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

Sabater‐Lleal, Maria; Martinez-Perez, Ángel; Buil, Alfonso; Folkersen, Lasse; Souto, Juan Carlos; Bruzelius, Maria; Borrell, Montserrat; Odeberg, Jacob; Silveira, Angela; Eriksson, Per; Almasy, Laura; Hamsten, Anders; Soria, José Manuel Nieto

doi:10.1161/atvbaha.112.248492

Cited by 36 publications

(38 citation statements)

References 42 publications

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“…Our results indicate that KNG1 plays a relevant role in the CIP not only at a molecular level, but also at a genetic level. This result is particularly interesting since allelic variants in KNG1 were previously associated with risk of thrombosis [33]. Our result strengthens previous conclusions concerning the association of KNG1 with thrombosis suggesting that KNG1 plays a role in the regulation of CIP, even without the influence of the FXI or the FXII levels, since neither FXI nor FXII levels show a specific weight within this metaphenotype (Fig 1.c).…”

Section: Discussionsupporting

confidence: 87%

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: 87%

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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“…Although some of these studies have identified the involvement of common single nucleotide polymorphisms in the structural F11 gene and alterations in other genes that might indirectly regulate plasma levels of this factor [11]–[13], the molecular mechanisms of FXI regulation are still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Coagulation Factor XI Expression by MicroRNAs in the Human Liver

et al. 2014

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High levels of factor XI (FXI) increase the risk of thromboembolic disease. However, the genetic and environmental factors regulating FXI expression are still largely unknown. The aim of our study was to evaluate the regulation of FXI by microRNAs (miRNAs) in the human liver. In silico prediction yielded four miRNA candidates that might regulate FXI expression. HepG2 cells were transfected with miR-181a-5p, miR-23a-3p, miR-16-5p and miR-195-5p. We used mir-494, which was not predicted to bind to F11, as a negative control. Only miR-181a-5p caused a significant decrease both in FXI protein and F11 mRNA levels. In addition, transfection with a miR-181a-5p inhibitor in PLC/PRF/5 hepatic cells increased both the levels of F11 mRNA and extracellular FXI. Luciferase assays in human colon cancer cells deficient for Dicer (HCT-DK) demonstrated a direct interaction between miR-181a-5p and 3′untranslated region of F11. Additionally, F11 mRNA levels were inversely and significantly correlated with miR-181a-5p levels in 114 healthy livers, but not with miR-494. This study demonstrates that FXI expression is directly regulated by a specific miRNA, miR-181a-5p, in the human liver. Future studies are necessary to further investigate the potential consequences of miRNA dysregulation in pathologies involving FXI.

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“…The genome-wide association studies (GWAS) of plasma FXI levels performed in the GAIT-1 Project showed significant associations with variants in the KNG1 and F11 loci. Those results were replicated in a population-based Swedish cohort [15]. The KNG1 encodes for a high molecular weight kininogen (HMWK).…”

Section: Introductionmentioning

confidence: 81%

Next generation sequencing to dissect the genetic architecture of KNG1 and F11 loci using factor XI levels as an intermediate phenotype of thrombosis

et al. 2017

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Venous thromboembolism is a complex disease with a high heritability. There are significant associations among Factor XI (FXI) levels and SNPs in the KNG1 and F11 loci. Our aim was to identify the genetic variation of KNG1 and F11 that might account for the variability of FXI levels. The KNG1 and F11 loci were sequenced completely in 110 unrelated individuals from the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia 2) Project using Next Generation Sequencing on an Illumina MiSeq. The GAIT-2 Project is a study of 935 individuals in 35 extended Spanish families selected through a proband with idiopathic thrombophilia. Among the 110 individuals, a subset of 40 individuals was chosen as a discovery sample for identifying variants. A total of 762 genetic variants were detected. Several significant associations were established among common variants and low-frequency variants sets in KNG1 and F11 with FXI levels using the PLINK and SKAT packages. Among these associations, those of rs710446 and five low-frequency variant sets in KNG1 with FXI level variation were significant after multiple testing correction and permutation. Also, two putative pathogenic mutations related to high and low FXI levels were identified by data filtering and in silico predictions. This study of KNG1 and F11 loci should help to understand the connection between genotypic variation and variation in FXI levels. The functional genetic variants should be useful as markers of thromboembolic risk.

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

Cited by 36 publications

References 42 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

Regulation of Coagulation Factor XI Expression by MicroRNAs in the Human Liver

Next generation sequencing to dissect the genetic architecture of KNG1 and F11 loci using factor XI levels as an intermediate phenotype of thrombosis

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