KNG1 Ile581Thr and susceptibility to venous thrombosis

Morange, Pierre‐Emmanuel; Oudot-Mellakh, Tiphaine; Cohen, William; Germain, Marine; Saut, Noémie; Antoni, Guillemette; Alessi, Marie‐Christine; Bertrand, Marion; Dupuy, Anne‐Marie; Letenneur, Luc; Lathrop, Mark; Lopez, Lorna M.; Lambert, Jean‐Charles; Emmerich, Joseph; Amouyel, Philippe; Trégouët, David‐Alexandre

doi:10.1182/blood-2010-11-319053

Cited by 52 publications

(50 citation statements)

References 19 publications

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“…Thus, the biological interpretation of the results may be done separately. The univariate GWAS confirmed that SNP rs9898 is associated with Histidine Rich Glycoprotein (HRG) levels, but previous results also reported that it was associated with Activated Prothrombin Time (aPTT) trait and consequently with thrombosis risk [8, 31]. This explains why, as observed in Fig 1.c, the metaphenotype obtained with PCA is oriented clearly to the HRG trait.…”

Section: Discussionsupporting

confidence: 58%

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

Brunel¹,

Massanet

Martinez-Perez³

et al. 2016

PLoS ONE

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Traditional genetic studies of single traits may be unable to detect the pleiotropic effects involved in complex diseases. To detect the correlation that exists between several phenotypes involved in the same biological process, we introduce an original methodology to analyze sets of correlated phenotypes involved in the coagulation cascade in genome-wide association studies. The methodology consists of a two-stage process. First, we define new phenotypic meta-variables (linear combinations of the original phenotypes), named metaphenotypes, by applying Independent Component Analysis for the multivariate analysis of correlated phenotypes (i.e. the levels of coagulation pathway–related proteins). The resulting metaphenotypes integrate the information regarding the underlying biological process (i.e. thrombus/clot formation). Secondly, we take advantage of a family based Genome Wide Association Study to identify genetic elements influencing these metaphenotypes and consequently thrombosis risk. Our study utilized data from the GAIT Project (Genetic Analysis of Idiopathic Thrombophilia). We obtained 15 metaphenotypes, which showed significant heritabilities, ranging from 0.2 to 0.7. These results indicate the importance of genetic factors in the variability of these traits. We found 4 metaphenotypes that showed significant associations with SNPs. The most relevant were those mapped in a region near the HRG, FETUB and KNG1 genes. Our results are provocative since they show that the KNG1 locus plays a central role as a genetic determinant of the entire coagulation pathway and thrombus/clot formation. Integrating data from multiple correlated measurements through metaphenotypes is a promising approach to elucidate the hidden genetic mechanisms underlying complex diseases.

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Section: Discussionsupporting

confidence: 58%

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

Brunel¹,

Massanet

Martinez-Perez³

et al. 2016

PLoS ONE

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“…35,36 In this regard, it is important to point out that SNP rs710446 has also recently been found to be associated with increased risk of venous thrombosis in 2 independent samples from Marseille (odds ratio=1.20 [1.07-1.34]). 37 Our findings, taken together with other observations in KNG1 knockout mice, 38 suggest that genetic variation in KNG1 may be important in determining both the function of the intrinsic pathway of coagulation and the risk of thrombosis. Furthermore, the mechanistic pathway by which KNG1 affects aPTT and risk of thrombosis may be to a large extent through regulation of FXI concentration, which has in fact been proposed as a risk factor for deep vein thrombosis too.…”

Section: Discussionmentioning

confidence: 88%

A Genome-Wide Association Study Identifies KNG1 as a Genetic Determinant of Plasma Factor XI Level and Activated Partial Thromboplastin Time

Sabater‐Lleal

Martinez-Perez

Buil

et al. 2012

ATVB

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Objective-Elevated plasma levels of coagulation factor XI (FXI) are implicated in the pathogenesis of venous thromboembolism and ischemic stroke, and polymorphisms in the F11 gene are associated both with risk of venous thromboembolism and an elevated plasma FXI level. Methods and Results-Here, we report the first hypothesis-free genome-wide genetic analysis of plasma FXI levels.Two genome-wide significant loci were detected in the family-based Genetic Analysis of Idiopathic Thrombophilia 1 cohort: one located in the kininogen 1 gene (KNG1) (rs710446; P=7.98×10) and one located in the structural F11 gene (rs4241824; P=1.16×10 −8 ). Both associations were replicated in a second population-based Swedish cohort. A significant effect on KNG1 mRNA expression was also seen for the 2 most robustly FXI-associated single nucleotide polymorphisms located in KNG1. Furthermore, both KNG1 single nucleotide polymorphisms were associated with activated partial thromboplastin time, suggesting that FXI may be the main mechanistic pathway by which KNG1 and F11 influence activated partial thromboplastin time and risk of thrombosis. Conclusion-These findings contribute to the emerging molecular basis of venous thromboembolism and, more importantly, help in understanding the biological regulation of a phenotype that has proved to have promising therapeutic properties in relation to thrombosis. (Arterioscler Thromb Vasc Biol. 2012;32

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“…27 In addition to studies in animals, global genetic linkage analysis of mutations in humans has identified a common HK variant located in domain 6 that is linked to greater susceptibility to deep vein thrombosis and changes in coagulation. 35 This missense mutation Ile563Thr is located directly N-terminal to the HK ISDFP sequence (highlighted in Figure 3A as a star). Directly C-terminal to the HK ISDFP sequence is the Cys596 residue, which is implicated in forming a disulfide bond with Cys10 from the HK N-terminus, although the complete disulfide bonding has been reported previously only for splice variant low-molecular-weight kininogen, 36 and not for HK.…”

Section: Discussionmentioning

confidence: 99%

A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain

Wong

Østergaard

Hall

et al. 2016

Blood

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Key Points• A novel FXI binding tripeptide motif has sequence Asp-PhePro (DFP).• FXI complex crystal structures reveal DFP peptides bound to the apple 2 domain.Factor XI (FXI) is the zymogen of FXIa, which cleaves FIX in the intrinsic pathway of coagulation. FXI is known to exist as a dimer and interacts with multiple proteins via its 4 apple domains in the "saucer section" of the enzyme; however, to date, no complex crystal structure has been described. To investigate protein interactions of FXI, a large random peptide library consisting of 10 6 to 10 7 peptides was screened for FXI binding, which identified a series of FXI binding motifs containing the signature Asp-Phe-Pro (DFP) tripeptide. Motifs containing this core tripeptide were found in diverse proteins, including the known ligand high-molecular-weight kininogen (HK), as well as the extracellular matrix proteins laminin and collagen V. To define the binding site on FXI, we determined the crystal structure of FXI in complex with the HK-derived peptide NPISDFPDT. This revealed the location of the DFP peptide bound to the FXI apple 2 domain, and central to the interaction, the DFP phenylalanine side-chain inserts into a major hydrophobic pocket in the apple 2 domain and the isoleucine occupies a flanking minor pocket. Two further structures of FXI in complex with the laminin-derived peptide EFPDFP and a DFP peptide from the random screen demonstrated binding in the same pocket, although in a slightly different conformation, thus revealing some flexibility in the molecular interactions of the FXI apple 2 domain. (Blood. 2016;127(23):2915-2923

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KNG1 Ile581Thr and susceptibility to venous thrombosis

Cited by 52 publications

References 19 publications

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

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

A Genome-Wide Association Study Identifies KNG1 as a Genetic Determinant of Plasma Factor XI Level and Activated Partial Thromboplastin Time

A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain

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