Genetic effects of BDKRB2 and KNG1 on deep venous thrombosis after orthopedic surgery and the potential mediator

Wang, Qingfeng; Cheng, Guoping; Wang, Xiaohui; Wang, Dandan; Yang, Yanmei; Chen, Ke; Ye, Jiumin; Zhong, Qing

doi:10.1038/s41598-018-34868-9

Cited by 4 publications

(7 citation statements)

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“…Although previously identified in a candidate gene experiment as a risk factor for thrombosis 38 and suggestively associated in other GWAS for VTE, 39 this work represents the first time that the KNG1 locus, with lead variant rs710446, has been significantly associated to risk of VTE and FVIII in GWAS. rs710446 is a missense variant in the KNG1 gene that causes an amino acid change at the position 581 (Ile581Thr) 40 . Colocalization results between VTE and FVIII (CPC > 0.8) suggest that rs710446 in KNG1 gene is associated both with FVIII and VTE (Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…rs710446 is a missense variant in the KNG1 gene that causes an amino acid change at the position 581 (Ile581Thr). 40 Colocalization results between VTE and FVIII (CPC > 0.8) suggest that rs710446 in KNG1 gene is associated both with FVIII and VTE (Figure 4B). Our results could not provide evidence for this variant being a significant eQTL or sQTL in any of the analyzed tissues which suggest an effect through protein function.…”

Section: Kng1mentioning

confidence: 97%

“…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%

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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: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Kng1mentioning

confidence: 97%

Section: Kng1 and Risk Of Vte Through Fviii Levelsmentioning

confidence: 99%

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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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“…[8] Bradykinin receptor B2 (BDKRB2) encodes a G-protein coupled receptor of bradykinin (BK). [12] Accumulating reports have confirmed that BDKRB2 is capable of regulating calcium signaling. Through binding to BDKRB2, BK allows calcium to enter, leads to calcium-induced calcium release and evokes calcium signaling via upregulating the expression of transient receptor potential melastatin 7 (TRPM7).…”

Section: Introductionmentioning

confidence: 99%

The genetic variants in calcium signaling related genes influence anti-tuberculosis drug induced liver injury

et al. 2019

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Although many genetic variants related to anti-tuberculosis drug induced liver injury (ATDILI) have been identified, the prediction and personalized treatment of ATDILI have failed to achieve, indicating there remains an area for further exploration. This study aimed to explore the influence of single nucleotide polymorphisms (SNPs) in Bradykinin receptor B2 (BDKRB2), Teneurin transmembrane protein 2 (TENM2), transforming growth factor beta 2 (TGFB2), and solute carrier family 2 member 13 (SLC2A13) on the risk of ATDILI.The subjects comprised 746 Chinese tuberculosis (TB) patients. Custom-by-design 2x48-Plex SNPscanTM kit was employed to genotype 28 selected SNPs. The associations of SNPs with ATDILI risk and clinical phenotypes were analyzed according to the distributions of allelic and genotypic frequencies and different genetic models. The odds ratio (OR) with corresponding 95% confidence interval (CI) was calculated.Among subjects with successfully genotyped, 107 participants suffered from ATDILI during follow-up. In BDKRB2, patients with rs79280755 G allele or rs117806152 C allele were more vulnerable to ATDILI (P Bonferronicorrection = .002 and .03, respectively). Rs79280755 increased the risk of ATDILI significantly whether in additive (OR = 3.218, 95% CI: 1.686-6.139, P Bonferroni correction = .003) or dominant model (P Bonferroni correction = .003), as well as rs117806152 (Additive model: P Bonferroni correction = .05; dominant model: P Bonferroni correction = .03). For TENM2, rs80003210 G allele contributed to the decreased risk of ATDILI (P Bonferroni correction = .02), while rs2617972 A allele conferred susceptibility to ATDILI (P Bonferroni correction = .01). Regarding rs2617972, significant findings were also observed in both additive (OR = 3.203, 95% CI: 1.487-6.896, P Bonferroni correction = .02) and dominant model (P Bonferroni correction = .02). Moreover, rs79280755 and rs117806152 in BDKRB2 significantly affected some laboratory indicators. However, no meaningful SNPs were observed in TGFB2 and SLC2A13.Our study revealed that both BDKRB2 and TENM2 genetic polymorphisms were interrogated in relation to ATDILI susceptibility and some laboratory indicators in the Western Chinese Han population, shedding a new light on exploring novel biomarkers and targets for ATDILI. Abbreviations: ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, ATDILI = antituberculosis drug induced liver injury, BDKRB2 = bradykinin receptor B2, BK = bradykinin, CHS = Southern Han Chinese, CI = confidence interval, EPTB = extra pulmonary tuberculosis, Foxa1 = formerly hepatic nuclear factor 3alpha, GGT = gamma glutamyl transpeptidase, HNF1A = hepatocyte nuclear factor 1 alpha, HNF4 = hepatocyte nuclear factor 4, HWE = Hardy-Weinberg equilibrium, LD = linkage disequilibrium, MAF = minor allele frequency, MAPK = mitogen-activated protein kinase, OR = odds ratio, PTB = pulmonary tuberculosis, PTB with EPTB = pulmonary tuberculosis combined with extra pulmonary tuberculosis, SLC2A13 = so...

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Deep sequencing of circulating miRNAs and target mRNAs level in deep venous thrombosis patients

Wang

Chang

Yang

et al. 2023

IET Systems Biology

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Deep venous thrombosis is one of the most common peripheral vascular diseases that lead to major morbidity and mortality. The authors aimed to identify potential differentially expressed miRNAs and target mRNAs, which were helpful in understanding the potential molecule mechanism of deep venous thrombosis. The plasma samples of patients with deep venous thrombosis were obtained for the RNA sequencing. Differentially expressed miRNAs were identified, followed by miRNA‐mRNA target analysis. Enrichment analysis was used to analyze the potential biological function of target mRNAs. GSE19151 and GSE173461 datasets were used for expression validation of mRNAs and miRNAs. 131 target mRNAs of 21 differentially expressed miRNAs were identified. Among which, 8 differentially expressed miRNAs including hsa‐miR‐150‐5p, hsa‐miR‐326, hsa‐miR‐144‐3p, hsa‐miR‐199a‐5p, hsa‐miR‐199b‐5p, hsa‐miR‐125a‐5p, hsa‐let‐7e‐5p and hsa‐miR‐381‐3p and their target mRNAs (PRKCA, SP1, TP53, SLC27A4, PDE1B, EPHB3, IRS1, HIF1A, MTUS1 and ZNF652) were found associated with deep venous thrombosis for the first time. Interestingly, PDE1B and IRS1 had a potential diagnostic value for patients. Additionally, 3 important signaling pathways including p53, PI3K‐Akt and MAPK were identified in the enrichment analysis of target mRNAs (TP53, PRKCA and IRS1). Identified circulating miRNAs and target mRNAs and related signaling pathways may be involved in the process of deep venous thrombosis.

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Genetic effects of BDKRB2 and KNG1 on deep venous thrombosis after orthopedic surgery and the potential mediator

Cited by 4 publications

References 40 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

The genetic variants in calcium signaling related genes influence anti-tuberculosis drug induced liver injury

Deep sequencing of circulating miRNAs and target mRNAs level in deep venous thrombosis patients

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