[Show abstract][Hide abstract] ABSTRACT: Class II alleles define the main HLA effect on type 1 diabetes, but there is an independent effect of certain class I alleles. Class II and class I molecules are differently involved in the initiation and effector phases of the immune response, suggesting that class I alleles would be important determinants in the rate of β-cell destruction. To test this hypothesis we analyzed the role of HLA class I and class II gene polymorphisms in the progression from diabetes-associated autoimmunity to clinical disease.
The effect of HLA-DR-DQ haplotypes and a panel of class I HLA-A and -B alleles on the progression from autoantibody seroconversion to clinical diabetes was studied in 249 children persistently positive for at least one biochemical diabetes-associated autoantibody in addition to islet cell autoantibody.
The progression to clinical disease was separately analyzed after the appearance of the first and the second persistent biochemical autoantibody using Cox regression. Multivariate analysis demonstrated a significant protective effect of the A*03 allele (odds ratio [OR] 0.61, P = 0.042 after the first and OR 0.55, P = 0.027 after the second autoantibody), whereas the B*39 allele had a promoting effect after seroconversion for the second autoantibody (OR 2.4, P = 0.014). When children with the DR3/DR4 genotype were separately analyzed, HLA-B*39 had a strong effect (OR 6.6, P = 0.004 and OR 7.5, P = 0.007, after the appearance of the first and the second autoantibody, respectively). The protective effect of A*03 was seen only among children without the DR3/DR4 combination.
These results confirm that class I alleles affect the progression of diabetes-associated autoimmunity and demonstrate interactions between class I and class II alleles.
[Show abstract][Hide abstract] ABSTRACT: Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and inducible T-cell co-stimulator (ICOS) genes are important mediators of T-cell activation in autoimmune diseases. The aim of the current study was to assess the impact of CTLA-4 and ICOS genes on the susceptibility to type 1 diabetes among two populations with different disease incidence rates. Three single nucleotide polymorphisms (SNPs) within the CTLA-4 region (+49A/G, CT60A/G, CTBC217_1C/T) and two SNPs within the ICOS region (CTIC154_1 C/T, CTIC159 C/G) were genotyped in 955 control subjects and 574 diabetic patients of Estonian and Finnish descent. The current study confirms the involvement of the CTLA-4 but not the ICOS gene in susceptibility to type 1 diabetes. However, the risk alleles and the defined main risk haplotype were more common in the Finnish controls compared with the Estonians, indicating that this gene locus might also be one of the contributing factors to the higher disease incidence in Finland.
Human immunology 05/2009; 70(7):536-9. DOI:10.1016/j.humimm.2009.04.023 · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The lowest incidence of childhood type 1 diabetes in Europe has been reported from the Republic of Macedonia. To assess the possible genetic contribution we analyzed the distribution of HLA-DR-DQ haplotypes among 163 diabetic children and 239 healthy controls. Similar disease associations were found as in other Caucasian populations. HLA-(DR3)-DQA1*05-DQB1*02 was the most common disease associated haplotype, but several DRB1*04-DQB1*0302 haplotypes were also found increased among patients. DRB1*0402 was the most common DR4 allele among them. The high frequency of protective (DR11/12)-DQA1*05-DQB1*0301 and (DR14)-DQB1*0503 haplotypes as well as of neutral (DR1/10)-DQB1*0501 and (DR16)-DQB1*0502 haplotypes were characteristic for the background population. Although a relatively low frequency of predisposing and a high frequency of protective haplotypes was detected, the haplotype frequency distribution did not markedly differ from that reported from other Eastern Mediterranean populations and these differences cannot be the sole explanation for the low disease incidence in Macedonia.
Human immunology 04/2009; 70(6):461-3. DOI:10.1016/j.humimm.2009.03.014 · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We analysed the contribution of the lymphoid protein tyrosine phosphatase (LYP) Arg620Trp variant (which corresponds to the PTPN22 C1858T polymorphism) to the emergence of beta-cell-specific humoral autoimmunity and progression to type 1 diabetes in man. We also explored the heterogeneity in the disease-predisposing effect of this polymorphism in relation to known disease loci, sex and age at disease onset.
A population-derived Finnish birth cohort with increased disease susceptibility conferred by HLA-DQB1 was monitored for the appearance of islet cell autoantibodies, and individuals found to be positive were tested for autoantibodies against insulin (IAA), glutamic acid decarboxylase and islet antigen-2 (n = 574; mean follow-up time 4.9 years). Gene interaction effects on disease susceptibility were analysed in case-control and family series (546 patients, 538 controls, 245 nuclear families). All subjects were typed for HLA DR-DQ, insulin gene (INS), CTLA4 and PTPN22 C1858T polymorphisms.
The PTPN22 1858TT genotype was associated with the appearance of IAA (adjusted hazard ratio = 4.6, 95% CI 2.4-9.0; p = 0.000013). PTPN22, INS and HLA-DRB1 had an additive effect on the emergence of IAA. The 1858TT and CT genotypes conferred an increased risk of developing additional autoantibodies or clinical disease (hazard ratio=4.1, 95% CI 1.5-11.6; and 1.6, 95% CI 1.1-2.4, respectively; p = 0.003). The strong effect of PTPN22 on disease susceptibility (p = 2.1 x 10(-8)) was more pronounced in males (p = 0.021) and in subjects with non-DR4-DQ8/low-risk HLA genotypes (p = 0.0004).
In the pathogenesis of type 1 diabetes the underlying mechanism of the PTPN22 C1858T polymorphism appears to involve regulation of insulin-specific autoimmunity. Importantly, it strongly affects progression from prediabetes to clinical disease.
[Show abstract][Hide abstract] ABSTRACT: 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.