Dataset Information

First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm.

ABSTRACT: Genetic causes for abdominal aortic aneurysm (AAA) have not been identified and the role of genes associated with familial thoracic aneurysms in AAA has not been explored. We analyzed nine genes associated with familial thoracic aortic aneurysms, the vascular Ehlers-Danlos gene COL3A1 and the MTHFR p.Ala222Val variant in 155 AAA patients. The thoracic aneurysm genes selected for this study were the transforming growth factor-beta pathway genes EFEMP2, FBN1, SMAD3, TGBF2, TGFBR1, TGFBR2, and the smooth muscle cells genes ACTA2, MYH11 and MYLK. Sanger sequencing of all coding exons and exon-intron boundaries of these genes was performed. Patients with at least one first-degree relative with an aortic aneurysm were classified as familial AAA (n = 99), the others as sporadic AAA. We found 47 different rare heterozygous variants in eight genes: two pathogenic, one likely pathogenic, twenty-one variants of unknown significance (VUS) and twenty-three unlikely pathogenic variants. In familial AAA we found one pathogenic and segregating variant (COL3A1 p.Arg491X), one likely pathogenic and segregating (MYH11 p.Arg254Cys), and fifteen VUS. In sporadic patients we found one pathogenic (TGFBR2 p.Ile525Phefs*18) and seven VUS. Thirteen patients had two or more variants. These results show a previously unknown association and overlapping genetic defects between AAA and familial thoracic aneurysms, indicating that genetic testing may help to identify the cause of familial and sporadic AAA. In this view, genetic testing of these genes specifically or in a genome-wide approach may help to identify the cause of familial and sporadic AAA.

SUBMITTER: van de Luijtgaarden KM

PROVIDER: S-EPMC4495250 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm.

van de Luijtgaarden Koen M KM Heijsman Daphne D Maugeri Alessandra A Weiss Marjan M MM Verhagen Hence J M HJ IJpma Arne A Brüggenwirth Hennie T HT Majoor-Krakauer Danielle D

Human genetics 20150528 8

Genetic causes for abdominal aortic aneurysm (AAA) have not been identified and the role of genes associated with familial thoracic aneurysms in AAA has not been explored. We analyzed nine genes associated with familial thoracic aortic aneurysms, the vascular Ehlers-Danlos gene COL3A1 and the MTHFR p.Ala222Val variant in 155 AAA patients. The thoracic aneurysm genes selected for this study were the transforming growth factor-beta pathway genes EFEMP2, FBN1, SMAD3, TGBF2, TGFBR1, TGFBR2, and the ...[more]

PMID: 26017485

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Project description:PurposeFerroptosis plays a crucial role in the development and progression of abdominal aortic aneurysm (AAA). The aim of this study was to identify differentially expressed genes associated with ferroptosis in AAA through bioinformatics analysis combined with experimental validation.Materials and methodsFirstly, the mRNA expression profile datasets GSE57691 and GSE47472 from Gene Expression Omnibus database were screened, and principal component analysis was carried out. Next, the R software (version 4.0.0) was used to analyze potentially differentially expressed genes associated with AAA and ferroptosis. Subsequently, protein-protein interaction analysis, gene ontology enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed on the selected candidate genes. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of the first five selected abnormal ferroptosis-related genes in clinical samples obtained from patients with AAA and healthy controls.ResultsBased on the information contained in the two datasets, a total of 20 differentially expressed ferroptosis-related genes (three upregulated genes and 17 downregulated genes) were selected. Protein-protein interaction analysis demonstrated interaction between these genes, while gene ontology enrichment analysis of ferroptosis genes with differential expression indicated that some enrichment items were associated with oxidative stress. The qRT-PCR results showed that the expression levels of interleukin-6 (IL-6), peroxiredoxin 1 (PRDX1), and stearoyl-CoA desaturase (SCD) were consistent with the bioinformatics prediction results obtained from the mRNA chip.ConclusionBioinformatics analysis identified 20 potential ferroptosis-related differentially expressed genes in AAA. Further verification by qRT-PCR showed that IL-6, PRXD1, and SCD might affect the process of AAA by regulating ferroptosis. Our results might assist in further understanding the pathogenesis of AAA and guiding treatment.

Project description:Background:Abdominal aortic aneurysm (AAA) is the full thickness dilation of the abdominal aorta. However, few effective medical therapies are available. Thus, elucidating the molecular mechanism of AAA pathogenesis and exploring the potential molecular target of medical therapies for AAA is of vital importance. Methods:Three expression datasets (GSE7084, GSE47472 and GSE57691) were downloaded from the Gene Expression Omnibus (GEO). These datasets were merged and then normalized using the "sva" R package. Differential expressed gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA) were conducted. We compared the co-expression patterns between AAA and normal conditions, and hub genes of each functional module were identified. DEGs were mapped to co-expression network under AAA condition and a DEG co-expression network was generated. Crucial genes were identified using molecular complex detection (MCODE) (a plugin in Cytoscape). Results:In our study, 6 and 10 gene modules were detected for the AAA and normal conditions, respectively, while 143 DEGs were screened. Compared to the normal condition, genes associated with immune response, inflammation and muscle contraction were clustered in three gene modules respectively under the AAA condition; the hub genes of the three modules were MAP4K1, NFIB and HPK1, respectively. A DEG co-expression network with 102 nodes and 303 edges was identified, and a hub gene cluster with 10 genes from the DEG co-expression network was detected. YIPF6, RABGAP1, ANKRD6, GPD1L, PGRMC2, HIGD1A, GMDS, MGP, SLC25A4 and FAM129A were in the cluster. The expression levels of these 10 genes showed potential diagnostic value. Conclusion:Based on WGCNA, we detected 6 modules under the AAA condition and 10 modules in the normal condition. Hub genes of each module and hub gene clusters of the DEG co-expression network were identified. These genes may act as potential targets for medical therapy and diagnostic biomarkers. Further studies are needed to elucidate the detailed biological function of these genes in the pathogenesis of AAA.

Project description:BackgroundAbdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability.MethodsWe performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease.ResultsThrough a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24-1.66]; P=1.6×10-6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97-1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18-1.36]; PPRS=2.7×10-11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14-1.35]; PPRS=1.27×10-6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines.ConclusionsWe identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

Dataset Information

First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm.

Publications

First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm.

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