Variants in the Atherogenic ALOX5AP, THBD, and KNG1 Genes Potentiate the Risk of Ischemic Stroke via a Genetic Main Effect and Epistatic Interactions in a Chinese Population

Hu, Zhongyang; Liu, Jia; Song, Zhi; Qiao, Huan; Fan, Xiaohui; Hou, Deren

doi:10.1016/j.jstrokecerebrovasdis.2015.04.036

Cited by 11 publications

(6 citation statements)

References 39 publications

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“…CTSG (cathepsin G) is a protein coding gene plays important roles in aortic aneurysms [ 166 ]. Evidence from Safa et al [ 167 ], Chen et al [ 168 ], Zhou et al [ 169 ], Hu et al [ 170 ], Lou et al [ 171 ], Zhang et al [ 172 ] and Chen et al [ 173 ] study indicated that the expression of CCL22, CCR1, FPR1, KNG1, CRISPLD2, CD38 and GPRC5A were linked with progression of ischemic heart disease. Li et al [ 174 ] showed that STEAP3 expression can be associated with cardiac hypertrophy progression.…”

Section: Discussionmentioning

confidence: 99%

Identification of candidate biomarkers and therapeutic agents for heart failure by bioinformatics analysis

Kolur¹,

Vastrad²,

Vastrad

et al. 2021

BMC Cardiovasc Disord

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Introduction Heart failure (HF) is a heterogeneous clinical syndrome and affects millions of people all over the world. HF occurs when the cardiac overload and injury, which is a worldwide complaint. The aim of this study was to screen and verify hub genes involved in developmental HF as well as to explore active drug molecules. Methods The expression profiling by high throughput sequencing of GSE141910 dataset was downloaded from the Gene Expression Omnibus (GEO) database, which contained 366 samples, including 200 heart failure samples and 166 non heart failure samples. The raw data was integrated to find differentially expressed genes (DEGs) and were further analyzed with bioinformatics analysis. Gene ontology (GO) and REACTOME enrichment analyses were performed via ToppGene; protein–protein interaction (PPI) networks of the DEGs was constructed based on data from the HiPPIE interactome database; modules analysis was performed; target gene—miRNA regulatory network and target gene—TF regulatory network were constructed and analyzed; hub genes were validated; molecular docking studies was performed. Results A total of 881 DEGs, including 442 up regulated genes and 439 down regulated genes were observed. Most of the DEGs were significantly enriched in biological adhesion, extracellular matrix, signaling receptor binding, secretion, intrinsic component of plasma membrane, signaling receptor activity, extracellular matrix organization and neutrophil degranulation. The top hub genes ESR1, PYHIN1, PPP2R2B, LCK, TP63, PCLAF, CFTR, TK1, ECT2 and FKBP5 were identified from the PPI network. Module analysis revealed that HF was associated with adaptive immune system and neutrophil degranulation. The target genes, miRNAs and TFs were identified from the target gene—miRNA regulatory network and target gene—TF regulatory network. Furthermore, receiver operating characteristic (ROC) curve analysis and RT-PCR analysis revealed that ESR1, PYHIN1, PPP2R2B, LCK, TP63, PCLAF, CFTR, TK1, ECT2 and FKBP5 might serve as prognostic, diagnostic biomarkers and therapeutic target for HF. The predicted targets of these active molecules were then confirmed. Conclusion The current investigation identified a series of key genes and pathways that might be involved in the progression of HF, providing a new understanding of the underlying molecular mechanisms of HF.

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Section: Discussionmentioning

confidence: 99%

Identification of candidate biomarkers and therapeutic agents for heart failure by bioinformatics analysis

Kolur¹,

Vastrad²,

Vastrad

et al. 2021

BMC Cardiovasc Disord

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“…Since a genome-wide scan identified a four-SNP haplotype within the gene encoding FLAP that predicted a nearly twofold greater risk of stroke [9], several groups attempted to replicate the association between stroke and ALOX5AP variants, but the results remained controversial [10-15]. Our previous study revealed that the ALOX5AP gene contributed to stroke risk via epistatic interaction but not genetic main effects [32]. Importantly, a meta-analysis study indicated insufficient evidence for claiming an association between variants in the ALOX5AP gene and risk of stroke, indicating that rigorous genetic association studies investigating gene–gene and gene–environment interactions may generate conclusive findings regarding the contribution of the ALOX5AP gene to stroke [33].…”

Section: Discussionmentioning

confidence: 99%

Genetic Variations of Oxidative Stress Related Genes ALOX5, ALOX5AP and MPO Modulate Ischemic Stroke Susceptibility Through Main Effects and Epistatic Interactions in a Chinese Population

Liu

Song

et al. 2017

Cell Physiol Biochem

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Background/Aims: To investigate the roles of the oxidative stress related-genes ALOX5, ALOX5AP and MPO in ischemic stroke susceptibility in the Han Chinese population. Methods: A total of 351 ischemic stroke patients and 417 controls were recruited. The ALOX5 rs10900213, ALOX5AP rs4293222 and MPO rs2107545 gene polymorphisms were genotyped. Results: We identified that rs2107545 of MPO gene was significantly associated with ischemic stroke susceptibility after adjusting for covariates. Furthermore, we also considered the likely complexity of oxidative stress and inflammatory process in stroke by assessing the combined effects of multiple genes. Generalized multifactor dimensionality reduction (GMDR) analysis revealed that the combination of ALOX5 rs10900213, ALOX5AP rs4293222 and MPO rs2107545 was significantly associated with increased risk of ischemic stroke (P=0.0040, OR (95% CI) =1.991 (1.241 to 3.195)). Additionally, the MPO rs2107545 genotype was significantly associated with clinical outcomes at 6 months after discharge from the hospital. Conclusion: Our study revealed that epistatic interaction among the ALOX5, ALOX5AP and MPO genes played a significant role in vulnerability to ischemic stroke. Furthermore, these results also suggest that the rs2107545 of MPO gene can be used as a biomarker for the susceptibility and prognosis of ischemic stroke patients.

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“…45 There is strong biological evidence that associate KNG1 gene with the coagulation system. 40,46,47 HMWK, along with FXII and prekallikrein (PK) complex, conform the plasma kallikrein-kinin system (KKS), that plays an important role in human physiology. The activation of KKS components results in the induction of genes and biomolecules that participate in blood coagulation, among other processes.…”

Section: Kng1 and Risk Of Vte Through Fviii Levelsmentioning

confidence: 99%

Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Temprano‐Sagrera

Sitlani

Bone

et al. 2022

Journal of Thrombosis and Haemostasis

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Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives:To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), wereThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Genome-wide association studies (GWAS) have identified dozens of loci underlying the variability of plasma levels for individual hemostatic traits. [1][2][3][4][5][6][7][8] Further, GWAS for venous thromboembolism (VTE), 9,10 coronary artery disease (CAD) [11][12][13] and ischemic stroke (IS), 11,14 have discovered 34, 169, and 20 genetic risk loci associated with these cardiovascular (CV) events, respectively.Results from GWAS indicate that several of these hemostatic traits are genetically correlated with each other, sharing genetic loci that regulate their plasma levels. 1,[4][5][6][7][8] There are also shared genetic loci between hemostatic traits and CV events, again suggesting common regulators and possibly a causal pathway between the hemostatic trait and the CV event. 4,[7][8][9]12,14 The common regulatory loci between traits-even if the traits are not causally associated with each other-can be used to advance discovery of novel genetic loci common to the traits. This discovery can be accomplished with multiphenotype methods that incorporate summary statistics from several GWAS, increasing the statistical power to detect loci affecting two or more phenotypes by increasing the effective sample size. [15][16][17] In the present study, we used summary statistics of published GWAS from 7 hemostatic traits (FVII, FVIII, VWF, FXI, fibrinogen, PAI-1, tPA), and 3 CV events (VTE, CAD, IS) to calculate their genetic correlations and to conduct multi-phenotype meta-analyses to detect new genetic loci not previously known to be associated with these phenotypes.

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Variants in the Atherogenic ALOX5AP, THBD, and KNG1 Genes Potentiate the Risk of Ischemic Stroke via a Genetic Main Effect and Epistatic Interactions in a Chinese Population

Cited by 11 publications

References 39 publications

Identification of candidate biomarkers and therapeutic agents for heart failure by bioinformatics analysis

Identification of candidate biomarkers and therapeutic agents for heart failure by bioinformatics analysis

Genetic Variations of Oxidative Stress Related Genes ALOX5, ALOX5AP and MPO Modulate Ischemic Stroke Susceptibility Through Main Effects and Epistatic Interactions in a Chinese Population

Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

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