Abstract
The purpose of this work was to assess the value of humoral
and genetic risk markers in the prediction of type 1 diabetes in
siblings of children with type 1 diabetes, to characterise preclinical
course of beta-cell autoimmunity in siblings, and to investigate
the frequency of autoantibodies and their relations to genetic markers,
beta-cell function and progression to type 1 diabetes in a schoolchild population.
The prevalence and predictive value of autoantibodies was
studied in 755 initially unaffected siblings, and the combination
of genetic markers and autoantibodies in 701 of these siblings.
Islet cell autoantibodies (ICA), insulin autoantibodies (IAA), glutamic
acid decarboxylase antibodies (GADA) and IA-2 antibodies (IA-2A)
were all shown to be of value in the prediction of type 1 diabetes
in siblings initially tested at or close to the diagnosis of type
1 diabetes in the index case in the family. The risk of progression
to type 1 diabetes was related to the number of autoantibodies detected,
and the PPV of multiple autoantibodies was 55% over a period
of 8 years. Autoantibodies were closely associated with HLA risk
markers. A combination of the genetic markers and autoantibodies increased
the PPVs of all autoantibodies substantially but also markedly reduced
the sensitivity.
The preclinical course of type 1 diabetes was investigated
in 39 initially unaffected siblings who progressed to clinical disease
during the follow-up. These individuals were characterised by the
high-risk genetic markers, decreased beta-cell function and humoral
autoimmunity against multiple beta-cell targets. However, all measures
implied a remarkable individual variation in the rate of the disease process
and the pattern of humoral beta-cell autoimmunity. Furthermore,
the autoimmune process resulting in clinical presentation of type
1 diabetes could not be unambiguously distinguished from autoimmunity
not leading to clinical disease within almost 10 years of follow-up.
The frequencies of ICA, IA-2A, GADA and IAA in 3652 healthy
Finnish schoolchildren were 2.8%, 0.6%, 0.5% and
0.9%, respectively, and multiple antibodies were detected
in 0.6% of these children. GADA and multiple antibodies
were related to the DQB1*0302 allele and the DQB1*02/0302
genotype. A reduced first-phase insulin reponse (FPIR) was associated
with IA-2A, GADA, IAA and multiple antibodies, but not with ICA
or any specific DQB1 allele or genotype. Four subjects progressed
to type 1 diabetes, all of them having multiple autoantibodies and
those two who underwent an intravenous glucose tolerance test had
also a reduced FPIR. None of the progressors carried the high risk
DQB1*0302 allele and two of them even carried the protective
DQB1*0602 or *0603 allele.
In conclusion, autoantibodies alone are recommended as first-line
screening in siblings, whereas subsequent determination of HLA-DQB1
markers and their combination with autoantibodies provides a valuable
tool for more precise risk assessment. Wide heterogeneity in the
course of preclinical type 1 diabetes complicates an accurate estimation
of the individual risk of progression to type 1 diabetes among siblings
of children with type 1 diabetes. Combined screening for autoantibodies
is recommended for the assessment of the risk of progression to
type 1 diabetes in schoolchild populations, whereas the present
observations challenge the value of current genetic risk markers
in predictive strategies targeting schoolchildren.
| Identifer | oai:union.ndltd.org:oulo.fi/oai:oulu.fi:isbn951-42-5647-6 |
| Date | 11 May 2000 |
| Creators | Kulmala, P. (Petri) |
| Publisher | University of Oulu |
| Source Sets | University of Oulu |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:eu-repo/semantics/publishedVersion |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess, © University of Oulu, 2000 |
| Relation | info:eu-repo/semantics/altIdentifier/pissn/0355-3221, info:eu-repo/semantics/altIdentifier/eissn/1796-2234 |
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