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Title: Genetic and functional studies provide insights into the aetiologies of familial combined hyperlipidemia
Author: Speedy, Helen Elizabeth
ISNI:       0000 0004 2718 8955
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2012
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The integration of biological and genetic data has established that diverse biological processes, involving multiple effectors, influence circulating levels of triglyceride and cholesterol. This diversity may underlie the genetic complexity of human dyslipidemias, including the common and highly atherogenic condition, Familial Combined Hyperlipidemia (FCHL). The aetiologies of FCHL are currently undetermined. In this thesis, a multi-pronged approach was employed to identify genes/variants contributing to the linkage observed between the chromosome 21q22.2-22.3 interval and lipid traits, in white-British FCHL families. Additionally GPIHBP1, which encodes glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1, was studied. GPIHBP1 represents a strong FCHL candidate gene due to its role in the lipolytic processing of triglyceride-rich lipoproteins. Combined genetic and gene expression analyses, focussed upon a refined 3.8Mb interval on chromosome 21q22.3 that was linked to lipid abnormalities in subsets of FCHL families, identified two genes (COL18A1 and PKNOX1 ) that warrant further investigation with regard to their contribution to FCHL. Promising results were also obtained for C21orf57, which resides just outside the 3.8Mb interval. Genetic association analyses in 1725 members of 239 FCHL families identified nominal association (P=0.0009) between a TSPEAR variant, rs34163868, and plasma triglyceride levels. Furthermore, transcript levels of CBS and TRPM2 were significantly altered by treatment with the PPAR-agonist bezafibrate in a rat hepatoma cell line, thus implicating these genes in triglyceride/fatty acid metabolism. In combined analysis of five independent cohorts, the minor allele of the GPIHBP1 variant, rs11538388 was protective against hypertriglyceridemia (P=2.98x10-4). The same allele was associated with decreased risk of coronary heart disease in the prospective Northwick Park Heart Study II (hazard ratio for carriers=0.76, P=0.0480) and delayed age of onset in the Southampton Atherosclerosis Study (odds ratio=0.76, P=0.0146). Collectively, these data demonstrate that the rs11538388 minor allele, or variant in linkage disequilibrium, is associated with more favourable processing of atherogenic lipoproteins.
Supervisor: Not available Sponsor: British Heart Foundation ; Queen Mary University of London
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine ; Familial Combined Hyperlipidemia ; Hyperlipidemia ; Atherosclerosis