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. Author summaryIn our study, we investigated how rare genetic variants affect the risk of developing type 2 diabetes, particularly when combined with common genetic and lifestyle factors. We analyzed data from over 146,000 Korean individuals, following their health outcomes for up to 18 years. During this time, 4,603 participants developed type 2 diabetes. We calculated a polygenic risk score (PRS) based on common genetic variants and examined lifestyle factors such as physical activity, diet, and smoking. We also identified individuals carrying a rare genetic variant (I349F) in the SLC30A8 gene, which appeared to have a protective effect against type 2 diabetes. Our findings show that individuals with high PRS and unhealthy lifestyles are at increased risk for the disease. However, those carrying the I349F variant had a significantly lower risk, even among those with high PRS and poor lifestyle habits. This suggests that rare genetic variants can play a crucial role, and that combining genetic and lifestyle factors provides a more accurate prediction of diabetes risk. Our work highlights the importance of including rare genetic variants in personalized risk assessments for type 2 diabetes.