Effect of healthy lifestyle on renal dysfunction risk: interactions with genetic risk

Abstract

Background Whether adherence to a healthy lifestyle can mitigate genetic risk for renal dysfunction remains unclear. Methods This prospective cohort study included 12 680 adults aged ≥20 years, free from chronic kidney disease at baseline, enrolled in the Tohoku Medical Megabank Community-based Cohort study. A healthy lifestyle score - based on normal weight, never smoking, never drinking, regular physical activity, and a low urinary sodium-to-potassium ratio - classified participants into ideal, intermediate, or poor lifestyle groups. A polygenic risk score (PRS) was constructed using estimated glomerular filtration rate (eGFR) data from a previous multi-ancestry genome-wide association meta-analysis. The primary outcome was renal dysfunction, defined as eGFR <60.0 ml/min/1.73 m2. Results Among the 12 680 adults, 123 participants (0.9%) developed renal dysfunction during a mean follow-up of 4.4±0.8 years. Poor lifestyle was consistently associated with higher risk of renal dysfunction across most PRS categories. Participants with intermediate genetic risk had elevated risk only when also exhibiting an intermediate lifestyle. Formal testing for effect modification by PRS provided modest evidence that the association between high genetic risk and increased risk of renal dysfunction was stronger among individuals with an intermediate lifestyle. Although the addition of the PRS to the model included the C-statistic, this improvement was not statistically significant. Conclusions Maintaining a healthy lifestyle is associated with lower risk of renal dysfunction, regardless of genetic risk. Combining PRSs with lifestyle information may enhance risk stratification, although further studies are needed to improve predictive accuracy.