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

Authors

Saba Iordanishvili, Nazibrola Chiradze, Dodo Agladze, Marine Kikvidze, Zaza Khuchua, Vincenzo Lagani, Revaz Solomonia

Published in

Frontiers in nutrition. Volume 13. Pages 1827989. Epub Jul 16, 2026.

Abstract

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.
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.
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.
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.

PMID:
42534588
Bibliographic data and abstract were imported from PubMed on 31 Jul 2026.

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