C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies.
Through its binding with protein S (PS), a key element of the coagulation/fibrinolysis cascade, the C4b-binding protein (C4BP) has been hypothesized to be involved in the susceptibility to venous thrombosis (VT). To identify genetic factors that may influence the plasma levels of the 3 C4BP existing isoforms, alpha(7)beta(1), alpha(6)beta(1), and alpha(7)beta(0), we conducted a genome-wide association study by analyzing 283 437 single nucleotide polymorphisms (SNPs) in the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study composed of 352 persons. Three SNPs at the C4BPB/C4BPA locus were found genome-wide significantly associated with alpha(7)beta(0) levels. One of these SNPs was further found to explain approximately 11% of the variability of mRNA C4BPA expression in the Gutenberg Heart Study composed of 1490 persons, with no effect on C4BPB mRNA expression. The allele associated with increased alpha(7)beta(0) plasma levels and increased C4BPA expression was further found associated with increased risk of VT (odds ratio [OR] = 1.24 [1.03-1.53]) in 2 independent case-control studies (MARseille THrombosis Association study [MARTHA] and FActeurs de RIsque et de récidives de la maladie thromboembolique VEineuse [FARIVE]) gathering 1706 cases and 1379 controls. This SNP was not associated with free PS or total PS. In conclusion, we observed strong evidence that the C4BPB/C4BPA locus is a new susceptibility locus for VT through a PS-independent mechanism that remains to be elucidated.
Buil
Alfonso
A
Unitat de Genómica de Malalties Complexes, Institut de Recerca Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Trégouët
David-Alexandre
DA
Souto
Juan Carlos
JC
Saut
Noémie
N
Germain
Marine
M
Rotival
Maxime
M
Tiret
Laurence
L
Cambien
Françcois
F
Lathrop
Mark
M
Zeller
Tanja
T
Alessi
Marie-Christine
MC
Rodriguez de Cordoba
Santiago
S
Münzel
Thomas
T
Wild
Philipp
P
Fontcuberta
Jordi
J
Gagnon
France
F
Emmerich
Joseph
J
Almasy
Laura
L
Blankenberg
Stefan
S
Soria
José-Manuel
JM
Morange
Pierre-Emmanuel
PE
D016022:Case-Control Studies; D002986:Clinical Trials as Topic; D050716:Complement C4b-Binding Protein; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006649:Histocompatibility Antigens / Q000097:blood / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017293:Protein S; D012307:Risk Factors; D020246:Venous Thrombosis / Q000097:blood / Q000235:genetics*
C055609:C4BPA protein, human; C489165:C4BPB protein, human; D050716:Complement C4b-Binding Protein; D006649:Histocompatibility Antigens; D017293:Protein S