The Central Role of KNG1 Gene as a Genetic Determinant of Coagulation Pathway-Related Traits: Exploring Metaphenotypes

Brunel, Héléna; Massanet, Raimon; Martinez-Perez, Ángel; Ziyatdinov, Andrey; Martín-Fernández, Laura; Souto, Juan Carlos; Perera, Alexandre; Soria, José Manuel Nieto

doi:10.1371/journal.pone.0167187

Cited by 8 publications

(7 citation statements)

References 30 publications

(30 reference statements)

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“…This association could be explained by a putative regulation of KNG1 also on FVIII, which would imply an effect of KNG1 on the common pathway of coagulation. Associations of KNG1 with the entire coagulation cascade, and not just the intrinsic pathway, have been proposed by others 72. The significant colocalization analysis between VTE and FVIII in this locus aligns with previous evidence and suggests that rs710446 affects the regulation of both phenotypes along with other related hemostatic phenotypes.…”

Section: Discussionsupporting

confidence: 87%

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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Section: Discussionsupporting

confidence: 87%

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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“…The essential component of the coagulation pathway KNG1 [75], was consistently reduced in AD CSF in 3 independent proteomic studies. KNG1 is particularly attractive for further investigation since a direct relation between KNG1 and AD has not yet been reported.…”

Section: Proteins Consistently Reduced In Ad Csfmentioning

confidence: 94%

A comprehensive systematic review of CSF proteins and peptides that define Alzheimer’s disease

et al. 2020

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Background: During the last two decades, over 100 proteomics studies have identified a variety of potential biomarkers in CSF of Alzheimer's (AD) patients. Although several reviews have proposed specific biomarkers, to date, the statistical relevance of these proteins has not been investigated and no peptidomic analyses have been generated on the basis of specific up-or down-regulation. Herein, we perform an analysis of all unbiased explorative proteomics studies of CSF biomarkers in AD to critically evaluate whether proteins and peptides identified in each study are consistent in distribution; direction change; and significance, which would strengthen their potential use in studies of AD pathology and progression. Methods: We generated a database containing all CSF proteins whose levels are known to be significantly altered in human AD from 47 independent, validated, proteomics studies. Using this database, which contains 2022 AD and 2562 control human samples, we examined whether each protein is consistently present on the basis of reliable statistical studies; and if so, whether it is over-or under-represented in AD. Additionally, we performed a direct analysis of available mass spectrometric data of these proteins to generate an AD CSF peptide database with 3221 peptides for further analysis. Results: Of the 162 proteins that were identified in 2 or more studies, we investigated their enrichment or depletion in AD CSF. This allowed us to identify 23 proteins which were increased and 50 proteins which were decreased in AD, some of which have never been revealed as consistent AD biomarkers (i.e. SPRC or MUC18). Regarding the analysis of the tryptic peptide database, we identified 87 peptides corresponding to 13 proteins as the most highly consistently altered peptides in AD. Analysis of tryptic peptide fingerprinting revealed specific peptides encoded by CH3L1, VGF, SCG2, PCSK1N, FBLN3 and APOC2 with the highest probability of detection in AD. Conclusions: Our study reveals a panel of 27 proteins and 21 peptides highly altered in AD with consistent statistical significance; this panel constitutes a potent tool for the classification and diagnosis of AD.

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“…However, some studies have indicated that they may interact with each other in the coagulation pathway. KNG1 and HRG have similar structures and are adjacent to each other on chromosome 3, which suggests that these proteins may exhibit similar functions ( 24 , 25 ). HRG deficiency is associated with enhanced blood coagulation, which indicates that decreased KNG1 is a potential cofactor to enhance coagulation ( 26 ).…”

Section: Discussionmentioning

confidence: 98%

Molecular basis of coronary artery dilation and aneurysms in patients with Kawasaki disease based on differential protein expression

Liu

Zhang

et al. 2017

Mol Med Report

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Kawasaki disease (KD) is an acquired cardiac disease with a high incidence that affects children. KD has various complications, including coronary artery dilation (CAD) and coronary artery aneurysms (CAA). The identification of differentially expressed proteins and the underlying mechanisms may be the key to understanding differences between these KD complications. In the present study, isobaric tags for relative and absolute quantitation were used to identify variations in serum proteins between KD patients with CAD and CAA. In total, 87 (37 upregulated and 50 downregulated) and 65 (33 upregulated and 32 downregulated) significantly differentially-expressed proteins were identified in comparisons between control samples (healthy individuals) and those obtained from patients with KD and with CAD or CAA. Investigation into the underlying biological process revealed that variations between the two complications were associated with the wound healing response, as well as lipoprotein- and cholesterol-associated processes. Important proteins involved in the formation of the wound healing signaling network were identified via enriched biological processes and pathway analysis using ClueGo and ReactomeFIViz software. In the present study, 5 significantly differentially-expressed proteins, including mannose binding lectin 2 (MBL2), complement factor H (CFH), kininogen 1 (KNG1), serpin family C member 1 (SERPINC1) and fibronectin 1 (FN1), were selected and confirmed by western blotting. Analysis indicated that these proteins were associated to immunity, inflammation and metabolism, serving a key role within each module, which has never been reported previously. The present study proposed that MBL2, CFH, KNG1, SERPINC1 and FN1 may be a potentially excellent indicator group for distinguishing the two major KD complications, CAD and CAA.

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The Central Role of KNG1 Gene as a Genetic Determinant of Coagulation Pathway-Related Traits: Exploring Metaphenotypes

Cited by 8 publications

References 30 publications

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

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

A comprehensive systematic review of CSF proteins and peptides that define Alzheimer’s disease

Molecular basis of coronary artery dilation and aneurysms in patients with Kawasaki disease based on differential protein expression

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