Autoantibodies directed toward a novel IA-2 variant protein enhance prediction of type 1 diabetes

Maria J. Acevedo-Calado; Susan L. Pietropaolo; Michael P. Morran; Santiago Schnell; Andrew D. Vonberg; Charles F. Verge; Roberto Gianani; Dorothy J. Becker; Shuai Huang; Carla J. Greenbaum; Liping Yu; Howard W. Davidson; Aaron W. Michels; Stephen S. Rich; Massimo Pietropaolo

doi:10.2337/db18-1351

Autoantibodies directed toward a novel IA-2 variant protein enhance prediction of type 1 diabetes

Maria J. Acevedo-Calado, Susan L. Pietropaolo, Michael P. Morran, Santiago Schnell, Andrew D. Vonberg, Charles F. Verge, Roberto Gianani, Dorothy J. Becker, Shuai Huang, Carla J. Greenbaum, Liping Yu, Howard W. Davidson, Aaron W. Michels, Stephen S. Rich, Massimo Pietropaolo

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

Weidentified autoantibodies (AAb) reacting with a variant IA-2 molecule (IA-2var) that has three amino acid substitutions (Cys²⁷, Gly⁶⁰⁸, and Pro⁶⁷¹) within the full-length molecule. We examined IA-2var AAb in first-degree relatives of type 1 diabetes (T1D) probands from the TrialNet Pathway to Prevention Study. The presence of IA-2var- specific AAb in relatives was associated with accelerated progression to T1D in those positive for AAb to GAD65 and/or insulin but negative in the standard test for IA-2 AAb. Furthermore, relatives with single islet AAb (by traditional assays) and carrying both IA-2var AAb and the high-risk HLA-DRB1∗04-DQB1∗03:02 haplotype progress rapidly to onset of T1D. Molecular modeling of IA-2var predicts that the genomic variation that alters the three amino acids induces changes in the threedimensional structure of the molecule, which may lead to epitope unmasking in the IA-2 extracellular domain. Our observations suggest that the presence of AAb to IA-2var would identify high-risk subjects who would benefit from participation in prevention trials who have one islet antibody by traditional testing and otherwise would be misclassified as "low risk" relatives.

Original language	English (US)
Pages (from-to)	1819-1829
Number of pages	11
Journal	Diabetes
Volume	68
Issue number	9
DOIs	https://doi.org/10.2337/db18-1351
State	Published - Sep 1 2019
Externally published	Yes

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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Acevedo-Calado, M. J., Pietropaolo, S. L., Morran, M. P., Schnell, S., Vonberg, A. D., Verge, C. F., Gianani, R., Becker, D. J., Huang, S., Greenbaum, C. J., Yu, L., Davidson, H. W., Michels, A. W., Rich, S. S., & Pietropaolo, M. (2019). Autoantibodies directed toward a novel IA-2 variant protein enhance prediction of type 1 diabetes. Diabetes, 68(9), 1819-1829. https://doi.org/10.2337/db18-1351

Acevedo-Calado, MJ, Pietropaolo, SL, Morran, MP, Schnell, S, Vonberg, AD, Verge, CF, Gianani, R, Becker, DJ, Huang, S, Greenbaum, CJ, Yu, L, Davidson, HW, Michels, AW, Rich, SS & Pietropaolo, M 2019, 'Autoantibodies directed toward a novel IA-2 variant protein enhance prediction of type 1 diabetes', Diabetes, vol. 68, no. 9, pp. 1819-1829. https://doi.org/10.2337/db18-1351

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title = "Autoantibodies directed toward a novel IA-2 variant protein enhance prediction of type 1 diabetes",

abstract = "Weidentified autoantibodies (AAb) reacting with a variant IA-2 molecule (IA-2var) that has three amino acid substitutions (Cys27, Gly608, and Pro671) within the full-length molecule. We examined IA-2var AAb in first-degree relatives of type 1 diabetes (T1D) probands from the TrialNet Pathway to Prevention Study. The presence of IA-2var- specific AAb in relatives was associated with accelerated progression to T1D in those positive for AAb to GAD65 and/or insulin but negative in the standard test for IA-2 AAb. Furthermore, relatives with single islet AAb (by traditional assays) and carrying both IA-2var AAb and the high-risk HLA-DRB1∗04-DQB1∗03:02 haplotype progress rapidly to onset of T1D. Molecular modeling of IA-2var predicts that the genomic variation that alters the three amino acids induces changes in the threedimensional structure of the molecule, which may lead to epitope unmasking in the IA-2 extracellular domain. Our observations suggest that the presence of AAb to IA-2var would identify high-risk subjects who would benefit from participation in prevention trials who have one islet antibody by traditional testing and otherwise would be misclassified as {"}low risk{"} relatives.",

author = "Acevedo-Calado, {Maria J.} and Pietropaolo, {Susan L.} and Morran, {Michael P.} and Santiago Schnell and Vonberg, {Andrew D.} and Verge, {Charles F.} and Roberto Gianani and Becker, {Dorothy J.} and Shuai Huang and Greenbaum, {Carla J.} and Liping Yu and Davidson, {Howard W.} and Michels, {Aaron W.} and Rich, {Stephen S.} and Massimo Pietropaolo",

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doi = "10.2337/db18-1351",

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AU - Acevedo-Calado, Maria J.

AU - Pietropaolo, Susan L.

AU - Morran, Michael P.

AU - Schnell, Santiago

AU - Vonberg, Andrew D.

AU - Verge, Charles F.

AU - Gianani, Roberto

AU - Becker, Dorothy J.

AU - Huang, Shuai

AU - Greenbaum, Carla J.

AU - Yu, Liping

AU - Davidson, Howard W.

AU - Michels, Aaron W.

AU - Rich, Stephen S.

AU - Pietropaolo, Massimo

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Weidentified autoantibodies (AAb) reacting with a variant IA-2 molecule (IA-2var) that has three amino acid substitutions (Cys27, Gly608, and Pro671) within the full-length molecule. We examined IA-2var AAb in first-degree relatives of type 1 diabetes (T1D) probands from the TrialNet Pathway to Prevention Study. The presence of IA-2var- specific AAb in relatives was associated with accelerated progression to T1D in those positive for AAb to GAD65 and/or insulin but negative in the standard test for IA-2 AAb. Furthermore, relatives with single islet AAb (by traditional assays) and carrying both IA-2var AAb and the high-risk HLA-DRB1∗04-DQB1∗03:02 haplotype progress rapidly to onset of T1D. Molecular modeling of IA-2var predicts that the genomic variation that alters the three amino acids induces changes in the threedimensional structure of the molecule, which may lead to epitope unmasking in the IA-2 extracellular domain. Our observations suggest that the presence of AAb to IA-2var would identify high-risk subjects who would benefit from participation in prevention trials who have one islet antibody by traditional testing and otherwise would be misclassified as "low risk" relatives.

AB - Weidentified autoantibodies (AAb) reacting with a variant IA-2 molecule (IA-2var) that has three amino acid substitutions (Cys27, Gly608, and Pro671) within the full-length molecule. We examined IA-2var AAb in first-degree relatives of type 1 diabetes (T1D) probands from the TrialNet Pathway to Prevention Study. The presence of IA-2var- specific AAb in relatives was associated with accelerated progression to T1D in those positive for AAb to GAD65 and/or insulin but negative in the standard test for IA-2 AAb. Furthermore, relatives with single islet AAb (by traditional assays) and carrying both IA-2var AAb and the high-risk HLA-DRB1∗04-DQB1∗03:02 haplotype progress rapidly to onset of T1D. Molecular modeling of IA-2var predicts that the genomic variation that alters the three amino acids induces changes in the threedimensional structure of the molecule, which may lead to epitope unmasking in the IA-2 extracellular domain. Our observations suggest that the presence of AAb to IA-2var would identify high-risk subjects who would benefit from participation in prevention trials who have one islet antibody by traditional testing and otherwise would be misclassified as "low risk" relatives.

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Autoantibodies directed toward a novel IA-2 variant protein enhance prediction of type 1 diabetes

Abstract

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