Detection of antibodies directed to the N-terminal region of GAD is dependent on assay format and contributes to differences in the specificity of GAD autoantibody assays for type 1 diabetes

Alistair Williams; Vito Lampasona; Schlosser Michael; Patricia Mueller; David Pittman; William Winter; Beena Akolkar; Rebecca Wyatt; Cristina Brigatti; Stephanie Krause; Peter Achenbach

doi:10.2337/db14-1693

Detection of antibodies directed to the N-terminal region of GAD is dependent on assay format and contributes to differences in the specificity of GAD autoantibody assays for type 1 diabetes

Alistair Williams, Vito Lampasona, Schlosser Michael, Patricia Mueller, David Pittman, William Winter, Beena Akolkar, Rebecca Wyatt, Cristina Brigatti, Stephanie Krause, Peter Achenbach

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

Autoantibodies to glutamate decarboxylase (GADA) are sensitive markers of islet autoimmunity and type 1 diabetes. They form the basis of robust prediction models and are widely used for recruitment of subjects at high risk of type 1 diabetes to prevention trials. However GADA are also found in many individuals at low risk of diabetes progression. To identify the sources of diabetes irrelevant GADA reactivity therefore, we analyzed data from the 2009 and 2010 Diabetes Autoantibody Standardization Program GADA workshop and found that binding of healthy control sera varied according to assay type. Characterization of control sera found positive by radiobinding assay, but negative by ELISA showed that many of these sera reacted to epitopes in the N-terminal region of the molecule. This finding prompted development of an N-terminally truncated GAD65 radiolabel, 35S-GAD65(96-585), which improved the performance of most GADA radiobinding assays (RBAs) participating in an Islet Autoantibody Standardization Program GADA substudy. These detailed workshop comparisons have identified a source of disease-irrelevant signals in GADA RBAs and suggest that N-terminally truncated GAD labels will enable more specific measurement of GADA in type 1 diabetes.

Original language	English
Pages (from-to)	3239-3246
Number of pages	18
Journal	Diabetes
Volume	64
Issue number	9
Early online date	13 May 2015
DOIs	https://doi.org/10.2337/db14-1693
Publication status	Published - 1 Sept 2015

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This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at http://diabetes.diabetesjournals.org.
Accepted author manuscript, 156 KB
Supplementary information PDF - Figures (Diabetes)Accepted author manuscript, 174 KB
Supplementary information PDF - Supplementary FiguresAccepted author manuscript, 145 KB
Supplementary information PDF - Table 1Accepted author manuscript, 10.8 KB
Supplementary information PDF - Participating Laboratories and contacts for the DASP and IASP GADA workshopsAccepted author manuscript, 79.6 KB

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Williams, A., Lampasona, V., Michael, S., Mueller, P., Pittman, D., Winter, W., Akolkar, B., Wyatt, R., Brigatti, C., Krause, S., & Achenbach, P. (2015). Detection of antibodies directed to the N-terminal region of GAD is dependent on assay format and contributes to differences in the specificity of GAD autoantibody assays for type 1 diabetes. Diabetes, 64(9), 3239-3246. https://doi.org/10.2337/db14-1693

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title = "Detection of antibodies directed to the N-terminal region of GAD is dependent on assay format and contributes to differences in the specificity of GAD autoantibody assays for type 1 diabetes",

abstract = "Autoantibodies to glutamate decarboxylase (GADA) are sensitive markers of islet autoimmunity and type 1 diabetes. They form the basis of robust prediction models and are widely used for recruitment of subjects at high risk of type 1 diabetes to prevention trials. However GADA are also found in many individuals at low risk of diabetes progression. To identify the sources of diabetes irrelevant GADA reactivity therefore, we analyzed data from the 2009 and 2010 Diabetes Autoantibody Standardization Program GADA workshop and found that binding of healthy control sera varied according to assay type. Characterization of control sera found positive by radiobinding assay, but negative by ELISA showed that many of these sera reacted to epitopes in the N-terminal region of the molecule. This finding prompted development of an N-terminally truncated GAD65 radiolabel, 35S-GAD65(96-585), which improved the performance of most GADA radiobinding assays (RBAs) participating in an Islet Autoantibody Standardization Program GADA substudy. These detailed workshop comparisons have identified a source of disease-irrelevant signals in GADA RBAs and suggest that N-terminally truncated GAD labels will enable more specific measurement of GADA in type 1 diabetes.",

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Williams, A, Lampasona, V, Michael, S, Mueller, P, Pittman, D, Winter, W, Akolkar, B, Wyatt, R, Brigatti, C, Krause, S & Achenbach, P 2015, 'Detection of antibodies directed to the N-terminal region of GAD is dependent on assay format and contributes to differences in the specificity of GAD autoantibody assays for type 1 diabetes', Diabetes, vol. 64, no. 9, pp. 3239-3246. https://doi.org/10.2337/db14-1693

Detection of antibodies directed to the N-terminal region of GAD is dependent on assay format and contributes to differences in the specificity of GAD autoantibody assays for type 1 diabetes. / Williams, Alistair; Lampasona, Vito; Michael, Schlosser et al.
In: Diabetes, Vol. 64, No. 9, 01.09.2015, p. 3239-3246.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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T1 - Detection of antibodies directed to the N-terminal region of GAD is dependent on assay format and contributes to differences in the specificity of GAD autoantibody assays for type 1 diabetes

AU - Williams, Alistair

AU - Lampasona, Vito

AU - Michael, Schlosser

AU - Mueller, Patricia

AU - Pittman, David

AU - Winter, William

AU - Akolkar, Beena

AU - Wyatt, Rebecca

AU - Brigatti, Cristina

AU - Krause, Stephanie

AU - Achenbach, Peter

PY - 2015/9/1

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N2 - Autoantibodies to glutamate decarboxylase (GADA) are sensitive markers of islet autoimmunity and type 1 diabetes. They form the basis of robust prediction models and are widely used for recruitment of subjects at high risk of type 1 diabetes to prevention trials. However GADA are also found in many individuals at low risk of diabetes progression. To identify the sources of diabetes irrelevant GADA reactivity therefore, we analyzed data from the 2009 and 2010 Diabetes Autoantibody Standardization Program GADA workshop and found that binding of healthy control sera varied according to assay type. Characterization of control sera found positive by radiobinding assay, but negative by ELISA showed that many of these sera reacted to epitopes in the N-terminal region of the molecule. This finding prompted development of an N-terminally truncated GAD65 radiolabel, 35S-GAD65(96-585), which improved the performance of most GADA radiobinding assays (RBAs) participating in an Islet Autoantibody Standardization Program GADA substudy. These detailed workshop comparisons have identified a source of disease-irrelevant signals in GADA RBAs and suggest that N-terminally truncated GAD labels will enable more specific measurement of GADA in type 1 diabetes.

AB - Autoantibodies to glutamate decarboxylase (GADA) are sensitive markers of islet autoimmunity and type 1 diabetes. They form the basis of robust prediction models and are widely used for recruitment of subjects at high risk of type 1 diabetes to prevention trials. However GADA are also found in many individuals at low risk of diabetes progression. To identify the sources of diabetes irrelevant GADA reactivity therefore, we analyzed data from the 2009 and 2010 Diabetes Autoantibody Standardization Program GADA workshop and found that binding of healthy control sera varied according to assay type. Characterization of control sera found positive by radiobinding assay, but negative by ELISA showed that many of these sera reacted to epitopes in the N-terminal region of the molecule. This finding prompted development of an N-terminally truncated GAD65 radiolabel, 35S-GAD65(96-585), which improved the performance of most GADA radiobinding assays (RBAs) participating in an Islet Autoantibody Standardization Program GADA substudy. These detailed workshop comparisons have identified a source of disease-irrelevant signals in GADA RBAs and suggest that N-terminally truncated GAD labels will enable more specific measurement of GADA in type 1 diabetes.

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DO - 10.2337/db14-1693

M3 - Article (Academic Journal)

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SN - 0012-1797

VL - 64

SP - 3239

EP - 3246

JO - Diabetes

JF - Diabetes

IS - 9

ER -

Detection of antibodies directed to the N-terminal region of GAD is dependent on assay format and contributes to differences in the specificity of GAD autoantibody assays for type 1 diabetes

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