Genosets for APOE and CYP7A1-rs3808607 variants do not predict low-density lipoprotein cholesterol lowering upon intervention with plant sterols in a randomized, double-blind, placebo-controlled trial.

BACKGROUND The consumption of 2 g/d plant sterols (PS) reduces circulating low-density lipoprotein cholesterol (LDL-C) up to 10%. The degree of LDL-C lowering was associated with specific apolipoprotein E (APOE, rs429358) and cholesterol 7α-hydroxylase (CYP7A1, rs3808607) genosets in previous post hoc analyses of randomized controlled trials. However, since post-hoc analyses do not conform to the randomization model, there is a greater potential that the findings may be due to type I error, thus warranting validation through an a priori-designed intervention trial. OBJECTIVE The GenePredict Plant Sterol study (GPS) was designed to validate associations of LDL-C lowering with specific APOE and CYP7A1 genosets through a priori recruitment of individuals carrying pre-specified genosets. METHODS A two center, double-blind, placebo-controlled, randomized two-period crossover dietary intervention with 2 g/d of PS for 28 days with a minimum 28 day washout was undertaken from July 2017 to December 2019. A priori recruitment of individuals with slightly elevated LDL-C was based on genosets of APOE isoforms and CYP7A1 rs3808607. Randomization was performed with stratification by sex and genoset. RESULTS The recruitment target of 64 participants with pre-specified genosets could not be reached, despite the screening of 477 individuals; 42 participants completed the intervention trial. Reductions in LDL-C were similar across all three genosets (-0.298 ±0.164, -0.357 ±0.115, -0.293 ±0.109 mmol/L, P = 0.0002 overall, P = 0.9126 for treatment*genoset), providing evidence that the shortfall in recruitment may not have stopped the trial from meeting the objective. CONCLUSIONS APOE and CYP7A1 genotypes did not influence the efficacy of LDL-C reductions upon dietary intervention with PS. Findings of previous post-hoc analyses could not be validated in a trial using a priori genotype-based recruitment. Obtaining adequate numbers of participants is challenging in trials using genoset-based recruitment, even for common variants.Trial Registration: Clinical Trials #NCT02765516 https://clinicaltrials.gov/ct2/show/NCT02765516.