3004-LB: DNA Methylation and Glycemic Control in Children at Risk for Type 1 Diabetes

Introduction and Objective: Hyperglycemia leads to hypomethylation of the thioredoxin-interacting protein gene TXNIP, causing its overexpression, oxidative stress, and inflammation. DCCT has demonstrated an association between higher A1c, TXNIP hypomethylation, and microvascular complications. In presymptomatic T1D, TXNIP overexpression in beta cells activates apoptosis and accelerates progression to insulin dependency; however, the role of dysglycemia and methylation is unknown. We explored the relationship between A1c and TXNIP methylation in children with presymptomatic T1D prospectively followed by the DAISY and TEDDY studies. Methods: Multivariable linear regression modeled the association between methylation measured with the 450K or EPIC array and A1c, prior to A1c = 6.5% or T1D diagnosis. Linear mixed effects models determined changes in methylation with age in TEDDY (subjects = 204, samples = 1,407) and DAISY (subjects = 420, samples = 932). We evaluated changes in gene expression due to methylation in TEDDY children via targeted expression quantitative trait methylation analysis. Results: Fifteen of 23 candidate CpGs (65%) reported by DCCT as associated with A1c had directionally concordant A1c-methylation effects in DAISY at pre-clinical levels of A1c (range: 4.7-6.4%). Methylation at cg19266329, near TXNIP, was inversely associated with A1c (est = -0.16; P = 0.01) in DAISY and decreased with age in both DAISY (est = -3.0; P = 0.003) and TEDDY (est = -8.4; P = 1.87e-16). Lower methylation at cg19266329 was associated with higher expression of TXNIP (est = -0.22; P = 0.0003). Conclusion: Youth with islet autoimmunity had dysglycemia-driven methylation patterns similar to those observed in adults with established T1D. Higher A1c resulted in hypomethylation and overexpression of TXNIP, currently a therapeutic target for stage 3 T1D prevention trials using TXNIP inhibitors, e.g., verapamil or SRI-37330 hydrochloride. TXNIP methylation may be an alternative therapeutic target for the prevention of stage 3 T1D and diabetes complications. Disclosure S.E. Ridoux: None. S.D. Slack: None. K. Hohsfield: None. D. Dabelea: None. M. Rewers: Consultant; Current; Sanofi. Advisory Panel; Current; Vertex Pharmaceuticals Incorporated. J. Norris: None. C. Kim: None. R.K. Johnson: None. Funding NIDDK (R01DK032493), NIDDK (R01DK104351), Foundation for Women's Health