Genetic variants linked to statin-associated Type 2 diabetes mellitus: Findings from the UK Biobank and the All of Us Research Program

Background and Purpose: Statins are widely prescribed for the prevention of cardiovascular disease, yet recent studies suggest an increased risk of new-onset Type 2 diabetes mellitus. This study aimed to identify genetic variants associated with statin-associated new-onset Type 2 diabetes mellitus from the UK Biobank and All of Us. Experimental Approach: Among statin users, cases were defined as those diagnosed with Type 2 diabetes mellitus after statin initiation and controls as those never having diabetes mellitus. A genome-wide association study (GWAS) was performed using logistic regression analysis with an additive model using the UK Biobank. We conducted a replication analysis in the All of Us cohort using the lead variants identified in the UK Biobank. Additionally, we tested interaction analyses between statin use and lead variants. Key Results: The GWAS identified four significant lead variants. The most significant, TCF7L2 rs7903146, increased risk of new-onset Type 2 diabetes mellitus by 1.3-fold. Similarly, POU5F1 rs879882 was associated with a higher risk. By contrast, CCND2 rs76895963 and ADCY5 rs35841686 were associated with a lower risk. In the replication analysis of the All of Us cohort, TCF7L2 rs7903146, CCND2 rs76895963 and POU5F1 rs879882 remained significant. In the interaction analyses, those three lead variants also exhibited additive interactions with statin use. Conclusion and Implications: These findings provide insights that may support personalized statin therapy to mitigate diabetic risk.