Abstract/Summary

Abnormal lipid concentrations have been shown to be risk factors for cardiovascular disease, which is influenced by a complex interaction between lifestyle (such as diet) and genetic factors. Given that lipoprotein lipase (LPL) and apolipoprotein E (APOE) are key regulatory proteins in lipid metabolism, the main aims of this thesis were to examine the association of single nucleotide polymorphisms (SNPs) at the LPL and APOE genes with lipid-related outcomes and to investigate the interaction of the SNPs with dietary factors on lipids. A total of six studies with different study designs were used. These studies included a postprandial study (n=261), a case-control study (CURES, Asian India, n=1,845), three cross-sectional studies [PRECISE study (UK, n=468; Denmark, n=192) and CaPS study (UK, n=1,238)], a 16- week intervention study DIVAS (n=120) and a crossover trial (n=18). For the LPL gene, the SNP rs328 showed a consistent association with HDL-C concentrations in the postprandial (P=0.015) and CURES studies (P=0.0004). In addition, in the CURES, there was an interaction between LPL SNP rs1121923 and fat intake (energy %) on HDL-C concentrations (P=0.003). For the APOE gene, significant associations were detected between the APOE haplotype (E2, E3, and E4) and APOE SNP rs445925 and total cholesterol (P=4x10-4 and P=0.003, respectively) in the PRECISE study. These associations were further replicated in the CaPS cohort. In the DIVAS study, the TT homozygotes of the APOE SNP rs1064725 showed a significant reduction in total cholesterol after the MUFA diet compared to the SFA (P=0.001). In the crossover trial, we examined the association vitamin D-related SNPs with lipids in 18 men with sup-optimal vitamin D status and found that the TT homozygotes of the SNP rs12785878 (T/G) at nicotinamide-adenine dinucleotide synthetase 1 gene had higher HDL-C levels compared to G allele carriers (P=0.0003). In conclusion, our findings suggest a role of dietary factors in modifying the genetic effect of LPL and APOE SNPs on lipid levels. Given the smaller sample size of some of the cohorts studied, replication of the findings is warranted.