Gene‐Lifestyle Interplay in Type 1 Diabetes: Joint Effects and Interactions From Cross‐Sectional and Longitudinal Cohort Analyses

BACKGROUND: Type 1 diabetes (T1D) is a complex autoimmune disorder heavily influenced by heritable traits. However, the interplay between modifiable lifestyle factors and genetic susceptibility remains insufficiently characterised. This study sought to elucidate how genetic background and lifestyle determinants jointly affect T1D liability. METHODS: Utilising the UK Biobank cohort, we performed both cross-sectional and longitudinal assessments. A polygenic risk score (PRS) was computed to quantify genetic predisposition to T1D across 403,778 subjects. Concurrently, a composite lifestyle index was generated based on six domains: adiposity, smoking status, alcohol intake, physical exertion, diet quality, and sleep duration. We evaluated cross-sectional relationships using multivariable logistic regression and assessed longitudinal outcomes using Cox proportional hazard models. RESULTS: In a 15-year longitudinal study (median follow-up: 12.3 years) of 402,005 participants, 1474 cases of T1D were identified. Stratified by genetic risk, participants in the intermediate (hazard ratio [HR] = 1.17; 95% CI: 1.00-1.37) and highest (HR = 2.89; 95% CI: 2.46-3.39) risk groups demonstrated significantly elevated risks of incident T1D compared to the lowest risk group, independent of lifestyle factors. Conversely, when categorised by lifestyle patterns, both intermediate (HR = 0.61; 95% CI: 0.52-0.71) and healthy (HR = 0.43; 95% CI: 0.37-0.52) lifestyle groups exhibited substantially reduced risks of T1D compared to the unhealthy lifestyle group, irrespective of genetic predisposition. A significant interaction between genetic risk and lifestyle on the risk of T1D was found in both cross-sectional and longitudinal analyses (p < 0.001). CONCLUSIONS: The data reveal a robust inverse relationship between adherence to a healthy lifestyle and T1D incidence across all genetic strata, even among those with elevated hereditary risk. These results underscore the critical role of lifestyle modification in mitigating T1D susceptibility, distinct from genetic inheritance.