Associations of Combined Genetic and Lifestyle Risks with Incident Type 2 Diabetes in the UK Biobank.

Background: Type 2 diabetes (T2D) results from a complex interplay between genetic predisposition and lifestyle factors. Both genetic susceptibility and unhealthy lifestyle are known to be associated with elevated T2D risk. However, their combined effects on T2D risk are not well studied. We aimed to determine whether unhealthy modifiable health behaviors were associated with similar increases in the risk of incident T2D among individuals with different levels of genetic risk.

Methods: We performed a genetic risk score (GRS) by lifestyle interaction analysis within 332,251 non-diabetic individuals at baseline from the UK Biobank. Multi-ancestry GRS were calculated by summing the effects of 783 T2D-associated variants and ranked into tertiles. We used baseline self-reported data on smoking, BMI, physical activity level, and diet quality to categorize participants as having a healthy, intermediate, or unhealthy lifestyle. Cox proportional hazards regression models were used to generate adjusted hazards ratios (HR) of T2D risk and associated 95% confidence intervals (CI).

Results: During follow-up (median 13.6 years), 13,128 (4.0%) participants developed T2D. GRS ( < 0.001) and lifestyle classification ( < 0.001) were independently associated with increased risk for T2D. Compared with healthy lifestyle, unhealthy lifestyle was associated with increased T2D risk in all genetic risk strata, with adjusted HR ranging from 7.11 (low genetic risk) to 16.33 (high genetic risk).

Conclusions: High genetic risk and unhealthy lifestyle were the most significant contributors to the development of T2D. Individuals at all levels of genetic risk can greatly mitigate their risk for T2D through lifestyle modifications.