Genetics
CETP variant rs5882 shows no association with LDL cholesterol lowering from plant sterols, unlike CYP7A1 and APOE variants (Am J Clin Nutr 2015)
Original title: CYP7A1-rs3808607 and APOE isoform associate with LDL cholesterol lowering after plant sterol consumption in a randomized clinical trial
In a randomized crossover trial testing 2 g/day plant sterols against placebo for 28 days in mildly hypercholesterolemic adults preselected for high (n=24) or low (n=39) endogenous cholesterol synthesis, researchers assessed candidate genetic variants for their association with LDL cholesterol response. While CYP7A1-rs3808607 and APOE isoform were found to associate with LDL-lowering after plant sterol consumption, the CETP variant rs5882 did not associate with LDL cholesterol lowering in response to plant sterols, nor did the ABCG8 variant rs4148217, indicating that unlike CYP7A1 and APOE, this CETP polymorphism is not a genetic determinant of individual response to plant-sterol cholesterol-lowering therapy.
Original abstract
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 μmol/mmol) or low endogenous cholesterol synthesis (n = 39; mean ± SEM: L:C ratio = 0.99 ± 0.28 μmol/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 ɛ3 carriers (mean ± SEM: -0.13 ± 0.05 mmol/L, P = 0.0370, n = 40) responded less than APOE ɛ4 carriers (mean ± SEM: -0.31 ± 0.07 mmol/L, P < 0.0001, n = 23). Moreover, genoset CYP7A1-rs3808607 T/T/APOE ɛ3 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. The trial was registered at clinicaltrials.gov as NCT01131832.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.