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

ABSTRACT: 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.

SUBMITTER: Martin-Fernandez L

PROVIDER: S-EPMC5405990 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Martin-Fernandez Laura L Gavidia-Bovadilla Giovana G Corrales Irene I Brunel Helena H Ramírez Lorena L López Sonia S Souto Juan Carlos JC Vidal Francisco F Soria José Manuel JM

PloS one 20170426 4

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 ...[more]

PMID: 28445521

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Project description:BackgroundExperimental data indicate that reducing factor XI levels attenuates thrombosis without causing bleeding, but the role of factor XI in the prevention of postoperative venous thrombosis in humans is unknown. FXI-ASO (ISIS 416858) is a second-generation antisense oligonucleotide that specifically reduces factor XI levels. We compared the efficacy and safety of FXI-ASO with those of enoxaparin in patients undergoing total knee arthroplasty.MethodsIn this open-label, parallel-group study, we randomly assigned 300 patients who were undergoing elective primary unilateral total knee arthroplasty to receive one of two doses of FXI-ASO (200 mg or 300 mg) or 40 mg of enoxaparin once daily. The primary efficacy outcome was the incidence of venous thromboembolism (assessed by mandatory bilateral venography or report of symptomatic events). The principal safety outcome was major or clinically relevant nonmajor bleeding.ResultsAround the time of surgery, the mean (±SE) factor XI levels were 0.38±0.01 units per milliliter in the 200-mg FXI-ASO group, 0.20±0.01 units per milliliter in the 300-mg FXI-ASO group, and 0.93±0.02 units per milliliter in the enoxaparin group. The primary efficacy outcome occurred in 36 of 134 patients (27%) who received the 200-mg dose of FXI-ASO and in 3 of 71 patients (4%) who received the 300-mg dose of FXI-ASO, as compared with 21 of 69 patients (30%) who received enoxaparin. The 200-mg regimen was noninferior, and the 300-mg regimen was superior, to enoxaparin (P<0.001). Bleeding occurred in 3%, 3%, and 8% of the patients in the three study groups, respectively.ConclusionsThis study showed that factor XI contributes to postoperative venous thromboembolism; reducing factor XI levels in patients undergoing elective primary unilateral total knee arthroplasty was an effective method for its prevention and appeared to be safe with respect to the risk of bleeding. (Funded by Isis Pharmaceuticals; FXI-ASO TKA ClinicalTrials.gov number, NCT01713361.).

Project description:ObjectiveTo evaluate the association between F11 rs2289252, rs2036914 polymorphisms and the activity of clotting factor XI in post-trauma patients with fractures receiving routine anticoagulation therapy for deep venous thrombosis (DVT).MethodsA case-control study involving 110 consecutive post-trauma patients with fractures and DVT in our hospital was conducted from April 2014 to October 2015; these patients comprised a DVT group. Another 40 sex- and age-matched patients with fractures but without DVT served as controls. Additionally, 40 sex- and age-matched healthy people were chosen as a normal group. Venous blood samples (2 mL) were drawn from all participants and genomic DNA extracted from the leukocytes of the patients with fracture-related DVT, whose genotype and allele frequency distribution of F11 gene rs2089252 and rs2036914 single nucleotide polymorphism were then assessed by a sequencing method. The activity of factor XI was measured by a solidification method in all participants, including those in control and normal groups.ResultsThe activity of factor XI in patients with fracture-related DVT and F11 rs2089252 CT was 1.16 times that of those with CC genotypes (P < 0.0001), whereas in patients with fracture-related DVT and F11 rs2089252 TT genotypes it was 1.32 times that of those with CC genotypes (P < 0.0001), in patients with fracture-related DVT and F11 rs2089252 T allele it was 1.24 times that of those with C allele (P < 0.05), in patients with fracture-related DVT and F11 rs2036914 CC it was 1.35 times that of those with TT genotypes, in patients with fracture-related DVT and F11 rs2036914 CT genotypes it was 1.12 times that of those with TT genotypes (P < 0.05), and in patients with fracture-related DVT F11 and rs2036914 C allele it was 1.22 times that of those with T allele (P < 0.05). The activity of factor XI was significantly higher in the control than in the normal group (P < 0.05).ConclusionsHigh activity of factor XI indicates a risk of occurrence of DVT in post-trauma patients with fractures. F11 rs2089252 and rs2036914 (single nucleotide polymorphisms) are associated with activity of factors XI in such patients despite prophylaxis.

Dataset Information

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

Publications

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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