Genetic basis for heterogeneity of response of LDL cholesterol to plant sterols
Stapenhorst MacKay, Dylan
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Plant sterols (PS) share a similar chemical structure to cholesterol, differing only in side chains and double bond placement. PS are naturally found in plants and are typically ingested in the 400mg/day range. Consumption of 1-3 g of PS a day has been repeatedly shown to lower total and LDL cholesterol. However, data from nutritional trials involving plant sterols demonstrate considerable inter-individual variations in response to PS consumption. The objective of this research was to investigate the metabolic and genetic factors that underlie this heterogeneity of responsiveness of LDL cholesterol to PS consumption. A study was conducted to test the effectiveness of lathosterol to cholesterol ratio (L/C), a surrogate marker of cholesterol synthesis, as a predictor of LDL cholesterol lowering in response to plant sterol consumption. 63 mildly hypercholesterolemic adults, with high (n=24, L/C = 2.03 ± 0.39umol/mmol) or low (n=39, L/C =0.99±0.28 umol/mmol) L/C ratio at baseline, consumed either 0 or 2g/d of PS for 28 days in a dual-center, single-blind, randomized, crossover design. Plasma lipid and non-cholesterol sterol concentrations were measured at the end of each phase. Single nucleotide polymorphisms (SNPs) in candidate genes involved in cholesterol metabolism were investigated for potential gene by nutrient interactions. Plant sterol consumption lowered total and LDL cholesterol concentrations overall, but only individuals with low L/C ratio responded to plant sterol treatment by lowering TC and LDL-C, while individuals with high L/C ratio showed no marked improvement. The rs3808607 T-allele in the promoter of the CYP7A1 gene was associated with decreased LDL-C responsiveness to PS consumption. The rs3808607 G-allele and ApoE ε4 were associated with increased LDL-C responsiveness to PS consumption. PS consumption did not lower TG overall (p=0.0506), but had an interaction with rs5882 in CETP (p=0.0080). Baseline L/C predicts LDL-C lowering due to PS consumption, which is associated with rs3808607 genotype in the promoter of the CYP7A1 gene. rs5882 in CETP is associated with TG lowering due to PS consumption. rs3808607, rs5882 and ApoE variant are potential genetic markers which could identify individuals who would derive maximum benefit from PS consumption.