Next generation sequencing to dissect the genetic architecture of KNG1 and F11 loci using factor XI levels as an intermediate phenotype of thrombosis
Por:
Martin-Fernandez, L, Gavidia-Bovadilla, G, Corrales, I, Brunel, H, Ramirez, L, Lopez, S, Souto, JC, Vidal, F, Soria, JM
Publicada:
26 abr 2017
Resumen:
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.
Filiaciones:
Martin-Fernandez, L:
Biomed Res Inst St Pau IIB St Pau, Unit Genom Complex Dis, Barcelona, Spain
Gavidia-Bovadilla, G:
Biomed Res Inst St Pau IIB St Pau, Unit Genom Complex Dis, Barcelona, Spain
Univ Politecn Cataluna, Dept ESAII, Ctr Biomed Engn Res CREB, Barcelona, Spain
Corrales, I:
Congenital Coagulopathies Blood & Tissue Bank, Barcelona, Spain
Univ Autanoma Barcelona VHI R UAB, Mol Diag & Therapy, Vail dHebron Res Inst, Barcelona, Spain
Brunel, H:
Biomed Res Inst St Pau IIB St Pau, Unit Genom Complex Dis, Barcelona, Spain
Ramirez, L:
Congenital Coagulopathies Blood & Tissue Bank, Barcelona, Spain
Univ Autanoma Barcelona VHI R UAB, Mol Diag & Therapy, Vail dHebron Res Inst, Barcelona, Spain
Lopez, S:
Biomed Res Inst St Pau IIB St Pau, Unit Genom Complex Dis, Barcelona, Spain
Souto, JC:
Hosp Santa Creu & Sant Pau, IIB St Pau, Unit Hemostasis & Thrombosis, Dept Hematol, Barcelona, Spain
Vidal, F:
Congenital Coagulopathies Blood & Tissue Bank, Barcelona, Spain
Univ Autanoma Barcelona VHI R UAB, Mol Diag & Therapy, Vail dHebron Res Inst, Barcelona, Spain
CIBER Enfermedades Cardiovasc, Barcelona, Spain
Soria, JM:
Biomed Res Inst St Pau IIB St Pau, Unit Genom Complex Dis, Barcelona, Spain
Gold, Green Published
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