Background: Diet is one of the most significant modifiable lifestyle factors influencing human health, contributing to both morbidity and mortality. Genetic variations in the pleiotropic 9p21 risk locus further shape premature aging, disease susceptibility, and have been strongly linked to cardiovascular disease (CVD), metabolic disorders, certain cancers, and neurodegenerative conditions. However, given that this region was discovered based on Genome-Wide Association Studies, the mechanisms by which 9p21 exerts its effects remain poorly understood and its interactions with diet and biomarkers are insufficiently explored. Methods: This study investigated the association between the rs2383206 SNP in 9p21, dietary patterns, and plasma proteomic biomarkers in a multi-ethnic cohort of 1280 young adults from the Toronto Nutrigenomics and Health Study. Participants' dietary intake was assessed using a validated food frequency questionnaire, and dietary patterns were categorized using principal component analysis. Plasma proteomics analyses quantified 54 abundant proteins involved in the cardiometabolic and inflammatory pathways. Genotyping identified individuals who were homozygous for the 9p21 risk allele (GG), known to confer the highest susceptibility risk to premature aging and multiple chronic diseases. Results: A significant interaction was observed between the 9p21 genotype and adherence to a micronutrient-rich Prudent dietary pattern for eight plasma proteins (α1 Antichymotrypsin, Complement C4 β chain, Complement C4 γ chain, Complement C9, Fibrinogen α chain, Hemopexin, and Serum amyloid P-component). However, only Complement C4-γ showed a pattern consistent with the risks associated with the 9p21 genotype and adherence to a Prudent diet. Individuals with the high-risk GG genotype had significantly higher concentrations of Complement C4-γ, but only among those with a low adherence to a Prudent diet. Conclusions: These findings suggest that Prudent dietary patterns rich in micronutrients may counteract genetic-mediated proinflammatory susceptibility by modulating key proteomic biomarkers in young adults, highlighting the potential for tailored dietary interventions to mitigate disease risk. This study also introduces a novel framework for post hoc micronutrient resolution within dietary pattern analysis, offering a new lens to interpret nutrient synergies in gene-diet interaction research.
Keywords: 9p21 genetic variant; complement C4-γ; dietary patterns; gene–diet interaction; micronutrients; plasma proteomics.