title: 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.
abstract: 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.
authors.affiliation: Unitat de Genómica de Malalties Complexes, Institut de Recerca Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Buil
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Trégouët
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Souto
authors.forename: Noémie
authors.initials: N
authors.lastname: Saut
authors.forename: Marine
authors.initials: M
authors.lastname: Germain
authors.forename: Maxime
authors.initials: M
authors.lastname: Rotival
authors.forename: Laurence
authors.initials: L
authors.lastname: Tiret
authors.forename: Françcois
authors.initials: F
authors.lastname: Cambien
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Alessi
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodriguez de Cordoba
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Philipp
authors.initials: P
authors.lastname: Wild
authors.forename: Jordi
authors.initials: J
authors.lastname: Fontcuberta
authors.forename: France
authors.initials: F
authors.lastname: Gagnon
authors.forename: Joseph
authors.initials: J
authors.lastname: Emmerich
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.forename: José-Manuel
authors.initials: JM
authors.lastname: Soria
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Morange
mesh_terms: 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*
chemical_list: C055609:C4BPA protein, human; C489165:C4BPB protein, human; D050716:Complement C4b-Binding Protein; D006649:Histocompatibility Antigens; D017293:Protein S