rs11203203 is associated with type 1 diabetes risk in population pre-screened for high-risk HLA-DR,DQ genotypes

Objective To evaluate UBASH3A (rs11203203) as a predictor of persistent islet autoimmunity (IA) and type 1 diabetes (T1D). Research design and methods The Diabetes Autoimmunity Study in the Young (DAISY) followed prospectively for development of persistent IA (autoantibodies to insulin, GAD65, IA‐2, or ZnT8 on at least two consecutive exams) and diabetes 1715 non‐Hispanic white children at increased genetic risk for T1D. The DAISY participants were genotyped for rs11202203 (UBASH3A). Results UBASH3A allele A was associated with development of IA [hazard ratio (HR) = 1.46, 95%CI = 1.11–1.91, p = 0.007] and diabetes (HR = 1.84, 95%CI = 1.28–2.64, p = 0.001), controlling for presence of HLA‐DR3/4,DQB1*0302 and having a first‐degree relative (FDR) with T1D. The UBASH3A AA genotype conferred higher risk of persistent IA (12.7%) and diabetes (6.1%) by age 10 than for AG (7.7 and 3.1%, respectively) or GG (5.3 and 2.0%) genotype (p = 0.009 for IA, p = 0.0004 for diabetes). Among children with no family history of T1D, but HLA‐DR3/4,DQB1*0302 and UBASH3A AA genotype, 35.9% developed IA and 50.6% developed diabetes by age 15. Conclusions UBASH3A appears to be an independent predictor of IA and T1D in children, including those free of family history of T1D but carrying the HLA‐DR3/4,DQB1*0302 genotype. If confirmed, UBASH3A may prove useful in T1D risk prediction and pre‐screening of the general population children for clinical trials.