A Genome-Wide Association Study Identifies KNG1 as a Genetic Determinant of Plasma Factor XI Level and Activated Partial Thromboplastin Time
Por:
Sabater-Lleal, M, Martinez-Perez, A, Buil, A, Folkersen, L, Souto, JC, Bruzelius, M, Borrell, M, Odeberg, J, Silveira, A, Eriksson, P, Almasy, L, Hamsten, A, Soria, JM
Publicada:
1 ago 2012
Resumen:
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=7.98x10(-10)) and one located in the structural F11 gene (rs4241824; P=1.16x10(-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;32:2008-2016.)
Filiaciones:
Sabater-Lleal, M:
Karolinska Univ Hosp Solna, Atherosclerosis Res Unit, Karolinska Inst, Dept Med,Cardiovasc Genet & Genom Grp, Stockholm, Sweden
Martinez-Perez, A:
Res Biomed Inst Sant Pau IIB Sant Pau, Unit Genom Complex Dis, Barcelona, Spain
Buil, A:
Res Biomed Inst Sant Pau IIB Sant Pau, Unit Genom Complex Dis, Barcelona, Spain
Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland
Folkersen, L:
Karolinska Univ Hosp Solna, Atherosclerosis Res Unit, Karolinska Inst, Dept Med,Cardiovasc Genet & Genom Grp, Stockholm, Sweden
Souto, JC:
Hosp Santa Creu & Sant Pau, Haemostasis & Thrombosis Unit, Dept Hematol, Barcelona 08025, Spain
Bruzelius, M:
Karolinska Univ Hosp Solna, Atherosclerosis Res Unit, Karolinska Inst, Dept Med,Cardiovasc Genet & Genom Grp, Stockholm, Sweden
Hosp Santa Creu & Sant Pau, Haemostasis & Thrombosis Unit, Dept Hematol, Barcelona 08025, Spain
Odeberg, J:
Karolinska Univ Hosp Solna, Atherosclerosis Res Unit, Karolinska Inst, Dept Med,Cardiovasc Genet & Genom Grp, Stockholm, Sweden
Silveira, A:
Karolinska Univ Hosp Solna, Atherosclerosis Res Unit, Karolinska Inst, Dept Med,Cardiovasc Genet & Genom Grp, Stockholm, Sweden
Eriksson, P:
Karolinska Univ Hosp Solna, Atherosclerosis Res Unit, Karolinska Inst, Dept Med,Cardiovasc Genet & Genom Grp, Stockholm, Sweden
Almasy, L:
SW Fdn Biomed Res, Dept Populat Genet, San Antonio, TX 78284 USA
Hamsten, A:
Karolinska Univ Hosp Solna, Atherosclerosis Res Unit, Karolinska Inst, Dept Med,Cardiovasc Genet & Genom Grp, Stockholm, Sweden
Soria, JM:
Res Biomed Inst Sant Pau IIB Sant Pau, Unit Genom Complex Dis, Barcelona, Spain
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