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


METHODS
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.


CONCLUSIONS
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.
Richardson Centre for Functional Foods and Nutraceuticals, Department of Human Nutritional Sciences.
Dylan S
http://orcid.org/0000-0002-0751-1634
DS
MacKay
Department of Human Nutritional Sciences.
Peter K
http://orcid.org/0000-0003-2371-9774
PK
Eck
USDA, Agricultural Research Service, Beltsville Human Nutrition Research Center, Beltsville, MD, and.
Sarah K
SK
Gebauer
USDA, Agricultural Research Service, Beltsville Human Nutrition Research Center, Beltsville, MD, and.
David J
DJ
Baer
Richardson Centre for Functional Foods and Nutraceuticals, Department of Human Nutritional Sciences, Department of Food Science, University of Manitoba, Winnipeg, Canada peter.jones@umanitoba.ca.
Peter Jh
http://orcid.org/0000-0001-5887-2846
PJ
Jones
D000328:Adult; D000368:Aged; D001057:Apolipoproteins E / Q000097:blood* / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D002790:Cholesterol 7-alpha-Hydroxylase / Q000097:blood* / Q000235:genetics; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood*; D018592:Cross-Over Studies; D023381:Endpoint Determination; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010840:Phytosterols / Q000008:administration & dosage*; D020641:Polymorphism, Single Nucleotide; D016037:Single-Blind Method
D001057:Apolipoproteins E; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL; D010840:Phytosterols; C001521:lathosterol; D002784:Cholesterol; C553219:CYP7A1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase
LDL cholesterol; cholesterol; gene-nutrient interactions; nutrigenetics; plant sterols