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
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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. / Buil, Alfonso; Trégouët, David-Alexandre; Souto, Juan Carlos; Saut, Noémie; Germain, Marine; Rotival, Maxime; Tiret, Laurence; Cambien, Françcois; Lathrop, Mark; Zeller, Tanja; Alessi, Marie-Christine; Rodriguez de Cordoba, Santiago; Münzel, Thomas; Wild, Philipp; Fontcuberta, Jordi; Gagnon, France; Emmerich, Joseph; Almasy, Laura; Blankenberg, Stefan; Soria, José-Manuel; Morange, Pierre-Emmanuel.
in: BLOOD, Jahrgang 115, Nr. 23, 10.06.2010, S. 4644-4650.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - 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
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 - Rodriguez de Cordoba, Santiago
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, 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.
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, 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.
KW - Case-Control Studies
KW - Clinical Trials as Topic
KW - Complement C4b-Binding Protein
KW - Female
KW - Gene Expression Regulation/genetics
KW - Genetic Loci
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Histocompatibility Antigens/blood
KW - Humans
KW - Male
KW - Polymorphism, Single Nucleotide
KW - Protein S
KW - Risk Factors
KW - Venous Thrombosis/blood
U2 - 10.1182/blood-2010-01-263038
DO - 10.1182/blood-2010-01-263038
M3 - SCORING: Journal article
C2 - 20212171
VL - 115
SP - 4644
EP - 4650
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 23
ER -