A genome-wide association study identifies KNG1 as a genetic determinant of plasma factor XI Level and activated partial thromboplastin time.
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.


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(-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.


CONCLUSIONS
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.
Department of Medicine, Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Maria
M
Sabater-Lleal
Angel
A
Martinez-Perez
Alfonso
A
Buil
Lasse
L
Folkersen
Juan Carlos
JC
Souto
Maria
M
Bruzelius
Montserrat
M
Borrell
Jacob
J
Odeberg
Angela
A
Silveira
Per
P
Eriksson
Laura
L
Almasy
Anders
A
Hamsten
José Manuel
JM
Soria
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D005172:Factor XI / Q000032:analysis* / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007704:Kininogens / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D020641:Polymorphism, Single Nucleotide
D007704:Kininogens; D005172:Factor XI