SLC30A8 rare variant modify contribution of common genetic and lifestyle factors toward type 2 diabetes

This study aimed to investigate the modifying effects of rare genetic variants on the risk of type 2 diabetes in the context of common genetic and lifestyle factors. We conducted a comprehensive analysis of genetic and lifestyle factors associated with type 2 diabetes in a cohort of 146,284 Korean individuals. Among them, 4,603 individuals developed type 2 diabetes during the follow-up period of up to 18 years. We calculated a polygenic risk score (PRS) for type 2 diabetes and identified carriers of the rare allele I349F at SLC30A8. A Healthy Lifestyle Score (HLS) was also derived from physical activity, obesity, smoking, diet, and sodium intake levels. Using Cox proportional hazards models, we analyzed how PRS, HLS, and I349F influenced type 2 diabetes incidence. Results showed that high PRS and poor lifestyle were associated with increased risk. Remarkably, I349F carriers exhibited a lower type 2 diabetes prevalence (5.4% compared to 11.7% in non-carriers) and reduced the impact of high PRS from 23.18% to 12.70%. This trend was consistent across different HLS categories, with I349F carriers displaying a lower risk of type 2 diabetes. The integration of common and rare genetic variants with lifestyle factors enhanced type 2 diabetes predictability in the Korean population. Our findings highlight the critical role of rare genetic variants in risk assessments and suggest that standard PRS and HLS metrics alone may be inadequate for predicting type 2 diabetes risk among carriers of such variants.