CYP7A1-rs3808607 and APOE isoform associate with LDL cholesterol lowering after plant sterol consumption in a randomized clinical trial

卷:102

MacKay, Dylan S. ; Eck, Peter K. ; Gebauer, Sarah K. ; Baer, David J. ; Jones, Peter J. H.

关键词: cholesterol;    gene-nutrient interactions;    LDL cholesterol;    nutrigenetics;    plant sterols;   

DOI  :  10.3945/ajcn.115.109231

学科分类：食品科学和技术

【 摘 要 】

Background: The benefits of plant sterols (PSs) for cholesterol lowering are hampered by large heterogeneity across individuals, potentially because of genetic polymorphisms. Objective: We investigated the impact of candidate genetic variations on cholesterol response to PSs in a trial that recruited individuals with high or low endogenous cholesterol synthesis, estimated by lathosterol to cholesterol (L:C) ratio. Design: Mildly hypercholesterolemic adults preselected as possessing either high endogenous cholesterol synthesis (n = 24; mean SEM: L:C ratio = 2.03 +/- 0.39 mu mol/mmol) or low endogenous cholesterol synthesis (n = 39; mean +/- SEM: L:C ratio = 0.99 +/- 0.28 mu mol/mmol) consumed 2 g PS/d or a placebo for 28 d by using a dual-center, single-blind, randomized crossover design. Cholesterol synthesis and change in cholesterol absorption were measured with stable isotopic tracers. Candidate single-nucleotide polymorphisms and apolipoprotein E (APOE) isoform were assessed by TaqMan genotyping assay. Results: The cholesterol fractional synthesis rate was higher (P < 0.001) in participants with high endogenous cholesterol synthesis (mean +/- SEM: placebo: 9.16% +/- 0.47%; PSs: 9.74% +/- 0.47%) than in participants with low endogenous cholesterol synthesis (mean +/- SEM placebo: 5.72% +/- 0.43%; PS: 7.10% +/- 0.43%). Low-density lipoprotein (LDL) cholesterol lowering in response to PSs was associated with individuals' genotypes. Cholesterol 7 alpha-hydroxylase (CYP7A1-rs3808607) T/T homozygotes showed no LDL cholesterol lowering (mean +/- SEM: -0.05 +/- 0.07 mmol/L, P = 0.9999, n = 20), whereas the presence of the G-allele associated with LDL cholesterol response in a dose-dependent fashion (mean +/- SEM G/T: -0.22 +/- 0.06 mmol/L, P = 0.0006, n = 35; G/G: -0.46 +/- 0.12 mmol/L, P = 0.0009, n = 8). Similarly, APOE 63 carriers (mean +/- SEM: -0.13 +/- 0.05 mmol/L, P = 0.0370, n = 40) responded less than APOE epsilon 4 carriers (mean +/- SEM: -0.31 +/- 0.07 mmol/L, P < 0.0001, n = 23). Moreover, genoset CYP7A1-rs3808607 T/T/APOE epsilon 3 was associated with nonresponsiveness (mean +/- SEM: +0.09 +/- 0.08 mmol/L, P = 0.9999, n = 14). rs5882 in cholesteryl ester transfer protein (CETP) and rs4148217 in ATP-binding cassette subfamily G member 8 (ABCG8) did not associate with LDL cholesterol lowering. Cholesterol absorption decreased as a result of PS consumption, but this decrease was not related to circulating LDL cholesterol concentrations, cholesterol synthesis phenotype, or genotypes. Conclusion: CYP7A1-rs3808607 and APOE isoform are associated with the extent of reduction in circulating LDL cholesterol in response to PS consumption and could serve as potential predictive genetic markers to identify individuals who would derive maximum LDL cholesterol lowering with PS consumption.