PMID- 26606528 OWN - NLM STAT- MEDLINE DCOM- 20160627 LR - 20220409 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 10 IP - 11 DP - 2015 TI - Use of a High-Density Protein Microarray to Identify Autoantibodies in Subjects with Type 2 Diabetes Mellitus and an HLA Background Associated with Reduced Insulin Secretion. PG - e0143551 LID - 10.1371/journal.pone.0143551 [doi] LID - e0143551 AB - 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 and suggests the presence of unidentified autoantibodies. While high-density protein microarrays have emerged as a useful technology to identify possible novel autoantigens in autoimmune diseases, its application in T2DM has lagged. In Pima Indians, the HLA haplotype (HLA-DRB1*02) is protective against T2DM and, when studied when they have normal glucose tolerance, subjects with this HLA haplotype have higher insulin secretion compared to those without the protective haplotype. Possible autoantibody biomarkers were identified using microarrays containing 9480 proteins in plasma from Pima Indians with T2DM without the protective haplotype (n = 7) compared with those with normal glucose regulation (NGR) with the protective haplotype (n = 11). A subsequent validation phase involving 45 cases and 45 controls, matched by age, sex and specimen storage time, evaluated 77 proteins. Eleven autoantigens had higher antibody signals among T2DM subjects with the lower insulin-secretion HLA background compared with NGR subjects with the higher insulin-secretion HLA background (p<0.05, adjusted for multiple comparisons). PPARG2 and UBE2M had lowest p-values (adjusted p = 0.023) while PPARG2 and RGS17 had highest case-to-control antibody signal ratios (1.7). A multi-protein classifier involving the 11 autoantigens had sensitivity, specificity, and area under the receiver operating characteristics curve of 0.73, 0.80, and 0.83 (95% CI 0.74-0.91, p = 3.4x10-8), respectively. This study identified 11 novel autoantigens which were associated with T2DM and an HLA background associated with reduced insulin secretion. While further studies are needed to distinguish whether these antibodies are associated with insulin secretion via the HLA background, T2DM more broadly, or a combination of the two, this study may aid the search for autoantibody biomarkers by narrowing the list of protein targets. FAU - Chang, Douglas C AU - Chang DC AD - Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States of America. FAU - Piaggi, Paolo AU - Piaggi P AD - Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States of America. FAU - Hanson, Robert L AU - Hanson RL AD - Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States of America. FAU - Knowler, William C AU - Knowler WC AD - Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States of America. FAU - Bucci, John AU - Bucci J AD - Life Technologies, Carlsbad, California, United States of America. FAU - Thio, Guene AU - Thio G AD - Life Technologies, Carlsbad, California, United States of America. FAU - Hohenadel, Maximilian G AU - Hohenadel MG AD - Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States of America. FAU - Bogardus, Clifton AU - Bogardus C AD - Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States of America. FAU - Krakoff, Jonathan AU - Krakoff J AD - Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States of America. LA - eng GR - Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural DEP - 20151125 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Autoantibodies) RN - 0 (Biomarkers) RN - 0 (HLA Antigens) RN - 0 (Insulin) RN - 0 (PPAR gamma) RN - EC 2.3.2.23 (Ubiquitin-Conjugating Enzymes) RN - EC 6.3.2.- (UBE2M protein, human) SB - IM MH - Adolescent MH - Adult MH - Autoantibodies/*immunology MH - Biomarkers MH - Cohort Studies MH - Diabetes Mellitus, Type 2/diagnosis/*etiology/*metabolism MH - Female MH - HLA Antigens/*genetics/metabolism MH - Haplotypes MH - Humans MH - Insulin/*metabolism MH - Insulin Secretion MH - Male MH - Middle Aged MH - PPAR gamma/metabolism MH - *Protein Array Analysis MH - Sensitivity and Specificity MH - Ubiquitin-Conjugating Enzymes/metabolism MH - Young Adult PMC - PMC4659622 COIS- Competing Interests: The authors J.B. and G.T. are employed by Life Technologies, a commercial company. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. EDAT- 2015/11/26 06:00 MHDA- 2016/06/28 06:00 PMCR- 2015/11/25 CRDT- 2015/11/26 06:00 PHST- 2015/07/27 00:00 [received] PHST- 2015/11/05 00:00 [accepted] PHST- 2015/11/26 06:00 [entrez] PHST- 2015/11/26 06:00 [pubmed] PHST- 2016/06/28 06:00 [medline] PHST- 2015/11/25 00:00 [pmc-release] AID - PONE-D-15-32945 [pii] AID - 10.1371/journal.pone.0143551 [doi] PST - epublish SO - PLoS One. 2015 Nov 25;10(11):e0143551. doi: 10.1371/journal.pone.0143551. eCollection 2015.