Linking single nucleotide polymorphisms to signaling blueprints in abdominal aortic aneurysms.
Linking single nucleotide polymorphisms to signaling blueprints in abdominal aortic aneurysms.
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DOI：
10.1038/s41598-022-25144-y
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发表时间：
2022-12-05
影响因子：
4.6
通讯作者：
Ramkhelawon, Bhama
中科院分区：
文献类型：
--
作者：
Lim, Chrysania;Pratama, Muhammad Yogi;Rivera, Cristobal;Silvestro, Michele;Tsao, Philip S. S.;Maegdefessel, Lars;Gallagher, Katherine A. A.;Maldonado, Thomas;Ramkhelawon, Bhama
腹主动脉瘤（AAA）是一种多因素的复杂疾病，具有危及生命的后果。虽然全基因组关联研究（GWAS）已经揭示了位于AAA个体基因组中的几种单核苷酸多态性（SNP），但SNP与相关病理信号之间的联系，危险因素对其分布的影响及其组合分析尚未完全了解。我们整合了来自GWAS和文献中临床队列的86个AAA SNP，以确定其表型脆弱性及其与AAA风险因素的相关性。使用snpXplorer AnnotateMe工具对SNP进行注释，以确定其染色体位置、次要等位基因频率、CADD（联合注释依赖性消耗）、基于注释的致病性评分、变异后果及其相关基因。使用Gene Ontology进行基因富集分析，并使用REVIGO进行聚类。Cytoscape中的插件GeneMANIA用于识别与相关基因和功能的网络整合。共鉴定出15个影响20个基因的SNPs，CADD评分大于10。AAA SNP主要位于3号和9号染色体上。终止获得的rs5516 SNP在AAA中获得高频率，并且与促炎和血管重塑表型相关。SNPs的存在与高血压、血脂异常和吸烟史呈正相关。GO表明AAA SNP及其相关基因可以调节脂质代谢，细胞外基质组织，平滑肌细胞增殖和氧化应激，这表明这些AAA性状的一部分可能源于遗传异常。我们展示了一个先天SNPs和相关基因的库，表现在AAA。我们揭示了他们的病理信号轨迹，可能会推动AAA的发展。
Abdominal aortic aneurysms (AAA) is a multifactorial complex disease with life-threatening consequences. While Genome-wide association studies (GWAS) have revealed several single nucleotide polymorphisms (SNPs) located in the genome of individuals with AAA, the link between SNPs with the associated pathological signals, the influence of risk factors on their distribution and their combined analysis is not fully understood. We integrated 86 AAA SNPs from GWAS and clinical cohorts from the literature to determine their phenotypical vulnerabilities and association with AAA risk factors. The SNPs were annotated using snpXplorer AnnotateMe tool to identify their chromosomal position, minor allele frequency, CADD (Combined Annotation Dependent Depletion), annotation-based pathogenicity score, variant consequence, and their associated gene. Gene enrichment analysis was performed using Gene Ontology and clustered using REVIGO. The plug-in GeneMANIA in Cytoscape was applied to identify network integration with associated genes and functions. 15 SNPs affecting 20 genes with a CADD score above ten were identified. AAA SNPs were predominantly located on chromosome 3 and 9. Stop-gained rs5516 SNP obtained high frequency in AAA and associated with proinflammatory and vascular remodeling phenotypes. SNPs presence positively correlated with hypertension, dyslipidemia and smoking history. GO showed that AAA SNPs and their associated genes could regulate lipid metabolism, extracellular matrix organization, smooth muscle cell proliferation, and oxidative stress, suggesting that part of these AAA traits could stem from genetic abnormalities. We show a library of inborn SNPs and associated genes that manifest in AAA. We uncover their pathological signaling trajectories that likely fuel AAA development.
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影响因子：
3.7
作者：
Nishihara M;Aoki H;Ohno S;Furusho A;Hirakata S;Nishida N;Ito S;Hayashi M;Imaizumi T;Fukumoto Y
通讯作者：
Fukumoto Y
影响因子：
3.5
作者：
通讯作者：
--
影响因子：
9.3
作者：
El-Lebedy D;Raslan HM;Mohammed AM
通讯作者：
Mohammed AM
影响因子：
3.5
作者：
Jablonska, Agnieszka;Zagrapan, Branislav;Huk, Ihor
通讯作者：
Huk, Ihor
影响因子：
5.3
作者：
Golledge, Jonathan;Biros, Erik;Norman, Paul E.
通讯作者：
Norman, Paul E.