Endothelial protein C receptor polymorphisms and risk of myocardial infarction

Medina, Pilar; Navarro, Silvia; Corral, Javier; Zorio, Esther; Roldán, Vanessa; Estellés, Amparo; Santamaría, Amparo; Marı́n, Francisco; Rueda, Joaquı́n; Bertina, Rogier M.; España, Francisco; Groups, Recava Thrombosis

doi:10.3324/haematol.13066

Cited by 32 publications

(28 citation statements)

References 34 publications

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“…Among South-Asian diabetics, the association was also positive, although not statistically significant (per-allele OR ϭ 1.25; 95% CI, 0.85-1.83). The largest inverse association was found in a Spanish study 48 of subjects with a history of MI (per-allele OR ϭ 0.55; 95% CI, 0.41-0.74). However, HWE was violated in this study and the results may not be comparable to other included studies.…”

Section: MImentioning

confidence: 93%

“…18,42 This stratification by race/ethnicity was maintained in the present meta-analysis for a total of 16 MI studies analyzed. Cases and controls were matched by age and gender in 3 studies, 18,31,48 whereas the age and/or gender distribution of cases and controls was either not reported or differed considerably in all but 1 42 of the other studies. One study was of first-event MI patients 18 and the case definition was a history of MI in 6 studies, whereas a composite case definition including coronary intervention procedures, angina, Ͼ 50% stenosis of coronary vessels, and MI was used in the other 11 studies.…”

Section: Resultsmentioning

confidence: 99%

“…Of the 8 studies included in the meta-analysis that examined levels of sEPCR relative to the PROCR rs867186 variant, all observed a significant increase associated with the G allele. 9,10,17,18,35,45,47,48 Four studies reported levels of PC or APC by genotype. Of these, two 19,45 observed a statistically significant increase in PC associated with the G allele, one 9 observed a statistically significant decrease in APC among G allele carriers, and one 17 found no association between genotype and APC levels.…”

Section: Vtementioning

confidence: 99%

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The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies

Dennis

Johnson

Adediran

et al. 2012

Blood

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The endothelial protein C receptor (EPCR) limits thrombus formation by enhancing activation of the protein C anticoagulant pathway, and therefore may play a role in the etiology of thrombotic disorders. The rs867186 single-nucleotide polymorphism in the PROCR gene (g.6936A > G, c.4600A > G), resulting in a serine-to-glycine substitution at codon 219, has been associated with reduced activation of the protein C pathway, although its association with thrombosis risk remains unclear. The present study is a highly comprehensive systematic review and meta-analysis, including unpublished genome-wide association study results, conducted to evaluate the evidence for an association between rs867186 and 2 common thrombotic outcomes, venous thromboembolism (VTE) and myocardial infarction (MI), which are hypothesized to share some etiologic pathways. MEDLINE, EMBASE, and HuGE Navigator were searched through July 2011 to identify relevant epidemiologic studies, and data were summarized using random-effects metaanalysis. Twelve candidate genes and 13 genome-wide association studies were analyzed (11 VTE and 14 MI, including 37 415 cases and 84 406 noncases). Under the additive genetic model, the odds of VTE increased by a factor of 1.22 (95% confidence interval, 1.11-1.33, P <

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Section: MImentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Vtementioning

confidence: 99%

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The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies

Dennis

Johnson

Adediran

et al. 2012

Blood

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“…H3 is tagged by the minor allele of g.4600A>G (Ser219Gly; rs867186) and has been associated with the risk of venous [8][9][10][11][12][13][14][15]18,19 and arterial thrombosis, [19][20][21][22][23] but with contradictory results. The presence of H3 results in increased plasma sEPCR levels, [8][9][10][11][12][13]18,20,22,24 which is largely explained by a Ser219Gly substitution, which renders EPCR more susceptible to cleavage by metalloproteinases such as tumor necrosis factor-α converting enzyme/ADAM17.…”

mentioning

confidence: 99%

Functional Analysis of Two Haplotypes of the Human Endothelial Protein C Receptor Gene

Medina

Navarro

Bonet

et al. 2014

ATVB

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Objective-To confirm the effect of the endothelial protein receptor gene (PROCR) haplotypes H1 and H3 on venous thromboembolism (VTE), to study their effect on endothelial protein C receptor (EPCR) expression in human umbilical vein endothelial cells, and to investigate the functionality of H1 tagging single-nucleotide polymorphisms in an in vitro model. Approach and Results-Protein C (PC), activated PC, and soluble EPCR (sEPCR) levels were measured in 702 patients with VTE and 518 healthy individuals. All subjects were genotyped for PROCR H1 and H3. Human umbilical vein endothelial cells isolated from 111 umbilical cords were used to study the relation between PROCR haplotypes, PROCR mRNA, cellular distribution of EPCR, and rate of PC activation. Finally, the functionality of the intragenic PROCR H1 singlenucleotide polymorphisms was analyzed using a luciferase-based method. We confirmed that individuals carrying H1 have reduced VTE risk, increased plasma activated PC levels, and reduced plasma sEPCR levels and that individuals with the H3H3 genotype have an increased VTE risk and increased plasma sEPCR levels. In cultured human umbilical vein endothelial cells, H1 is associated with increased membrane-bound EPCR, increased rate of PC activation, and reduced sEPCR in conditioned medium, but does not significantly influence PROCR mRNA levels. In contrast, H3 is associated with reduced membrane-bound EPCR and increased sEPCR in human umbilical vein endothelial cell-conditioned medium, higher levels of a truncated mRNA isoform, and a lower rate of PC activation. Finally, we identified the g.2132T>C singlenucleotide polymorphism in intron 1 as an intragenic H1-specific functional single-nucleotide polymorphism. Conclusions-These Medina et al Functional Analysis of PROCR Haplotypes 685H3 is tagged by the minor allele of g.4600A>G (Ser219Gly; rs867186) and has been associated with the risk of venous [8][9][10][11][12][13][14][15]18,19 and arterial thrombosis, [19][20][21][22][23] but with contradictory results. The presence of H3 results in increased plasma sEPCR levels, [8][9][10][11][12][13]18,20,22,24 which is largely explained by a Ser219Gly substitution, which renders EPCR more susceptible to cleavage by metalloproteinases such as tumor necrosis factor-α converting enzyme/ADAM17. 7 Another mechanism that could link H3 to high plasma levels of sEPCR is its association with a truncated form of PROCR mRNA lacking the transmembrane and intracellular domains. 25 Recently, PROCR H3 has also been found to be associated with increased plasma levels of PC. 20,26Therefore, we aimed to verify the effects of H1 and H3 on VTE risk in a case-control study to investigate their effects on EPCR expression in human umbilical vein endothelial cells (HUVECs) and to identify the functional SNP that mediates the protection of H1 against VTE using luciferase constructs.In the present study, we confirm previous reports on a protective effect of PROCR H1 against VTE 8,[11][12][13][14][15] and show, for the first time, that it is prob...

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“…Because 2 haplotypes of the PROCR, H1 and H3, have been associated with the rate of activation of PC in cultured HUVEC 30 and with the levels of APC in human plasma, 28,31 we selected HUVEC with the same PROCR genotype (H1H2). The rate of PC activation increased in parallel with the increase of the number of 1418T alleles present.…”

Section: Pc Activation On Huvecmentioning

confidence: 99%

Association of the Thrombomodulin Gene c.1418C>T Polymorphism With Thrombomodulin Levels and With Venous Thrombosis Risk

Navarro

Medina

Bonet

et al. 2013

ATVB

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Objective— To investigate the association of the THBD c.1418C>T polymorphism, which encodes for the replacement of Ala455 by Val in thrombomodulin (TM), with venous thromboembolism (VTE), plasma soluble TM, and activated protein C levels. In addition, human umbilical vein endothelial cells (HUVEC) isolated from 100 umbilical cords were used to analyze the relation between this polymorphism and THBD mRNA and TM protein expression. Approach and Results— The THBD c.1418C>T polymorphism was genotyped in 1173 patients with VTE and 1262 control subjects. Levels of soluble TM and activated protein C were measured in 414 patients with VTE (not on oral anticoagulants) and 451 controls. HUVECs were genotyped for the polymorphism and analyzed for THBD mRNA and TM protein expression and for the ability to enhance protein C activation by thrombin. The 1418T allele frequency was lower in patients than in controls ( P <0.001), and its presence was associated with a reduced VTE risk, reduced soluble TM levels, and increased circulating activated protein C levels ( P <0.001). In cultured HUVEC, the 1418T allele did not influence THBD expression but was associated with increased TM in cell lysates, increased rate of protein C activation, and reduced soluble TM levels in conditioned medium. Conclusions— The THBD 1418T allele is associated with lower soluble TM, both in plasma and in HUVEC-conditioned medium, and with an increase in functional membrane–bound TM in HUVEC, which could explain the increased activated protein C levels and the reduced VTE risk observed in individuals carrying this allele.

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Endothelial protein C receptor polymorphisms and risk of myocardial infarction

Cited by 32 publications

References 34 publications

The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies

The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies

Functional Analysis of Two Haplotypes of the Human Endothelial Protein C Receptor Gene

Association of the Thrombomodulin Gene c.1418C>T Polymorphism With Thrombomodulin Levels and With Venous Thrombosis Risk

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