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Functional association of a single nucleotide polymorphism in the human CD40 gene with the pathogenesis of atherosclerosis

Sultan, Cheryl Sophia

PDF, English (PhD Dissertation)
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The binding of the co-stimulatory receptor CD40 to its ligand CD154 (CD40L) is imperative for orchestrating a complete and adequate immune response. However, there is also compelling evidence from mice and human studies to indicate an involvement of this co-stimulatory receptor-ligand dyad in the development and progression of chronic inflammation. In endothelial cells, the proinflammatory response triggered by CD40-CD40L interactions facilitates a shift from a quiescent to a prothrombotic and procoagulant state; a process which precedes atherosclerosis and is implicated in the etiology of cardiovascular and rheumatic diseases. A functional single nucleotide polymorphism (SNP) in the Kozak consensus sequence of the CD40 gene (-1C>T, rs1883832) is associated with autoimmune and immune-inflammatory diseases by altering the efficiency of protein translation. Based on this context, we hypothesized that this SNP could enhance the risk of coronary heart disease (CHD) in the Caucasian population of Baden-Württemberg via influencing endothelial CD40 expression and signaling. To test this hypothesis, distribution of the -1C/T SNP of the CD40 gene was examined in a hospital-based case-control study of CHD. The findings showed an increased risk of CHD associated with the C allele (odds ratio = 1.43; 95% confidence interval: 1.13-1.86). Genotype-phenotype analysis revealed that endothelial cells from carriers with the -1CC versus -1TT genotype exhibited significantly higher CD40 protein expression, along with an enhanced proinflammatory phenotype. Additionally, higher circulating soluble CD40 protein was observed in -1CC compared with -1TT carriers. These results indicate that the -1C/T SNP of the CD40 gene may induce susceptibility to CHD via enhanced endothelial cell activation. Lastly, the C allele was also significantly over-represented in patients with psoriatic arthritis compared to non-diseased controls, indicating a more general role for this SNP in driving chronic inflammation. Collectively, this study provides novel evidence suggesting that the C allele of -1C/T SNP of the CD40 gene may increase susceptibility to CHD by imparting a proinflammatory phenotype to endothelial cells through enhanced CD40 protein expression and signaling and therefore augmenting an already exaggerated cellular immune response.

Item Type: Dissertation
Supervisor: Hecker, Prof. Dr. Markus
Date of thesis defense: 6 July 2017
Date Deposited: 25 Aug 2017 05:53
Date: 2017
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Uncontrolled Keywords: CD40, Single Nucleotide Polymorphism, Kozak consensus sequence, Coronary Heart Disease, Psoriatic Arthritis.
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