DNA Methylation Smoking Scores and Risk of Islet Autoimmunity and Type 1 Diabetes

Objective: Multiple studies have reported an inverse association between self-reported smoking during pregnancy and offspring type 1 diabetes (T1D) risk. We investigated the association between DNA methylation (DNAm) smoke exposure scores, parental self-reported smoking and islet autoimmunity (IA) and T1D risk in children at high-risk for T1D. Research Design and Methods: We used longitudinal data from the Diabetes Autoimmunity Study in the Young (DAISY) cohort, including 205/206 IA cases/controls (87/88 were T1D cases/controls), matched by age, race/ethnicity, and sample availability. DNAm profiles were obtained from cord or peripheral blood using the Infinium HumanMethylation450K or EPIC Beadchip. Three published DNAm smoking scores were calculated at every timepoint. To estimate in utero smoke exposure, subject-specific intercepts were derived from mixed-effects models of longitudinal DNAm scores. These intercepts strongly correlated with a cord blood scores (r: 0.85-0.95, n =179), indicating their utility as proxies for in utero smoke exposure. Associations with IA/T1D were evaluated using logistic regression, adjusting for HLA-DR3/4, first-degree relative status and sex. Results: Multivariable models showed both maternally reported smoking during pregnancy and higher DNAm smoking scores associated with lower risk of IA and T1D. Maternal smoking showed a strong inverse association with IA (OR = 0.24, 95% CI: 0.10–0.54). Rauschert and McCartney DNAm scores showed consistent inverse associations with both outcomes (ORs 0.65 to 0.83 for a SD increase). Conclusions: Our study supports existing literature, indicating in utero smoke exposure is associated with a reduced IA and T1D risk. Further research is essential to uncover the underlying mechanisms.