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.