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Soluble CD40L levels are regulated by the -3459 A>G polymorphism and predict myocardial infarction and the efficacy of antithrombotic treatment in non-ST elevation acute coronary syndrome
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
2006 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 26, no 7, 1667-1673 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES - Current evidence suggests the CD40-CD40L pathway as a key process in the development, progression, and outcome of acute coronary syndrome (ACS). The aim was to investigate the prognostic importance of soluble (s) CD40L levels, single nucleotide polymorphisms (SNP) in the CD40LG gene, and the relation between sCD40L and SNPs in patients with acute coronary syndromes (ACS). METHODS AND RESULTS - Samples were obtained on admission from 2359 patients with non-ST elevation ACS randomized to an early invasive versus a conservative and to placebo controlled long-term dalteparin treatment in the FRISC-II study. The -3459 A>G SNP was identified as a novel regulator of sCD40L levels (P=0.001). In the placebo-treated group, sCD40L levels above median were associated with a 2.5-fold increased risk of myocardial infarction (MI) (P≤0.001) but not with raised mortality. In the dalteparin treated group, sCD40L showed no association with MI (P=0.75). Consequently, dalteparin treatment was effective in reducing the risk of MI only in patients with sCD40L levels above median. A combined assessment of troponin-T and sCD40L complemented the prognostic information on risk of MI. CONCLUSIONS - We identified a SNP in the CD40LG gene as a novel regulator of sCD40L plasma concentrations. Soluble CD40L levels above median reflect a prothrombotic state, which can be managed with the use of intense anti-thrombotic treatments.

Place, publisher, year, edition, pages
2006. Vol. 26, no 7, 1667-1673 p.
Keyword [en]
ACS, CD40L, Myocardial infarction, Outcome, SNP, Thrombosis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94462DOI: 10.1161/01.ATV.0000222908.78873.36ISI: 000243408900039PubMedID: 16627810OAI: oai:DiVA.org:uu-94462DiVA: diva2:168310
Available from: 2006-05-02 Created: 2006-05-02 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Tissue Factor and CD40 Ligand: Markers for the Interplay of Coagulation and Inflammation in the Acute Coronary Syndrome
Open this publication in new window or tab >>Tissue Factor and CD40 Ligand: Markers for the Interplay of Coagulation and Inflammation in the Acute Coronary Syndrome
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

BACKGROUND: Tissue factor (TF) is a 47 kDa transmembrane glycoprotein known as the main initiator of blood coagulation. CD40 ligand is another membrane molecule, which ligates to cell types associated with atherosclerotic plaques thereby mediating intraplaque inflammation and weakening of the fibrous cap. Acute coronary syndrome (ACS) is a multi-factorial disease in which TF and CD40 ligand have prominent roles. Single nucleotide poly-morphisms (SNPs) in the TF and CD40 ligand genes may influence the development, pro-gression and outcome in ACS. AIM: The aim of this thesis was to investigate the genetic and molecular control of TF expression in healthy individuals and in patients with ACS. More-over, the aim was to investigate whether SNPs in the TF and CD40L genes respectively were associated with risk and outcome in ACS and / or with plasma concentrations of these pro-teins. RESULTS: A real-time PCR method that allowed sensitive and dynamic quantification of TF mRNA was established and used for the identification of a high and low response phe-nomenon of TF mRNA. The TF high and low response correlated with the expression of toll-like receptor 4 (TLR-4) thus linking TF to innate immunity in a novel fashion. Investigation of several SNPs in the TF and CD40L genes led to the identification of the 5466 A>G in the TF gene and the -3459 A>G SNP in the CD40L gene. The 5466 G allele was associated with cardiovascular death in patients with ACS and increased TF procoagulant activity in human monocytes, which explained the clinical association. The -3459 G allele regulated the produc-tion of soluble CD40L but was not related with patient outcome. Soluble CD40L levels above median were associated with the risk of MI in patients with ACS. A prolonged treatment with dalteparin was more efficient in patients presenting with high levels of sCD40L, which further supports sCD40L as a marker of a prothrombotic state. CONCLUSIONS: The results of this thesis adds to our current knowledge of factors influencing TF expression and activity by demonstrating the effects of TF gene variants, cell signalling molecules, CD40 ligand protein and gene variation. All of these effects have the potential to modify the risk of development, progression and outcome in the acute coronary syndrome and exemplify the interplay between coagulation and inflammation, in which both TF and CD40 ligand are active.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 149
Keyword
Molecular medicine, tissue factor, CD40 ligand, gene expression, single nucleotide polymorphism, acute coronary syndrome, myocardial infarction, coagulation, inflammation, Molekylärmedicin
Identifiers
urn:nbn:se:uu:diva-6841 (URN)91-554-6558-7 (ISBN)
Public defence
2006-05-23, Ebba Enghoffsalen, Ingång 50, Uppsala Akademiska Sjukhus, Uppsala, 13:15
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Supervisors
Available from: 2006-05-02 Created: 2006-05-02Bibliographically approved

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Lindahl, BertilWallentin, LarsSiegbahn, Agneta

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