or the other 2 polymorphisms. Our meta-analysis suggested that T786C polymorphism was associated with increased risk of IA among Asians, whereas G894T and 27-bp-VNTR polymorphisms might have no influence on the susceptibility of IA.
| S-EPMC4602985 | biostudies-literature
Project description:Background and purposeMatrix metalloproteinases (MMPs) are expected to play an important role in extracellular matrix (ECM) remodeling in response to hemodynamic stress. We investigated the association between MMPs and intracranial aneurysms (IAs) via a genome-wide association study (GWAS) of IAs.MethodsA GWAS data set of 250 IAs and 294 controls was used to analyze the genetic link between MMPs and IAs via single-nucleotide polymorphisms (SNPs), MMP gene families, and in silico functional analyses of gene ontology (GO) enrichment and protein-protein interaction (PPI).ResultsForty-eight SNPs and 1 indel out of 342 markers of MMP genes were related to IAs. The rs2425024 SNP located on MMP24 was the most strongly associated with IAs (OR=0.43, CI=0.30-0.61, p=2.4×10-6), suggesting a protective effect. The 16938619 SNP of MMP26 significantly increased the risk of an IA (OR=3.12, 95% CI=1.76-5.50, p=8.85×10-5). Five MMP genes (MMP24, MMP13, MMP2, MMP17, and MMP1) increased the susceptibility to an IA. MMP24 was the gene most closely related to IAs (p=7.96×10-7). GO analysis showed that collagen catabolism was the most-enhanced biological process. Further, metalloendopeptidase activity and ECM were predominantly detected in the cellular component and molecular function, respectively. PPI provided evidence that MMP2, TIMP2 (tissue inhibitor of metalloproteinase 2), and TIMP3 genes constitute a network for predicting IA formation.ConclusionsThe present results provide comprehensive insight into the occurrence of IAs associated with MMPs.
| S-EPMC8926758 | biostudies-literature
Project description:Gene expression information is useful in prioritizing candidate genes in linkage intervals. The data can also identify pathways involved in the pathophysiology of disease. We used microarrays to identify which genes are expressed in either intracranial arteries (control) or in intracranial aneurysms (case), and can therefore contribute to the disease phenotypes. We used microarrays to identify the pathway membership of expressed genes and the overrepresentation of pathways with expressed genes in the known linkage intervals for intracranial aneurysms. Keywords: Characterization of expression in both diseased and non-diseased intracranial arteries.
2007-11-20 | GSE6551 | GEO
Project description:RationaleThoracic aortic aneurysms leading to acute aortic dissections (TAAD) can be inherited in families in an autosomal dominant manner. As part of the spectrum of clinical heterogeneity of familial TAAD, we recently described families with multiple members that had TAAD and intracranial aneurysms or TAAD and intracranial and abdominal aortic aneurysms inherited in an autosomal dominant manner.ObjectiveTo identify the causative mutation in a large family with autosomal dominant inheritance of TAAD with intracranial and abdominal aortic aneurysms by performing exome sequencing of 2 distantly related individuals with TAAD and identifying shared rare variants.Methods and resultsA novel frame shift mutation, p. N218fs (c.652delA), was identified in the SMAD3 gene and segregated with the vascular diseases in this family with a logarithm of odds score of 2.52. Sequencing of 181 probands with familial TAAD identified 3 additional SMAD3 mutations in 4 families, p.R279K (c.836G>A), p.E239K (c.715G>A), and p.A112V (c.235C>T), resulting in a combined logarithm of odds score of 5.21. These 4 mutations were notably absent in 2300 control exomes. SMAD3 mutations were recently described in patients with aneurysms osteoarthritis syndrome and some of the features of this syndrome were identified in individuals in our cohort, but these features were notably absent in many SMAD3 mutation carriers.ConclusionsSMAD3 mutations are responsible for 2% of familial TAAD. Mutations are found in families with TAAD alone, along with families with TAAD, intracranial aneurysms, abdominal aortic and bilateral iliac aneurysms segregating in an autosomal dominant manner.
| S-EPMC4115811 | biostudies-literature