Hall, Stephen; (1999) Common variation in the human lipoprotein lipase gene and characterisation of a new promoter polymorphism. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Lipoprotein lipase (LPL) is a multifunctional protein important in triglyceride and lipoprotein metabolism. As well as its primary enzymatic role which is to hydrolyse circulating plasma triglycerides, LPL also has a role as a "bridging" molecule in the binding of lipoproteins to the endothelium, leading to intracellular uptake that is independent of its lipolytic activity. This thesis describes work undertaken to characterise a new, common variant in the promoter of the human lipoprotein lipase gene and its effects on the plasma lipid profile. New PCR based assays were developed to rapidly genotype 3050 middle-aged men in the Second Northwick Park Heart Study, 191 men and women from the New York Postprandial Trial and 1314 individuals from the Wandsworth Heart and Stroke Study for common variants in the human lipoprotein lipase gene. The novel promoter variant -93G was found to be over 20 times more frequent in Blacks than Caucasians and associated with 20% to 25% lower plasma triglyceride concentrations in carriers compared with non-carriers. Investigation of the allelic frequencies, distributions and associations of five LPL variants among three ethnic groups in the Wandsworth Heart and Stroke Study revealed higher frequencies of -93G, N9 and HindIII in Blacks compared with Whites and South Asians and a higher frequency of S291 in Whites compared with South Asians and Blacks. No differences in frequencies of X447 between the groups were observed. Study of the interaction of smoking with N9 carrier status and risk of ischaemic heart disease in the Second Northwick Park Heart Study revealed that in N9 carriers, smoking increased the risk of ischaemic heart disease 17.6 fold. Functional studies on the IPL promoter revealed that the -93G containing promoter had approximately 20% more activity than the -93T containing promoter in vitro. In addition, it was found that the ubiquitous transcription factors Sp1 and Sp3 bind to this region of the promoter and that their binding is affected by the variation at -93.

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