Exploratory whole-exome analysis of low-density lipoprotein cholesterol and triglyceride response to Mediterranean-style dietary guidance: a focus on plasma lipoprotein pathways

Objectives Inter-individual variability in lipid response to dietary modification highlights the critical need for precision nutrition. Current evidence remains fragmented, relying predominantly on restricted candidate-gene studies rather than comprehensive genomic approaches. To bridge this gap, we applied a biologically informed analytical framework to whole-exome sequencing (WES) data to evaluate the nutrigenetics of lipid response in an underrepresented Georgian cohort. Specifically, we explored whether exome-wide and pathway-aggregated genetic variation may contribute to inter-individual differences in LDL cholesterol (ΔLDL-C) and triglyceride (ΔTAG) response to Mediterranean-style dietary guidance. Methods A longitudinal study was conducted with 51 dyslipidemic patients who received Mediterranean-style dietary guidance for at least 2 months. High-depth whole-exome sequencing (mean 112×) was performed, and a parallel analytical approach was used: an exploratory exome-wide association analysis to screen for nominal variant-level signals, and a targeted gene-level analysis of the ‘Plasma Lipoprotein Assembly, Remodeling, and Clearance’ pathway to prioritize biologically plausible signals. Results The intervention resulted in mean reductions of 33.5 mg/dL in LDL-C and 18.6 mg/dL in TAG. Exome-wide screening identified no variants reaching exome-wide significance. The lowest nominal p -values were observed for ΔLDL-C at KIF6 ( p = 4.87 × 10 −7 ; FDR = 0.122) and for ΔTAG at SLC35F2 ( p = 3.08 × 10 −6 ; FDR = 0.521). These results were therefore reported only descriptively, without biological interpretation as candidate diet-response loci. In the targeted Reactome pathway analysis, APOC3 was the top-ranked ΔLDL-C gene-level signal and the only pathway-level result surviving FDR correction (Simes p = 7.84 × 10 −4 ; FDR = 0.0361), whereas no ΔTAG pathway-level result survived FDR correction. Variant-level inspection showed that the APOC3 signal was driven primarily by an intronic variant with low model-specific genotype-complete sample size ( N = 10), supporting interpretation as a hypothesis-generating locus-level signal rather than confirmatory evidence of a gene-diet association. Conclusion This exploratory WES study provides a pragmatic framework for pathway-focused nutrigenomic analysis of lipid response in an underrepresented clinical cohort. The results prioritize APOC3 as a hypothesis-generating LDL-C response locus, while emphasizing the need for larger replication studies before gene-diet associations can be inferred.