TY - JOUR
T1 - C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism
T2 - Results from genome-wide association and gene expression analyses followed by case-control studies
AU - Buil, Alfonso
AU - Trégouët, David Alexandre
AU - Souto, Juan Carlos
AU - Saut, Noémie
AU - Germain, Marine
AU - Rotival, Maxime
AU - Tiret, Laurence
AU - Cambien, Françcois
AU - Lathrop, Mark
AU - Zeller, Tanja
AU - Alessi, Marie Christine
AU - De Cordoba, Santiago Rodriguez
AU - Münzel, Thomas
AU - Wild, Philipp
AU - Fontcuberta, Jordi
AU - Gagnon, France
AU - Emmerich, Joseph
AU - Almasy, Laura
AU - Blankenberg, Stefan
AU - Soria, José Manuel
AU - Morange, Pierre Emmanuel
PY - 2010/6/10
Y1 - 2010/6/10
N2 - 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, α7β1, α 6β1, and α7β0, we conducted a genomewide 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 locuswere found genomewide significantly associated with α7β0 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 C4BPBmRNAexpression. The allele associated with increased α7β0 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.
AB - 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, α7β1, α 6β1, and α7β0, we conducted a genomewide 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 locuswere found genomewide significantly associated with α7β0 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 C4BPBmRNAexpression. The allele associated with increased α7β0 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.
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U2 - 10.1182/blood-2010-01-263038
DO - 10.1182/blood-2010-01-263038
M3 - Article
C2 - 20212171
AN - SCOPUS:77954752114
VL - 115
SP - 4644
EP - 4650
JO - Blood
JF - Blood
SN - 0006-4971
IS - 23
ER -