Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2beta) 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.
OBJECTIVE
We investigated whether screening for insulinoma-associated protein (IA-2) beta (IA-2beta) autoantibodies (IA-2betaA) 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-2betaA 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 (<40 years) of type 1 diabetic patients consecutively recruited by the Belgian Diabetes Registry. The median (interquartile range) age of the first-degree relatives was 12 (6-19) years.


RESULTS
Of the first-degree relatives, 24% were IA-2A(+) (n = 97), 14% (n = 59) IA-2betaA(+) and 20% (n = 80) ZnT8A(+). IA-2betaA 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-2betaA 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
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.
De Grijse
J
J
Diabetes Research Center, Brussels Free University-VUB, Laarbeeklaan 103, B-1090 Brussels, Belgium.
Asanghanwa
M
M
Nouthe
B
B
Albrecher
N
N
Goubert
P
P
Vermeulen
I
I
Van Der Meeren
S
S
Decochez
K
K
Weets
I
I
Keymeulen
B
B
Lampasona
V
V
Wenzlau
J
J
Hutton
J C
JC
Pipeleers
D
D
Gorus
F K
FK
D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000737:chemistry; D027682:Cation Transport Proteins / Q000096:biosynthesis*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism*; D005192:Family Health; D005260:Female; D006683:HLA-DQ Antigens / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male; D011237:Predictive Value of Tests; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000096:biosynthesis*; D015032:Zinc / Q000737:chemistry
D001323:Autoantibodies; D027682:Cation Transport Proteins; D006683:HLA-DQ Antigens; D007328:Insulin; C486299:SLC30A2 protein, human; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D015032:Zinc