Gene–Lifestyle Interactions in Renal Dysfunction: Polygenic Risk Modulation via Plant-Based Diets, Coffee Intake, and Bioactive Compound Interactions

<b>Background:</b> This study aimed to investigate genetic variants associated with the estimated glomerular filtration rate (eGFR) and their interactions with lifestyle factors and bioactive compounds in large hospital-based cohorts, assessing their impact on renal dysfunction risk. <b>Methods:</b> Participants were categorized into two groups based on eGFR: High-GFR (control; <i>n</i> = 51,084) and Low-GFR (renal dysfunction; <i>n</i> = 7617), using an eGFR threshold of 60 mL/min/1.73 m². Genetic variants were identified through a genome-wide association analysis, and their interactions with lifestyle factors were assessed a using generalized multifactor dimensionality reduction (GMDR) analysis. Additionally, interactions between polygenic risk scores (PRS) and nutrient intake were examined. <b>Results:</b> Low eGFR was associated with higher urinary protein levels (4.67-fold) and correlated with a Western-style diet and with saturated fat, arginine, and isoleucine intakes but not sodium intake. The genetic model for low eGFR included variants linked to energy production and amino acid metabolism, such as rs1047891_<i>CPS1</i>, rs3770636_<i>LRP2</i>, rs5020545_<i>SHROOM3</i>, rs3812036_<i>SLC34A1</i>, and rs4715517_<i>HCRTR2</i>. A high PRS was associated with a 1.78-fold increased risk of low eGFR after adjusting for sociodemographic and lifestyle factors. The PRS from the 6-SNP model interacted with plant-based diets (PBDs) and coffee intake, where individuals with higher PBD and coffee consumption had a lower risk of renal dysfunction. Additionally, <i>CPS1</i> rs1047891 interacted with vitamin D intake (<i>p</i> = 0.0436), where the risk allele was linked to lower eGFR with low vitamin D intake but not with high intake. Molecular docking showed that vitamin D3 had a lower binding energy to the CPS1 mutant type (-9.9 kcal/mol) than the wild type (-7.5 kcal/mol), supporting a potential gene-nutrient interaction influencing renal function. <b>Conclusions:</b> Middle-aged and elderly individuals with a high genetic risk for renal dysfunction may benefit from a plant-based diet, moderate coffee consumption, and sufficient vitamin D intake.