Life table analysis of the risk of Type 1 (insulin-dependent) diabetes mellitus in siblings according to islet cell antibodies and HLA markers

Deschamps, I; Hors, J; Busson, Marc; Marcelli-Barge, A; Mogenet, Alice; Robert, J. J.

doi:10.1007/bf00401424

Cited by 51 publications

(46 citation statements)

References 40 publications

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“…In this regard it is notable however that subject number 5, who has been positive for CF-ICA and GADt~ antibodies for more than 12 years, has the HLA-DR3, DQw2 and DR4,DQw8 haplotype, which confers the highest known relative risk of IDDM [7]. Thus, even this high risk MHC allele in conjunction with both CF-ICA and GAD65 autoantibodies is still not sufficient to rapidly induce the onset of IDDM.…”

Section: Discussionmentioning

confidence: 99%

“…Antibody assays that detect early signs of humoral autoimmunity associated with beta-cell destruction are obvious candidates for this purpose. Furthermore, susceptibility to develop diabetes is associated with certain MHC-class II haplotypes [6] and analysis of both HLA haplotypes and autoantibodies provide a test of high predictive value in family members of IDDM patients [3,7]. Since most new cases of [DDM involve individuals without a first degree relative with the disease [8, 9], predictive meth-…”

mentioning

confidence: 99%

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Value of antibodies to GAD65 combined with islet cell cytoplasmic antibodies for predicting IDDM in a childhood population

Aanstoot

Sigurdsson²,

Jaffe

et al. 1994

Diabetologia

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SummaryThe value of a test for islet cell cytoplasmic antibodies together with a test for GAD6s antibodies to predict the subsequent development of diabetes over a period of 11.5 years was assessed in an open childhood population comprising 2,805 individuals. A single serum sample was obtained from each individual between 1975 and 1977 and screened for islet cell cytoplasmic antibodies for which eight individuals were positive (0.29 %). During the average follow-up period of 11.5 years, four of eight islet cell antibody positive and three islet cell antibody negative individuals developed clinical diabetes. Sera from all individuals, who were islet cell antibody positive and/ or developed diabetes (total of 11) and from 100 randomly selected control subjects were analysed for GAD65 antibodies. Six of eight islet cell antibody positive individuals were GAD65 antibody positive including all four who subsequently developed IDDM. Furthermore, one of the three islet cell antibody negative individuals who developed IDDM was GAD65 antibody positive both in 1976 and in 1989. Thus, a positive test for GAD6s antibodies alone correctly predicted diabetes in five of seven children, who developed the disease. Only one of the children, who developed diabetes was positive for insulin autoantibodies and this individual was also positive for islet cell cytoplasmic antibodies and GAD65 antibodies. One of the 100 control subjects was positive for GAD6s antibodies (1%). The results suggest that a single GAD65 antibody test may have a higher sensitivity for predicting IDDM than a test for islet cell cytoplasmic antibodies, but that a combined positive test for both antibodies increases the specificity for predicting IDDM over a period of 11.5 years. [Diabetologia (1994) 37: 917-924] Key words GAD65 antibodies, islet cell cytoplasmic antibodies, predictive value, IDDM in childhood.The destruction of pancreatic beta cells, which precedes the clinical onset of IDDM, is mediated by autoimmune mechanisms [1]. The presence of islet specific autoantibodies in the pre-diabetic period [2-4] is likely to reflect the ongoing autoimmune process, one that eventually leads to critical beta-cell depletion and insulin dependency. A major goal of diabetes research is to develop immune interventions that block or otherwise interfere with the destruction of beta cells and the development of clinical diabetes. Concomitant with this goal is the necessity for methods for early accurate identification of susceptible individuals [5]. Antibody assays that detect early signs of humoral autoimmunity associated with beta-cell destruction are obvious candidates for this purpose. Furthermore, susceptibility to develop diabetes is associated with certain MHC-class II haplotypes [6] and analysis of both HLA haplotypes and autoantibodies provide a test of high predictive value in family members of IDDM patients [3,7]. Since most new cases of [DDM involve individuals without a first degree relative with the disease [8, 9], predictive meth-

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Value of antibodies to GAD65 combined with islet cell cytoplasmic antibodies for predicting IDDM in a childhood population

Aanstoot

Sigurdsson²,

Jaffe

et al. 1994

Diabetologia

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“…Of 22 offspring with islet autoantibodies, 11 (50 %) had either the DR3/4 or DR4/4 genotype and 4 have already progressed to diabetes. The DR3/4 genotype has been shown previously to be associated with a more rapid progression to diabetes in islet autoantibody positive siblings of patients with Type I diabetes [18]. Moreover, in the DAISY study, 62.5 % of DR3/4 positive children with islet autoantibodies were diabetic before the age of 5 years [19].…”

Section: Discussionmentioning

confidence: 99%

Early expression and high prevalence of islet autoantibodies for DR3/4 heterozygous and DR4/4 homozygous offspring of parents with Type I diabetes: The German BABYDIAB study

et al. 1999

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“…Furthermore, HLA type differences related to age at onset have been found (20). An increased frequency has recently been reported of diabetes-associated insulin gene genotypes in concordant twins (21).…”

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confidence: 98%

Genetic Liability of Type 1 Diabetes and the Onset Age Among 22,650 Young Finnish Twin Pairs

Hyttinen¹,

Kaprio²,

Kinnunen³

et al. 2003

Diabetes

360

231

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Finland has the world's highest incidence of type 1 diabetes, and it is steadily increasing. We determined concordance rates and estimated heritability for type 1 diabetes in the Finnish Twin Cohort, a population-based twin cohort of 22,650 twin pairs. In addition, we studied age of onset in the first affected twin and discordance time between concordant twin pairs. Finnish twins born between 1958 and 1986 were followed for type 1 diabetes until 1998. We identified 228 twin pairs with type 1 diabetes: 44 monozygotic (MZ), 183 dizygotic (DZ), and 1 pair with unknown zygosity. The pairwise concordance for type 1 diabetes was 27.3% (95% CI 22.8 -31.8) in MZ and 3.8% (2.7-4.9) in DZ twins. The probandwise concordance was 42.9% (26.7-59.2) and 7.4% (2.2-12.6), respectively. The longest discordance times were 6.9 years among concordant MZ twins and 23.6 years among DZ twins. The risk for type 1 diabetes was highest in cotwins of the index twins diagnosed at a very young age. The model with additive genetic and individual environmental effects was the best-fitting liability model, with 88% of phenotypic variance due to genetic factors and the remaining variance due to unshared environmental factors. In conclusion, these nationwide twin data demonstrated high genetic liability for type 1 diabetes. Early-onset diabetes increases the risk in cotwins. However, the majority of affected MZ twin pairs remain discordant for type 1 diabetes. Diabetes 52: 1052-1055, 2003A recent study showed that Finland's record type 1 diabetes incidence increased predominantly in younger age-groups (1,2). The exact mechanism underlying the process leading to type 1 diabetes remains elusive, despite years of research. It is known that genes in the HLA region substantially influence the risk of type 1 diabetes and familial clustering (3,4). Several environmental factors have been proposed to contribute to its pathogenesis, but their causative role has not been established (5-7).Twins provide a powerful tool to investigate relative importance of genetic and environmental factors on traits by comparing of concordance in monozygotic (MZ) and dizygotic (DZ) twins. Finland is one of the few countries with a population-based twin cohort (8) offering uniquely large, representative, and therefore unbiased data on type 1 diabetes among twins. The objective of this study was to determine concordance rates and to estimate heritability for type 1 diabetes in the Finnish population-based cohort. Furthermore, we examined risk for progression to diabetes in cotwins in relation to age at onset of the first affected twin (index twin) and the discordance time among concordant twin pairs.Of 303 diabetic twins identified from different sources, 247 cases (in 228 pairs) had type 1 diabetes (116 females, 131 males), 28 had type 2 diabetes, 15 had secondary diabetes, and 13 had gestational diabetes. Of the type 1 diabetic twin pairs, 44 belonged to MZ pairs, 90 to opposite-sex DZ pairs, 93 to same-sex DZ pairs, and 1 to a same-sex pair of unknown zygosity, totaling 22...

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Life table analysis of the risk of Type 1 (insulin-dependent) diabetes mellitus in siblings according to islet cell antibodies and HLA markers

Cited by 51 publications

References 40 publications

Value of antibodies to GAD65 combined with islet cell cytoplasmic antibodies for predicting IDDM in a childhood population

Value of antibodies to GAD65 combined with islet cell cytoplasmic antibodies for predicting IDDM in a childhood population

Early expression and high prevalence of islet autoantibodies for DR3/4 heterozygous and DR4/4 homozygous offspring of parents with Type I diabetes: The German BABYDIAB study

Genetic Liability of Type 1 Diabetes and the Onset Age Among 22,650 Young Finnish Twin Pairs

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