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Effects of common genetic variation on fasting and postprandial lipid metabolism and atherosclerosis

Peacock, Rachel Elizabeth; (1994) Effects of common genetic variation on fasting and postprandial lipid metabolism and atherosclerosis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Fasting triglyceride (TG) levels are a strong determinant of postprandial lipaemia, which is thought to influence the development of coronary artery disease (CAD) because of the delayed clearance or prolonged presence of atherogenic remnant lipoproteins. Associations were thus sought between common genetic variation in apolipoprotein (apo) B, AI, CIII and E and lipoprotein lipase (LPL) and both levels of the TG-rich lipoproteins and severity of atherosclerosis. The role of the LPL gene was emphasized because of the known metabolic relationship between LPL activity and lipid metabolism. In Swedish healthy individuals, the C-265 allele of the C to T polymorphism in the apoB promoter was associated with higher apoB levels, the X+ allele of the apoB-XbaI polymorphism with higher low density cholesterol (LDL) cholesterol levels, the common allele (V+) of the apoCIII-PvuII polymorphism with higher LDL-TG levels, and both the T allele of the apoCIII C1100 to T polymorphism and the common allele (H+) of the LPL-HindIII polymorphism with higher TG levels. In Swedish myocardial infarction survivors, fasting lipids and lipoproteins were associated with variation at the apoE gene but not at the apoB, apoCIII or LPL genes. However homozygosity for the insertion allele of the apoB signal peptide polymorphism, homozygosity for the C allele of the apoCIII C1100 to T polymorphism and the presence of the rare alleles of the HindIII and Serine-Stop447 polymorphisms in the LPL gene were associated with worse baseline severity of atherosclerosis in the MI survivors. When genotypes associated with severe atherosclerosis were considered together, individuals with all three genotypes had a 6-fold greater severity of atherosclerosis compared to those with none. In a British patient sample with CAD, variation at the apoB and apoAI-CIII-AIV genes were associated with baseline severity and progression, respectively, of atherosclerosis; homozygosity for the X- allele of the apoB-Xbal polymorphism and homozygosity for the G allele of the apoAI-G-75 to A polymorphism being associated with worse atherosclerosis. In neither of these patient samples, did the genotype effect on atherosclerosis appear to be mediated through genotype-associated differences in fasting lipid and lipoprotein traits. To test the hypothesis that genetic variation was influencing atherosclerosis severity via modulation of postprandial lipaemia rather than through fasting lipids, the effects of common genetic variation on levels of postprandial TG-rich lipoproteins and their atherogenic remnants were examined. The apoB signal peptide variants influenced production of postprandial lipoproteins of both intestinal and hepatic origin. Polymorphisms in the apoCIII, LPL and apoB genes exerted their largest effect on lipolysis or catabolism of postprandial lipoproteins, and the H+ allele of the LPL-HindIII polymorphism was associated with higher postprandial LPL activity and levels of free fatty acids. Using Single Strand Conformation Polymorphism analysis and sequencing, an A1127 to G substitution that changes Asparagine-291 to Serine was found in exon 6. The frequency of the Serine-291 variant, found on the haplotype defined by the common alleles (presence of cutting site) of the PvuII and HindIII polymorphisms, was approximately 0.1 in two independent samples. The effects of this substitution on fasting and postprandial lipids and lipoproteins, LPL activity, interrelationships between plasma traits and influence on apoE phenotype-mediated effects have been investigated, but do not explain all the effects associated with genotypes of the LPL-HindIII polymorphism. Common variation in the genes for apoB, apoCIII and LPL influences fasting serum lipid and lipoprotein levels, with LPL having the largest effect on TGs, and modulating postprandial lipaemia and interrelationships between lipid traits; these may explain associations seen between genetic variation and atherosclerosis. Additive effects occur between common genetic polymorphisms, modulated by environmental factors, with implications for future population studies.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Effects of common genetic variation on fasting and postprandial lipid metabolism and atherosclerosis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10098524
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