Elrayess, Mohamed Aghar; (2002) Genetic variation in the PECAM-1 gene and its role in atherosclerosis and coronary heart disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes an investigation of the effects of polymorphisms in the platelet endothelial cell adhesion molecule-1 (PECAM-1) gene on progression of atherosclerosis and risk of coronary heart disease (CHD). Selected regions of the PECAM-1 gene were screened by single-strand conformation polymorphism analysis. Four novel variants were identified, one in the promoter region (-564C>T), one in the 5' untranslated region (UTR) (53G>A), one in intron-9 (IVS9-42T>C) and one in exon 12 altering codon 670 from arginine to glycine (R670G). The association of the 53G>A polymorphism with progression of atherosclerosis was determined in the Lopid Coronary Angiography Trial (LOCAT) and Regression Growth Evaluation Statin Study (REGRESS). Both studies looked at progression of atherosclerosis in male patients of the same age group using coronary angiography at baseline and after two and two and half years follow up respectively. Patients carrying the 53A allele showed less focal progression in the LOCAT study, suggesting that the 53A allele is protective against progression of atherosclerosis. The 53G>A change alters a putative shear stress responsive element in the gene. Experiments showed that PECAM-1 is responsive to shear stress with a 1.8 fold induction of mRNA levels following 24 hours shear stress conditions. Transient transfection of human umbilical vein endothelial cells (HUVECs) with two luciferase reporter constructs driven by the PECAM-1 promoter and 5' UTR showed a response of the 53G allele, but not the 53A allele, to shear stress. Thus, lower expression of PECAM-1 under shear stress conditions in 53A carriers may account for the slower progression of atherosclerotic plaque formation. The association of the R670G polymorphism with progression of atherosclerosis and CHD was determined in the LOCAT study and the second Northwick Park Heart (NPHSII) study, a large prospective study of healthy UK men followed for 10 years, respectively. The 670G allele was found to be associated with progression of disease in the LOCAT study, while the 670R allele was found to be associated with CHD in smokers of the NPHSII study. The effect of the R670G genotype on the adhesion of monocytes to HUVECs and their transendothelial migration following IL-1β or TNF-α was investigated. There was no significant genotype effect on transendothelial migration of monocytes, however a post-hoc analysis following adjustment for age and gender showed greater transendothelial migration of monocytes homozygous for the 670G allele compared to those homozygous for the 670R allele following IL-1β or TNF-α stimulation. The effect of the R670G genotype on PECAM-1 tyrosine phosphorylation in HUVECs was also examined. PECAM-1 tyrosine phosphorylation in HUVECs homozygous for the 670G was significantly greater than that of cells homozygous for the 670R at base line. This effect was no longer significant following IL-1β stimulation. Genotype-dependent tyrosine phosphorylation of PECAM-1 and the potential modulation of transendothelial migration of leukocytes and platelet/collagen interactions may explain the association of the R670G polymorphism with progression of disease and CHD.

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