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A population-based study of polymorphisms in genes related to sex hormones and abdominal aortic aneurysm.

ABSTRACT: Male gender and family history are risk factors for abdominal aortic aneurysm (AAA). We hypothesized that genes involved in sex hormones might be important in AAA. We investigated the association of aortic diameter with single-nucleotide polymorphisms (SNPs) in genes determining circulating sex hormones and their action. We genotyped 74 tagging SNPs across four genes (steroid 5? reductase, subfamily A, polypeptide 1 (SRD5A1), cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1), androgen receptor (AR) and estrogen receptor 2 (ESR2)) related to sex hormone production and action in 1711 men, 640 of whom had an AAA. One genotype was also assessed in an independent cohort of 782 men, of whom 513 had large AAAs. Associations were assessed adjusting for other risk factors for AAA. One SNP in CYP19A1 was strongly associated with aortic diameter. Subjects who had the rare homozygote genotype (TT) for CYP19A1g.49412370C>T (SNP ID rs1961177), had an increased aortic diameter (coefficient 5.058, SE 1.394, P=0.0003, under a recessive model). This SNP was not associated with aortic diameter in an independent cohort, which included patients with larger AAAs. Our findings do not support an important role of genetic polymorphisms in genes determining sex hormones in aortic dilatation in men. The association of one SNP in CYPA9A1 with small but not large AAA may suggest differences between AAA formation and progression. This SNP warrants further investigation in another large population, including patients with small AAAs.

SUBMITTER: Golledge J

PROVIDER: S-EPMC3062004 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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A population-based study of polymorphisms in genes related to sex hormones and abdominal aortic aneurysm.

Golledge Jonathan J Biros Erik E Warrington Nicole N Jones Gregory T GT Cooper Matthew M van Rij Andre M AM Palmer Lyle J LJ Norman Paul E PE

European journal of human genetics : EJHG 20101201 3

Male gender and family history are risk factors for abdominal aortic aneurysm (AAA). We hypothesized that genes involved in sex hormones might be important in AAA. We investigated the association of aortic diameter with single-nucleotide polymorphisms (SNPs) in genes determining circulating sex hormones and their action. We genotyped 74 tagging SNPs across four genes (steroid 5α reductase, subfamily A, polypeptide 1 (SRD5A1), cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1), andr ...[more]

PMID: 21119710

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Project description:Approximately 13,000 people die of an abdominal aortic aneurysm (AAA) every year. This study aimed to identify the immune response-related genes that play important roles in AAA using bioinformatics approaches. We downloaded the GSE57691 and GSE98278 datasets related to AAA from the Gene Expression Omnibus database, which included 80 AAA and 10 normal vascular samples. CIBERSORT was used to analyze the samples and detect the infiltration of 22 types of immune cells and their differences and correlations. The principal component analysis showed significant differences in the infiltration of immune cells between normal vascular and AAA samples. High proportions of CD4+ T cells, activated mast cells, resting natural killer cells, and 12 other types of immune cells were found in normal vascular tissues, whereas high proportions of macrophages, CD8+ T cells, resting mast cells, and six other types of immune cells were found in AAA tissues. In the selected samples, we identified 39 upregulated (involved in growth factor activity, hormone receptor binding, and cytokine receptor activity) and 133 downregulated genes (involved in T cell activation, cell chemotaxis, and regulation of immune response mediators). The key differentially expressed immune response-related genes were screened using the STRING database and Cytoscape software. Two downregulated genes, PI3 and MAP2K1, and three upregulated genes, SSTR1, GPER1, and CCR10, were identified by constructing a protein-protein interaction network. Functional enrichment of the differentially expressed genes was analyzed, and the expression of the five key genes in AAA samples was verified using quantitative polymerase chain reaction, which revealed that MAP2K1 was downregulated in AAA, whereas SSTR1, GEPR1, and CCR10 were upregulated; there was no significant difference in PI3 expression. Our study shows that normal vascular and AAA samples can be distinguished via the infiltration of immune cells. Five genes, PI3, MAP2K1, SSTR1, GPER1, and CCR10, may play important roles in the development, diagnosis, and treatment of AAA.

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:BackgroundRandomized trials and observational studies have shown that perioperative morbidity and mortality are lower with endovascular repair of abdominal aortic aneurysm than with open repair, but the survival benefit is not sustained. In addition, concerns have been raised about the long-term risk of aneurysm rupture or the need for reintervention after endovascular repair.MethodsWe assessed perioperative and long-term survival, reinterventions, and complications after endovascular repair as compared with open repair of abdominal aortic aneurysm in propensity-score-matched cohorts of Medicare beneficiaries who underwent repair during the period from 2001 through 2008 and were followed through 2009.ResultsWe identified 39,966 matched pairs of patients who had undergone either open repair or endovascular repair. The overall perioperative mortality was 1.6% with endovascular repair versus 5.2% with open repair (P<0.001). From 2001 through 2008, perioperative mortality decreased by 0.8 percentage points among patients who underwent endovascular repair (P=0.001) and by 0.6 percentage points among patients who underwent open repair (P=0.01). The rate of conversion from endovascular to open repair decreased from 2.2% in 2001 to 0.3% in 2008 (P<0.001). The rate of survival was significantly higher after endovascular repair than after open repair through the first 3 years of follow-up, after which time the rates of survival were similar. Through 8 years of follow-up, interventions related to the management of the aneurysm or its complications were more common after endovascular repair, whereas interventions for complications related to laparotomy were more common after open repair. Aneurysm rupture occurred in 5.4% of patients after endovascular repair versus 1.4% of patients after open repair through 8 years of follow-up (P<0.001). The rate of total reinterventions at 2 years after endovascular repair decreased over time (from 10.4% among patients who underwent procedures in 2001 to 9.1% among patients who underwent procedures in 2007).ConclusionsEndovascular repair, as compared with open repair, of abdominal aortic aneurysm was associated with a substantial early survival advantage that gradually decreased over time. The rate of late rupture was significantly higher after endovascular repair than after open repair. The outcomes of endovascular repair have been improving over time. (Funded by the National Institutes of Health.).

Dataset Information

A population-based study of polymorphisms in genes related to sex hormones and abdominal aortic aneurysm.

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A population-based study of polymorphisms in genes related to sex hormones and abdominal aortic aneurysm.

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