Genetic correlation between plasma levels of C4BP isoforms containing   chains and susceptibility to thrombosis

Esparza-Gordillo, Jorge

doi:10.1136/jmg.2003.010611

Cited by 6 publications

(5 citation statements)

References 37 publications

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Section: C4bpb/c4bpa Locus and Risk Of Venous Thrombosis 4647mentioning

confidence: 82%

“…34 These results suggest a pleiotropic effect of the locus on different phenotypes related to C4BP. 16 To sum up, the effect of this SNP was observed on C4BPA mRNA expression, plasma levels of %␣ 7 ␤ 0 , to a lesser extent on those of total C4BP␣, and on VT risk but not on fPS or total PS.These observations suggest that molecular excess of C4BP␣-chains unbound to C4BP␤-chain could be a new disease-associated mechanism relating C4BPB/C4BPA locus to VT susceptibility independently of PS regulation. This hypothesis is supported by several studies showing that increased plasma levels of C4BP␣-chains, but not of C4BP␤-chains, are observed during inflammation, 35,36 a biologic process whose role in thrombosis is increasingly advocated.…”

mentioning

confidence: 82%

“…12 Such complex and elusive mechanisms could explain why, despite the key role of PS in the regulation of thrombin generation, its involvement in the susceptibility of venous thrombosis (VT) remains obscure. Although PS deficiency is considered a risk factor for VT, [13][14][15] total PS and fPS show very little correlation with VT. 16,17 C4BP is a large plasma protein existing in 3 different isoforms, ␣ 7 ␤ 1 , ␣ 7 ␤ 0 , and ␣ 6 ␤ 1 , according to the number of identical ␣-chains (6 or 7) and the presence/absence of a single ␤-chain. 18 The main isoform is ␣ 7 ␤ 1 , whereas the ␣ 7 ␤ 0 isoform lacking the ␤-chain represents approximately 17% of the C4BP molecules.…”

Section: Introductionmentioning

confidence: 99%

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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

Trégouët

Souto

et al. 2010

Blood

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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, ␣ 7 ␤ 1 , ␣ 6 ␤ 1 , and ␣ 7 ␤ 0 , 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 locus were found genomewide significantly associated with ␣ 7 ␤ 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 ␣ 7 ␤ 0 plasma levels and increased C4BPA expression was further found associated with increased risk of VT (odds ratio [ IntroductionProtein S (PS), a vitamin K-dependent plasma protein, is a key regulator of the coagulation/fibrinolysis cascade. PS has no enzymatic activity but acts mainly as a cofactor for activated protein C (APC). 1 It participates in the inactivation of factors Va (FVa) and FVIIIa, leading to inhibition of thrombin generation. [2][3][4] Even in absence of APC, PS could still inhibit thrombin generation by decreasing the conversion of prothrombin to thrombin and that of FX to FXa. 5 PS is also a cofactor for tissue factor pathway inhibitor (TFPI) for inhibiting FXa. 6 In plasma, PS circulates either in a free form (fPS; ϳ 40%) or as a complex with the C4b-binding protein (C4BP; ϳ 60%). [7][8][9][10] It was initially thought that the C4BP-bound PS was not active and that only the circulating fPS was. [7][8][9] However, more recent works shed new light on a more complex mechanism, as C4BP-PS complex was shown to directly participate in the FVa and FVIIIa inactivation, 11 and C4BP could inhibit APC-catalyzed FVa inactivation even in the absence of PS. 12 Such complex and elusive mechanisms could explain why, despite the key role of PS in the regulation of thrombin generation, its involvement in the susceptibility of venous thrombosis (VT) remains obscure. Although PS deficiency is considered a risk factor for VT, 13-15 total PS and fPS show very little correlation with VT. 16,17 C4BP is a large plasma protein existing in 3 different isoforms, ␣ 7 ␤ 1 , ␣ 7 ␤ 0 , and ␣ 6 ␤ 1 , according to the number of identical ␣-chains (6 or 7) and the presence/absence of a single ␤-chain. 18 The main isoform is ␣ 7 ␤ 1 , whereas the ␣ 7 ␤ 0 isoform lacking the ␤-chain represents approximately 17% of the C4BP molecules. 7,18 Whereas the ␣-chain binds for many ligands, 19 the ␤-chain is specific for the binding of PS. As a consequence, the amount of ␤-chaincontaining isoforms can be viewed as a surrogate marker for fPS levels. Plasma levels of all 3 isoforms have documented high heritability estimates (ϳ 40% each), 20 but little is know ab...

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Section: C4bpb/c4bpa Locus and Risk Of Venous Thrombosis 4647mentioning

confidence: 82%

mentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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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

Trégouët

Souto

et al. 2010

Blood

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“…It is possible to have a significant genetic correlation without a significant phenotypic correlation. Similarly, Esparza-Gordillo et al (2004) reported that total C4BP plasma level showed no statistically significant phenotypic correlation with thrombosis susceptibility, but it was genetically correlated with the disease. The authors explained the pattern with the same reason as we provided above.…”

Section: Discussionmentioning

confidence: 94%

Bivariate linkage confirms genetic contribution to fetal origins of childhood growth and cardiovascular disease risk in Hispanic children

et al. 2007

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Birth weight has been shown to be associated with obesity and metabolic diseases in adulthood, however, the genetic contribution is still controversial. The objective of this analysis is to explore the genetic contribution to the relationship between birth weight and later risk for obesity and metabolic diseases in Hispanic children. Subjects were 1,030 Hispanic children in the Viva La Familia Study. Phenotypes included body size, body composition, blood pressure, fasting glucose, insulin, lipids, and liver enzymes. Birth weights were obtained from Texas birth certificates. Quantitative genetic analyses were conducted using SOLAR software. Birth weight was highly heritable, as were all other phenotypes. Phenotypically, birth weight was positively correlated to childhood body size parameters. Decomposition of these phenotypic correlations into genetic and environmental components revealed significant genetic correlations, ranging from 0.30 to 0.59. Negative genetic correlations were seen between birth weight and lipids. The genome scan of birth weight mapped to a region near marker D10S537 (LOD = 2.6). The bivariate genome-wide scan of birth weight and childhood weight or total cholesterol, improved the LOD score to 3.09 and 2.85, respectively. Chromosome 10q22 harbors genes influencing both birth weight and childhood body size and cardiovascular disease risk in Hispanic children.

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“…A few linkage scans on quantitative traits identified linked loci that did not correspond to the structural gene. This was the case for the C4BPA/C4BPB gene cluster that was found to be linked to the levels of free PS Esparza-Gordillo et al, 2004). These genes code for the C4b-binding protein (C4BP), a complement regulatory protein that forms a high-affinity complex with protein S in plasma (Dahlback & Stenflo, 1981).…”

Section: Agnostic Searchmentioning

confidence: 96%

Deciphering the molecular basis of venous thromboembolism: where are we and where should we go?

Morange

Trégouët

2010

Br J Haematol

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SummaryVenous thromboembolism (VTE) is a frequent disease that has a major genetic component of risk. However, known identified genetic risk factors account for <30% of idiopathic (without any environmental origin) VTE cases. This article aims to review the lessons learnt during recent decades in the field of the genetics of VTE, describe the present state-of-art methods and discuss promising themes for finding new susceptibility loci.

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Genetic correlation between plasma levels of C4BP isoforms containing chains and susceptibility to thrombosis

Cited by 6 publications

References 37 publications

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

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

Bivariate linkage confirms genetic contribution to fetal origins of childhood growth and cardiovascular disease risk in Hispanic children

Deciphering the molecular basis of venous thromboembolism: where are we and where should we go?

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