Population‐based genetic screening for the estimation of Type 1 diabetes mellitus risk in Finland: selective genotyping of markers in the HLA‐DQB1, HLA‐DQA1 and HLA‐DRB1 loci

Nejentsev, S; Sjöroos, Minna; Soukka, T; Knip, Mikael; Simell, Olli; Lövgren, Timo; Ilonen, Jorma

doi:10.1046/j.1464-5491.1999.00186.x

Cited by 149 publications

(126 citation statements)

References 27 publications

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“…The selection criteria for the study cohort comprising ICA-positive children limited our possibilities to analyse thoroughly the HLA effects, since most study subjects carried the DR4-DQB1*0302 haplotype, however, the contribution of the insulin and CTLA4 loci to the diseasespecific autoimmune phenomena could be fully explored. We also analysed the effect of DRB1*04 alleles on the DR4-DQB1*0302 haplotypes, since they confer different degrees of disease susceptibility in the Finnish population, as the DRB1*0401 allele is associated with higher risk than the DRB1*0404 variant and the DRB1*0403 allele is protective [28,35]. At the INS locus the −23 HphI polymorphism was used as genetic risk marker, where the A alleles are in strong linkage disequilibrium with the 5′ INS VNTR class I susceptibility variants and the T alleles are linked with the protective class III alleles [12,21].…”

Section: Discussionmentioning

confidence: 99%

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The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

et al. 2005

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Aims/hypothesis: The aim of this study was to explore the contribution of genetic factors to the emergence of beta-cell-specific humoral autoimmunity. Subjects and methods: We analysed the effect of HLA class II, insulin (INS; −23 HphI variant) and cytotoxic T-lymphocyteassociated protein 4 (CTLA4 [+49 and CT60]) genes on the appearance of beta-cell-specific autoantibodies in a large population-based birth cohort recruited in Finland. Infants carrying increased risk HLA DQB1 genotypes were monitored for the appearance of autoantibodies (islet cell autoantibodies [ICA], insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA] and islet antigen 2 antibodies ). Those who developed betacell-specific autoantibodies were studied (n=574, mean follow-up time: 4.9 years; range 0.5-9.3). Results: IAA emerged at a higher rate in children with the −23 HphI AA INS genotype than in those carrying AT or TT variants (hazard ratio 2.1, 95% CI 1.4-2.9, p<0.001). This effect of the INS locus was present in both HLA DQB1 risk groups. The appearance of IAA showed a strong association also with the HLA DRB1*0401 allele (hazard ratio 13.1, 95% CI 1.8-93.4, p<0.001). The development of IA-2A was also somewhat accelerated by the DRB1*0401 variant (p=0.03). Isolated ICA positivity was independent of the HLA and INS genotypes. None of the humoral immune markers showed association with the CTLA4 gene. Conclusions/interpretation: The INS and the DRB1 loci appear to contribute to the pathogenesis of type 1 diabetes by initiating/modifying insulin-specific autoimmunity. The emergence of IAA represents a crucial step in the development of beta cell autoimmunity in young children, in whom the appearance of GADA and IA-2A is linked to IAA.

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Section: Discussionmentioning

confidence: 99%

“…Genotyping The methods and the resolutions for the HLA DQB1 'full house' for the DQA1 and DRB1*04 typing were described earlier [27][28][29]. The INS −23 HphI and the CTLA4+49 polymorphisms were analysed using PCR and a lanthanide-labelled oligonucleotide hybridisation method [27,30].…”

Section: Methodsmentioning

confidence: 99%

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

et al. 2005

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“…In Caucasians, islet autoimmunity and type 1 diabetes are strongly associated with HLA DR3-DQ2 and DR4-DQ8 haplotypes (23), and recent studies from different European countries have confirmed that the HLA DR3-DQ2/DR4-DQ8 genotype is associated with the highest diabetes risk (29 -34). This genotype is found in 20 -30% of type 1 diabetic patients and in almost 50% of patients diagnosed in early childhood (23,(31)(32)(33)(34). Islet autoantibodies differ in their association with HLA haplotypes.…”

Section: Factors Influencing the Development Of Islet Autoimmunitymentioning

confidence: 99%

Natural History of Type 1 Diabetes

Achenbach

Bonifacio²,

Koczwara³

et al. 2005

Diabetes

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The natural history of autoimmune type 1 diabetes in children is associated with the appearance of islet autoantibodies early in life, which is influenced by genetic and environmental factors. Once islet autoantibodies have developed, the progression to diabetes in antibody-positive individuals is determined by the age of antibody appearance and by the magnitude of the autoimmunity, in turn related to the age of the subject. Characteristics that describe the magnitude of the autoimmunity can stage progression to type 1 diabetes in islet autoantibody-positive subjects regardless of genetic background or age. Diabetes 54 (Suppl. 2):S25-S31, 2005

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“…Three nonsynonymous SNPs were located in exon 9 [rs712701 (P321H), rs2233583 (V330A), and rs2233584 (Ter333W)], whereas the rs2233578 SNP (R133W) was in exon 3. HLA typing was performed in all Finnish subjects using methods described earlier (12,13). The INS Ϫ23 HphI SNP was typed with a similar oligonucleotide hybridization format (T probe 5Ј-Europium-CTGTCTCCCAGA-3Ј; A probe 5Ј-Terbium-CTG TCACCCAGA-3Ј).…”

Section: Hungarian Population Seriesmentioning

confidence: 99%

Lack of Association of PAX4 Gene With Type 1 Diabetes in the Finnish and Hungarian Populations

et al. 2005

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We aimed to assess the possible contribution of the PAX4 transcription factor gene to the genetic background of type 1 diabetes. We analyzed four coding polymorphisms of the PAX4 gene in 498 cases with type 1 diabetes and 825 control subjects from Finland and Hungary. All patients were diagnosed under the age of 15 years according to the World Health Organization criteria. All four PAX4 variants (three in exon 9 and one in exon 3) were genotyped using DNA sequencing. In addition, all Finnish subjects were typed for HLA DR-DQ, insulin gene (؊23) HphI, and CTLA4 CT60 polymorphisms. The ؉1,168 C/A coding variant of PAX4 was found to be polymorphic in both populations (P321H, rs712701). No difference was observed in the genotype frequencies between cases and control subjects, nor was any disease association detected when patients were stratified according to age at diagnosis, sex, HLA, insulin gene, or CTLA4 genotypes. Our data indicate that the ؉1,168 C/A variant of PAX4 gene does not play any essential role in genetic type 1 diabetes susceptibility. The strong coherence between the datasets of the two ethnic groups studied with highly contrasting disease incidence, socioeconomic characteristics, and profoundly diverse environment emphasizes the impact of this finding. Diabetes 54:2816 -2819, 2005

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Population‐based genetic screening for the estimation of Type 1 diabetes mellitus risk in Finland: selective genotyping of markers in the HLA‐DQB1, HLA‐DQA1 and HLA‐DRB1 loci

Abstract: The described strategy for genetic prediction of Type 1 diabetes mellitus relies on the convenient genotyping procedure and could be applied in large scale screening projects such as DIPP.

Cited by 149 publications

References 27 publications

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

Natural History of Type 1 Diabetes

Lack of Association of PAX4 Gene With Type 1 Diabetes in the Finnish and Hungarian Populations

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