Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2β) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease: Implications for prevention trials

J. De Grijse; M. Asanghanwa; B. Nouthe; N. Albrecher; P. Goubert; I. Vermeulen; S. Van Der Meeren; K. Decochez; I. Weets; B. Keymeulen; V. Lampasona; J. Wenzlau; J. C. Hutton; D. Pipeleers; F. K. Gorus

doi:10.1007/s00125-009-1618-y

Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2β) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease: Implications for prevention trials

J. De Grijse, M. Asanghanwa, B. Nouthe, N. Albrecher, P. Goubert, I. Vermeulen, S. Van Der Meeren, K. Decochez, I. Weets, B. Keymeulen, V. Lampasona, J. Wenzlau, J. C. Hutton, D. Pipeleers, F. K. Gorus

IRCCS Ospedale San Raffaele

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

Abstract

Aims/hypothesis: We investigated whether screening for insulinoma- associated protein (IA-2) beta (IA-2β) autoantibodies (IA-2βA) and zinc transporter-8 (ZnT8) autoantibodies (ZnT8A) improves identification of first-degree relatives of type 1 diabetic patients with a high 5-year disease risk, which to date has been based on assays for insulin autoantibodies (IAA), GAD autoantibodies (GADA) and IA-2 autoantibodies (IA-2A). Methods: IA-2βA and ZnT8A (using a ZnT8 carboxy-terminal hybrid construct, CW-CR, carrying 325Arg and 325Trp) were determined by radiobinding assay in 409 IAA⁺, GADA⁺ and/or IA-2A⁺ siblings or offspring (+ (n = 97), 14% (n = 59) IA-2βA⁺ and 20% (n = 80) ZnT8A⁺. IA-2βA and ZnT8A were significantly (p <0.001) associated with IA-2A and prediabetes (n = 86); in IA-2A^- first-degree relatives (n = 312) the presence of IA-2βA and ZnT8A was associated with an increased progression rate to diabetes (p <0.001). Positivity for IA-2A and/or ZnT8A emerged as the most sensitive combination of two markers to identify first-degree relatives with a 5-year progression rate to diabetes of 45% (survival analysis) and as strongest predictor of diabetes (Cox regression analysis). Omission of first-degree relatives protected by HLA-DQ genotypes or maternal diabetes reduced the group to be followed from n = 409 to n = 246 (40%) with minor loss in the number of prediabetic IA-2A⁺ or ZnT8A⁺ first-degree relatives identified (n = 3). Conclusions/interpretation: IA-2A⁺ and/or ZnT8A⁺ first-degree relatives may be the participants of choice in future secondary prevention trials with immunointervention in relatives of type 1 diabetic patients.

Original language	English
Pages (from-to)	517-524
Number of pages	8
Journal	Diabetologia
Volume	53
Issue number	3
DOIs	https://doi.org/10.1007/s00125-009-1618-y
Publication status	Published - Mar 2010

Keywords

Autoantibodies
HLA-DQ
IA-2
IA-2β
Prediction
Type 1 diabetes
Zinc transporter-8

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Medicine(all)

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De Grijse, J., Asanghanwa, M., Nouthe, B., Albrecher, N., Goubert, P., Vermeulen, I., Van Der Meeren, S., Decochez, K., Weets, I., Keymeulen, B., Lampasona, V., Wenzlau, J., Hutton, J. C., Pipeleers, D., & Gorus, F. K. (2010). Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2β) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease: Implications for prevention trials. Diabetologia, 53(3), 517-524. https://doi.org/10.1007/s00125-009-1618-y

Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2β) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease : Implications for prevention trials. / De Grijse, J.; Asanghanwa, M.; Nouthe, B.; Albrecher, N.; Goubert, P.; Vermeulen, I.; Van Der Meeren, S.; Decochez, K.; Weets, I.; Keymeulen, B.; Lampasona, V.; Wenzlau, J.; Hutton, J. C.; Pipeleers, D.; Gorus, F. K.

In: Diabetologia, Vol. 53, No. 3, 03.2010, p. 517-524.

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

De Grijse, J, Asanghanwa, M, Nouthe, B, Albrecher, N, Goubert, P, Vermeulen, I, Van Der Meeren, S, Decochez, K, Weets, I, Keymeulen, B, Lampasona, V, Wenzlau, J, Hutton, JC, Pipeleers, D & Gorus, FK 2010, 'Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2β) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease: Implications for prevention trials', Diabetologia, vol. 53, no. 3, pp. 517-524. https://doi.org/10.1007/s00125-009-1618-y

De Grijse J, Asanghanwa M, Nouthe B, Albrecher N, Goubert P, Vermeulen I et al. Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2β) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease: Implications for prevention trials. Diabetologia. 2010 Mar;53(3):517-524. https://doi.org/10.1007/s00125-009-1618-y

De Grijse, J. ; Asanghanwa, M. ; Nouthe, B. ; Albrecher, N. ; Goubert, P. ; Vermeulen, I. ; Van Der Meeren, S. ; Decochez, K. ; Weets, I. ; Keymeulen, B. ; Lampasona, V. ; Wenzlau, J. ; Hutton, J. C. ; Pipeleers, D. ; Gorus, F. K. / Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2β) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease : Implications for prevention trials. In: Diabetologia. 2010 ; Vol. 53, No. 3. pp. 517-524.

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abstract = "Aims/hypothesis: We investigated whether screening for insulinoma- associated protein (IA-2) beta (IA-2β) autoantibodies (IA-2βA) and zinc transporter-8 (ZnT8) autoantibodies (ZnT8A) improves identification of first-degree relatives of type 1 diabetic patients with a high 5-year disease risk, which to date has been based on assays for insulin autoantibodies (IAA), GAD autoantibodies (GADA) and IA-2 autoantibodies (IA-2A). Methods: IA-2βA and ZnT8A (using a ZnT8 carboxy-terminal hybrid construct, CW-CR, carrying 325Arg and 325Trp) were determined by radiobinding assay in 409 IAA+, GADA+ and/or IA-2A+ siblings or offspring (+ (n = 97), 14% (n = 59) IA-2βA+ and 20% (n = 80) ZnT8A+. IA-2βA and ZnT8A were significantly (p <0.001) associated with IA-2A and prediabetes (n = 86); in IA-2A- first-degree relatives (n = 312) the presence of IA-2βA and ZnT8A was associated with an increased progression rate to diabetes (p <0.001). Positivity for IA-2A and/or ZnT8A emerged as the most sensitive combination of two markers to identify first-degree relatives with a 5-year progression rate to diabetes of 45% (survival analysis) and as strongest predictor of diabetes (Cox regression analysis). Omission of first-degree relatives protected by HLA-DQ genotypes or maternal diabetes reduced the group to be followed from n = 409 to n = 246 (40%) with minor loss in the number of prediabetic IA-2A+ or ZnT8A+ first-degree relatives identified (n = 3). Conclusions/interpretation: IA-2A+ and/or ZnT8A+ first-degree relatives may be the participants of choice in future secondary prevention trials with immunointervention in relatives of type 1 diabetic patients.",

keywords = "Autoantibodies, HLA-DQ, IA-2, IA-2β, Prediction, Type 1 diabetes, Zinc transporter-8",

author = "{De Grijse}, J. and M. Asanghanwa and B. Nouthe and N. Albrecher and P. Goubert and I. Vermeulen and {Van Der Meeren}, S. and K. Decochez and I. Weets and B. Keymeulen and V. Lampasona and J. Wenzlau and Hutton, {J. C.} and D. Pipeleers and Gorus, {F. K.}",

year = "2010",

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doi = "10.1007/s00125-009-1618-y",

language = "English",

volume = "53",

pages = "517--524",

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T1 - Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2β) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease

T2 - Implications for prevention trials

AU - De Grijse, J.

AU - Asanghanwa, M.

AU - Nouthe, B.

AU - Albrecher, N.

AU - Goubert, P.

AU - Vermeulen, I.

AU - Van Der Meeren, S.

AU - Decochez, K.

AU - Weets, I.

AU - Keymeulen, B.

AU - Lampasona, V.

AU - Wenzlau, J.

AU - Hutton, J. C.

AU - Pipeleers, D.

AU - Gorus, F. K.

PY - 2010/3

Y1 - 2010/3

N2 - Aims/hypothesis: We investigated whether screening for insulinoma- associated protein (IA-2) beta (IA-2β) autoantibodies (IA-2βA) and zinc transporter-8 (ZnT8) autoantibodies (ZnT8A) improves identification of first-degree relatives of type 1 diabetic patients with a high 5-year disease risk, which to date has been based on assays for insulin autoantibodies (IAA), GAD autoantibodies (GADA) and IA-2 autoantibodies (IA-2A). Methods: IA-2βA and ZnT8A (using a ZnT8 carboxy-terminal hybrid construct, CW-CR, carrying 325Arg and 325Trp) were determined by radiobinding assay in 409 IAA+, GADA+ and/or IA-2A+ siblings or offspring (+ (n = 97), 14% (n = 59) IA-2βA+ and 20% (n = 80) ZnT8A+. IA-2βA and ZnT8A were significantly (p <0.001) associated with IA-2A and prediabetes (n = 86); in IA-2A- first-degree relatives (n = 312) the presence of IA-2βA and ZnT8A was associated with an increased progression rate to diabetes (p <0.001). Positivity for IA-2A and/or ZnT8A emerged as the most sensitive combination of two markers to identify first-degree relatives with a 5-year progression rate to diabetes of 45% (survival analysis) and as strongest predictor of diabetes (Cox regression analysis). Omission of first-degree relatives protected by HLA-DQ genotypes or maternal diabetes reduced the group to be followed from n = 409 to n = 246 (40%) with minor loss in the number of prediabetic IA-2A+ or ZnT8A+ first-degree relatives identified (n = 3). Conclusions/interpretation: IA-2A+ and/or ZnT8A+ first-degree relatives may be the participants of choice in future secondary prevention trials with immunointervention in relatives of type 1 diabetic patients.

AB - Aims/hypothesis: We investigated whether screening for insulinoma- associated protein (IA-2) beta (IA-2β) autoantibodies (IA-2βA) and zinc transporter-8 (ZnT8) autoantibodies (ZnT8A) improves identification of first-degree relatives of type 1 diabetic patients with a high 5-year disease risk, which to date has been based on assays for insulin autoantibodies (IAA), GAD autoantibodies (GADA) and IA-2 autoantibodies (IA-2A). Methods: IA-2βA and ZnT8A (using a ZnT8 carboxy-terminal hybrid construct, CW-CR, carrying 325Arg and 325Trp) were determined by radiobinding assay in 409 IAA+, GADA+ and/or IA-2A+ siblings or offspring (+ (n = 97), 14% (n = 59) IA-2βA+ and 20% (n = 80) ZnT8A+. IA-2βA and ZnT8A were significantly (p <0.001) associated with IA-2A and prediabetes (n = 86); in IA-2A- first-degree relatives (n = 312) the presence of IA-2βA and ZnT8A was associated with an increased progression rate to diabetes (p <0.001). Positivity for IA-2A and/or ZnT8A emerged as the most sensitive combination of two markers to identify first-degree relatives with a 5-year progression rate to diabetes of 45% (survival analysis) and as strongest predictor of diabetes (Cox regression analysis). Omission of first-degree relatives protected by HLA-DQ genotypes or maternal diabetes reduced the group to be followed from n = 409 to n = 246 (40%) with minor loss in the number of prediabetic IA-2A+ or ZnT8A+ first-degree relatives identified (n = 3). Conclusions/interpretation: IA-2A+ and/or ZnT8A+ first-degree relatives may be the participants of choice in future secondary prevention trials with immunointervention in relatives of type 1 diabetic patients.

KW - Autoantibodies

KW - HLA-DQ

KW - IA-2

KW - IA-2β

KW - Prediction

KW - Type 1 diabetes

KW - Zinc transporter-8

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