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ARS Home » Northeast Area » Beltsville, Maryland (BHNRC) » Beltsville Human Nutrition Research Center » Food Components and Health Laboratory » Research » Publications at this Location » Publication #314504

Research Project: Metabolism and Molecular Targets of Macro and Micro Food Components in the Development and Management of Obesity and Chronic Diseases

Location: Food Components and Health Laboratory

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

Author
item Mackay, Dylan - University Of Manitoba
item Eck, Peter - University Of Manitoba
item Gebauer, Sarah
item Baer, David
item Jones, Peter - University Of Manitoba

Submitted to: American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/31/2015
Publication Date: 10/1/2015
Citation: Mackay, D.S., Eck, P.K., Gebauer, S.K., Baer, D.J., Jones, P.J. 2015. CYP7A1-rs3808607 and APOE isoform associate with LDL cholesterol lowering after plant sterol consumption in a randomized clinical trial. American Journal of Clinical Nutrition. 102:951-957.

Interpretive Summary: Plant sterols lower LDL-cholesterol but there is large variability in the response among individuals. The variability may be due to small differences in genetic make-up (single nucleotide polymorphisms). We studied the effect of selected gene polymorphisms on cholesterol response to plant sterols in a study which recruited individuals who were classified as either having a high or low ability to synthesize their own cholesterol. Adults who had mild elevation of their LDL-cholesterol were selected and classified as having either high (n=24) cholesterol synthesis or low endogenous cholesterol synthesis (n=39) based on their lathosterol to cholesterol (L/C) ratio. They consumed 2 g/d of plant sterol or a placebo for 28 days. Cholesterol synthesis and change in cholesterol absorption were measured using stable isotope tracers. Candidate genes for single nucleotide polymorphisms and ApoE isoform were assessed. As anticipated, cholesterol fractional synthesis rate was higher in high cholesterol synthesizing participants than in the low synthesizing participants during both placebo and the plant sterol periods of consumption. LDL-cholesterol lowering in response to plant sterol consumption indeed was associated with individuals’ genotypes. SNP rs3808607-T/T homozygotes showed no LDL-cholesterol lowering, while the presence of the G allele was associated with LDL-cholesterol response in a dose dependent fashion. Similarly, ApoE e3 carriers responded less than ApoE e4 carriers. Moreover, the gene combination of CYP7A1-SNP-rs3808607-T/T/ApoE e3 was associated with non-responsiveness. rs5882 in CETP and rs4148217 in ABCG8 did not associate with LDL-cholesterol lowering. Cholesterol absorption was decreased due to plant sterol consumption, but was not related to circulating LDL-cholesterol concentrations, cholesterol synthesis phenotype or genotypes. rs3808607 and ApoE isoform are associated with the extent of reduction in circulating LDL-cholesterol in response to plant sterol consumption and could serve as potential predictive genetic markers to identify individuals who would derive maximum LDL-cholesterol lowering with plant sterol consumption. These data are of interest to food manufacturers, allied health and medical professionals, and consumers.

Technical Abstract: The benefits of plant sterols (PS) for cholesterol lowering are hampered by large heterogeneity across individuals, potentially due to genetic polymorphisms. We investigated the impact of candidate genetic variations on cholesterol response to PS, in a trial which recruited individuals with high or low endogenous cholesterol synthesis, estimated by lathosterol to cholesterol (L/C) ratio. Mildly hypercholesterolemic adults pre-selected as possessing either high endogenous cholesterol synthesis (HS, n=24, L/C=2.03 ± 0.39µmol/mmol) or low endogenous cholesterol synthesis (LS, n=39, L/C=0.99±0.28µmol/mmol) consumed 2g/d of PS or a placebo for 28 days using a dual-center, single-blind, randomized, crossover design. Cholesterol synthesis and change in cholesterol absorption was measured using stable isotopic tracers. Candidate SNPs and ApoE isoform were assessed by TaqMan genotyping assay. Cholesterol fractional synthesis rate (FSR) was higher in HS participants than LS participants during both placebo and PS period. LDL-C lowering in response to PS associated with individuals’ genotypes. SNP rs3808607-T/T homozygotes showed no LDL-C lowering (-0.05±0.07 mmol/L, p=0.9999, n=20), while the presence of the G allele associated with LDL-C response in a dose dependent fashion (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 e3 carriers (-0.13 ± 0.05 mmol/L, p=0.0370, n=40) responded less than ApoE e4 carriers (-0.31±0.07 mmol/L, p<.0001, n=23). Moreover, genoset CYP7A1-SNP-rs3808607-T/T/ApoE e3 associated with non-responsiveness (+0.09±0.08 mmol/L, p=0.9999, n=14). rs5882 in CETP and rs4148217 in ABCG8 did not associate with LDL-C lowering. Cholesterol absorption was decreased due to PS consumption, but was not related to circulating LDL-C concentrations, cholesterol synthesis phenotype or genotypes. rs3808607 and ApoE isoform are associated with the extent of reduction in circulating LDL-C in response to PS consumption and could serve as potential predictive genetic markers to identify individuals who would derive maximum LDL-C lowering with PS consumption.