2 research outputs found
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A randomized trial and novel SPR technique identifies altered lipoprotein-LDL receptor binding as a mechanism underlying elevated LDL-cholesterol in APOE4s
At a population level APOE4 carriers (~25% Caucasians) are at higher risk of cardiovascular diseases. The penetrance of genotype is however variable and influenced by dietary fat composition, with the APOE4 allele associated with greater LDL-cholesterol elevation in response to saturated fatty acids (SFA). The etiology of this greater responsiveness is unknown. Here a novel surface plasmon resonance technique (SPR) is developed and used, along with hepatocyte (with the liver being the main organ modulating lipoprotein metabolism and plasma lipid levels) uptake studies to establish the impact of dietary fatty acid composition on, lipoprotein-LDL receptor (LDLR) binding, and hepatocyte uptake, according to APOE genotype status. In men prospectively recruited according to APOE genotype (APOE3/3 common genotype, or APOE3/E4), triglyceride-rich lipoproteins (TRLs) were isolated at fasting and 4-6 h following test meals rich in SFA, unsaturated fat and SFA with fish oil. In APOE4s a greater LDLR binding affinity of postprandial TRL after SFA, and lower LDL binding and hepatocyte internalization, provide mechanisms for the greater LDL-cholesterol raising effect. The SPR technique developed may be used for the future study of the impact of genotype, and physiological and behavioral variables on lipoprotein metabolism
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Association of apolipoprotein E gene polymorphisms with blood lipids and their interaction with dietary factors
Several candidate genes have been identified in relation to lipid metabolism, and among these, lipoprotein lipase (LPL) and apolipoprotein E (APOE) gene polymorphisms are major sources of genetically determined variation in lipid concentrations. This study investigated the association of two single nucleotide polymorphisms (SNPs) at LPL, seven tagging SNPs at the APOE gene, and a common APOE haplotype (two SNPs) with blood lipids, and examined the interaction of these SNPs with dietary factors.
METHODS:
The population studied for this investigation included 660 individuals from the Prevention of Cancer by Intervention with Selenium (PRECISE) study who supplied baseline data. The findings of the PRECISE study were further replicated using 1238 individuals from the Caerphilly Prospective cohort (CaPS). Dietary intake was assessed using a validated food-frequency questionnaire (FFQ) in PRECISE and a validated semi-quantitative FFQ in the CaPS. Interaction analyses were performed by including the interaction term in the linear regression model adjusted for age, body mass index, sex and country.
RESULTS:
There was no association between dietary factors and blood lipids after Bonferroni correction and adjustment for confounding factors in either cohort. In the PRECISE study, after correction for multiple testing, there was a statistically significant association of the APOE haplotype (rs7412 and rs429358; E2, E3, and E4) and APOE tagSNP rs445925 with total cholesterol (Pβ=β4βΓβ10-β4 and Pβ=β0.003, respectively). Carriers of the E2 allele had lower total cholesterol concentration (5.54βΒ±β0.97 mmol/L) than those with the E3 (5.98βΒ±β1.05 mmol/L) (Pβ=β0.001) and E4 (6.09βΒ±β1.06 mmol/L) (Pβ=β2βΓβ10-β4) alleles. The association of APOE haplotype (E2, E3, and E4) and APOE SNP rs445925 with total cholesterol (Pβ=β2βΓβ10-β6 and Pβ=β3βΓβ10-β4, respectively) was further replicated in the CaPS. Additionally, significant association was found between APOE haplotype and APOE SNP rs445925 with low density lipoprotein cholesterol in CaPS (Pβ=β4βΓβ10-β4 and Pβ=β0.001, respectively). After Bonferroni correction, none of the cohorts showed a statistically significant SNP-diet interaction on lipid outcomes.
CONCLUSION:
In summary, our findings from the two cohorts confirm that genetic variations at the APOE locus influence plasma total cholesterol concentrations, however, the gene-diet interactions on lipids require further investigation in larger cohorts