Smoking, GAD65 autoimmunity, genetic susceptibility to type 1 diabetes and incident adult-onset diabetes in the EPIC-InterAct case–cohort study

Aims/hypothesis: Smoking increases the risk of type 2 diabetes, but its role in autoimmune diabetes remains unclear. We investigated whether smoking is associated with being GAD65 autoantibody (GAD65Ab) positive or the risk of progressing to diabetes. We also assessed its interaction with genetic susceptibility to type 1 diabetes. Methods: We used data from the EPIC-InterAct case-cohort study including 11,161 incident cases of adult-onset diabetes and 14,922 subcohort participants. Logistic regression was used to estimate odds ratios (ORs) for being GAD65Ab positive at baseline by smoking status. Hazard ratios (HRs) of diabetes by baseline smoking and GAD65Ab status were estimated using Prentice-weighted Cox regression. Two- and three-way interactions between smoking, GAD65Ab status and a type 1 diabetes genetic risk score (T1D-GRS) were assessed by attributable proportion due to interaction (AP). Results: There was no evidence that smoking was associated with being GAD65Ab positive (OR 1.00, 95% CI 0.82, 1.22 current vs never smoking), but among GAD65Ab-positive participants current smokers were more likely to progress to diabetes than never smokers (HR 1.40, 95% CI 1.03, 1.90) and there was an interaction between being GAD65Ab positive and heavy smoking for diabetes risk (AP 0.32, 95% CI 0.15, 0.49 ≥ 15 pack-years vs never smoking). Three-way interaction between heavy smoking, being GAD65Ab positive and the highest T1D-GRS tertile was also observed (combined HR 7.30, 95% CI 5.17, 10.31; AP 0.46, 95% CI 0.23, 0.70). Conclusions/interpretation: While smoking may not be associated with being GAD65Ab positive, it may increase the risk of progressing to diabetes in GAD65Ab-positive individuals and in those with genetic susceptibility to type 1 diabetes. Supplementary Information: The online version contains supplementary material available at 10.1007/s44357-026-00003-9.