Identification of Novel Autoantibodies Including Anti-PPARG among Individuals with Type 2 Diabetes

New biomarkers for type 2 diabetes mellitus (T2DM) may aid diagnosis, drug development or clinical treatment. Evidence is increasing for the adaptive immune system’s role in T2DM. To search for novel autoantibody biomarkers, a protein microarray including 9480 human proteins was screened with plasma from Pima Indians with T2DM without an HLA haplotype (HLA-DRB1*02) protective for T2DM compared with Pimas with normal glucose regulation (NGR) with the protective haplotype. Among 77 proteins evaluated in a subsequent validation phase including 45 matched cases and controls for T2DM, 11 autoantigens had higher antibody signals among T2DM subjects compared with NGR subjects (p<0.05, adjusted for multiple comparisons). PPARG2 and UBE2M had the lowest p-values (adj. p=0.023) while PPARG2 and RGS17 had the highest signal ratios (1.7). Prevalence of antibodies for PPARG2, UBE2M and RGS17 were 17%, 26%, and 34%, respectively, in the T2DM group, and 2%, 6%, and 15%, respectively, in the NGR group. A multi-protein classifier involving the 11 significant autoantigens achieved a sensitivity of 0.73, specificity 0.80, accuracy 0.77, and area under the receiver operating characteristics curve 0.83 (95% confidence interval: 0.74-0.91, p=3.4x10-8). This study identified 11 novel autoantigens associated with T2DM which both aids the search for new biomarkers and supports the adaptive immune system’s role in T2DM.