Dataset Information

Association of non-synonymous variants in WIPF3 and LIPA genes with abdominal aortic aneurysm: an autopsy study.

ABSTRACT: BACKGROUND:Abdominal aortic aneurysm (AAA) is a multifactorial disease with strong genetic components. Various genetic loci have been associated with clinical AAA, but few studies have investigated pathological AAA, an intermediate phenotype of the disease. METHODS:We examined 2263 consecutive autopsies of older Japanese subjects from a study on geriatric diseases in Japanese individuals (The JG-SNP study). The presence of AAA was determined with a pathological diagnosis during autopsy. Single nucleotide variants (SNVs) associated with AAA were determined with an Illumina HumanExome Beadchip array. Logistic regression analyses were performed to determine genetic associations. Age, gender, and other risk factors of AAA were analyzed as covariates. RESULTS:118 subjects with AAA and 2145 subjects without AAA were analyzed in a case-control setting. No variants reached significance after applying the Bonferroni correction (P < 2.05×10-6). The strongest associations were found with rs3750092 (p.E321G, OR: 0.36, 95% CI: 0.24-0.56, P = 6.09 × 10-6), a variant in the WAS/WASL interacting protein family 3 (WIPF3), and with rs1051338 (p.T16P, OR: 2.50, 95% CI: 1.70-3.66, P = 2.79 × 10-6) and rs2246942 (intronic, OR: 2.32, 95% CI: 1.58-3.41, P = 1.61 × 10-5), variants in the lysosomal acid lipase A (LIPA). LIPA is essential for macrophage cholesterol metabolism. Immunohistological analyses of WIPF3 protein in AAA samples from three subjects revealed that WIPF3 was expressed in macrophages of atheromatous plaques. CONCLUSIONS:This study suggests that WIPF3 and LIPA, both of which are expressed in the macrophages are involved in pathological AAA. These results should be regarded as hypothesis-generating; thus, replication study is warranted.

SUBMITTER: Maeda Y

PROVIDER: S-EPMC5351826 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Association of non-synonymous variants in <i>WIPF3</i> and <i>LIPA</i> genes with abdominal aortic aneurysm: an autopsy study.

Maeda Yuko Y Sato Noriko N Naka-Mieno Makiko M Mori Seijiro S Arai Tomio T Tanaka Masashi M Muramatsu Masaaki M Sawabe Motoji M

Journal of geriatric cardiology : JGC 20161201 12

<h4>Background</h4>Abdominal aortic aneurysm (AAA) is a multifactorial disease with strong genetic components. Various genetic loci have been associated with clinical AAA, but few studies have investigated pathological AAA, an intermediate phenotype of the disease.<h4>Methods</h4>We examined 2263 consecutive autopsies of older Japanese subjects from a study on geriatric diseases in Japanese individuals (The JG-SNP study). The presence of AAA was determined with a pathological diagnosis during au ...[more]

PMID: 28321238

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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.

Dataset Information

Association of non-synonymous variants in WIPF3 and LIPA genes with abdominal aortic aneurysm: an autopsy study.

Publications

Association of non-synonymous variants in <i>WIPF3</i> and <i>LIPA</i> genes with abdominal aortic aneurysm: an autopsy study.

Similar Datasets

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