Identification of a novel risk factor for intracranial aneurysms in ADPKD using iPSC models
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE74453 | GEO | 2016/08/04
SECONDARY ACCESSION(S): PRJNA300444
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-08-04 | E-GEOD-74453 | biostudies-arrayexpress
Project description:Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca2+ entry and gene expression profiles compared with those from control-iPSCs. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in the iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed a statistically significant correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that the serum MMP1 levels may be a novel risk factor and become more beneficial when combined with other risk factors. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors. The gene expression profiles of vascular endothelia and smooth muscle cells derived from ADPKD-iPSCs were analyzed. Seven ADPKD-iPSC derived ECs, and seven ADPKD-iPSC derived SMCs were analyzed.
2016-08-04 | E-GEOD-74452 | biostudies-arrayexpress
Project description:Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca2+ entry and gene expression profiles compared with those from control-iPSCs. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in the iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed a statistically significant correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that the serum MMP1 levels may be a novel risk factor and become more beneficial when combined with other risk factors. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors. The gene expression profiles of vascular endothelia and smooth muscle cells derived from control- and ADPKD-iPSCs were analyzed. Seven control-iPSC derived endothelial cells (ECs), seven ADPKD-iPSC derived ECs, ten control-iPSC derived vascular smooth muscle cells (SMCs), and seven ADPKD-iPSC derived SMCs were analyzed.
2016-08-04 | E-GEOD-74451 | biostudies-arrayexpress
Project description:Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca(2+) entry and gene expression profiles compared with those of iPSCs from non-ADPKD subjects. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed the correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that high serum MMP1 levels may be a novel risk factor. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors.
| S-EPMC4945931 | biostudies-literature
Project description:Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca2+ entry and gene expression profiles compared with those from control-iPSCs. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in the iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed a statistically significant correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that the serum MMP1 levels may be a novel risk factor and become more beneficial when combined with other risk factors. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors.
2016-08-04 | GSE74451 | GEO
Project description:Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca2+ entry and gene expression profiles compared with those from control-iPSCs. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in the iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed a statistically significant correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that the serum MMP1 levels may be a novel risk factor and become more beneficial when combined with other risk factors. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors.
2016-08-04 | GSE74452 | GEO
Project description:Identification of a novel risk factor for intracranial aneurysms in ADPKD using iPSC models
| PRJNA300444 | ENA
Project description:We carried out a case control study in an attempt to identify changes in circulating microRNAs in patients with intracranial aneurysms (IAs). We selected 40 cases (20 ruptured and 20 unruptured) and 20 healthy controls. We randomly selected 5 samples from each group and combined them into a sample pool. In this way we obtained 12 sample pools and one pool was used for a single microarray. Changes in microRNA levels in the plasma were surveyed with Agilent Human microRNA Microarray (Release 14.0, 8x15K). We identified 20 microRNAs that were unanimously changed in both ruptured and unruptured patients.
2013-09-14 | GSE50867 | GEO
Project description:We carried out a case control study in an attempt to identify changes in circulating microRNAs in patients with intracranial aneurysms (IAs). We selected 40 cases (20 ruptured and 20 unruptured) and 20 healthy controls. We randomly selected 5 samples from each group and combined them into a sample pool. In this way we obtained 12 sample pools and one pool was used for a single microarray. Changes in microRNA levels in the plasma were surveyed with Agilent Human microRNA Microarray (Release 14.0, 8x15K). We identified 20 microRNAs that were unanimously changed in both ruptured and unruptured patients. We included 40 cases (20 ruptured and 20 unruptured) and 20 healthy controls. We randomly selected 5 plasma samples from each group and combined them into a sample pool. In this way we obtained 12 sample pools and one pool was used for a single microarray. Total RNA was isolated from 1 ml plasma from each sample pool and resuspended in the same volume of buffer. A fixed volume of RNA sample was used for microarray detection.
2013-09-14 | E-GEOD-50867 | biostudies-arrayexpress
Project description:BACKGROUND:Intracranial aneurysm (IA) is usually a late-onset disease, affecting 1% to 3% of the general population and leading to life-threatening subarachnoid hemorrhage. Genetic susceptibility has been implicated in IAs, but the causative genes remain elusive. METHODS:We performed next-generation sequencing in a discovery cohort of 20 Chinese IA patients. Bioinformatics filters were exploited to search for candidate deleterious variants with rare and low allele frequency. We further examined the candidate variants in a multiethnic sample collection of 86 whole exome sequenced unsolved familial IA cases from 3 previously published studies. RESULTS:We identified that the low-frequency variant c.4394C>A_p.Ala1465Asp (rs2298808) of ARHGEF17 was significantly associated with IA in our Chinese discovery cohort (P=7.3×10-4; odds ratio=7.34). It was subsequently replicated in Japanese familial IA patients (P=0.039; odds ratio=4.00; 95% confidence interval=0.832-14.8) and was associated with IA in the large Chinese sample collection comprising 832 sporadic IA-affected and 599 control individuals (P=0.041; odds ratio=1.51; 95% confidence interval=1.02-Inf). When combining the sequencing data of all familial IA patients from 4 different ethnicities (ie, Chinese, Japanese, European American, and French-Canadian), we identified a significantly increased mutation burden for ARHGEF17 (21/106 versus 11/306; P=8.1×10-7; odds ratio=6.6; 95% confidence interval=2.9-15.8) in cases as compared with controls. In zebrafish, arhgef17 was highly expressed in the brain blood vessel. arhgef17 knockdown caused blood extravasation in the brain region. Endothelial lesions were identified exclusively on cerebral blood vessels in the arhgef17-deficient zebrafish. CONCLUSIONS:Our results provide compelling evidence that ARHGEF17 is a risk gene for IA.
| S-EPMC6141028 | biostudies-literature