What question did this study set out to answer?

To investigate the association between smoking and GAD65 autoantibody positivity as well as the risk of progressing to diabetes.

April 18, 2026Open Access

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

Puntos clave

To investigate the association between smoking and GAD65 autoantibody positivity as well as the risk of progressing to diabetes.
Analyzed data from the EPIC-InterAct case-cohort study with incident cases of diabetes and subcohort participants.
Employed logistic regression to estimate the odds of being GAD65Ab positive by smoking status.
Used Cox regression to estimate hazard ratios of diabetes based on baseline smoking and GAD65Ab status.
Assessed interactions between smoking, GAD65Ab status, and genetic susceptibility using attributable proportions.
No association between smoking and being GAD65Ab positive was found.
Current smokers who were GAD65Ab positive had a 40% higher risk of progressing to diabetes.
Strong interaction noted between heavy smoking and GAD65Ab status, suggesting increased diabetes risk.
Combined effect of heavy smoking, GAD65Ab positivity, and high genetic risk score significantly increased diabetes risk.

Resumen

Abstract 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. Graphical Abstract

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