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J Ilonen

Publications and source records attributed to J Ilonen.

At least 19 recordsLinked to original sources
PubMed2006

Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes.

AIMS/HYPOTHESIS: 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. SUBJECTS AND METHODS: 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. RESULTS: 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). CONCLUSIONS/INTERPRETATION: 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.

Adolescent↗
PubMed2006

Age at introduction of new foods and advanced beta cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes.

AIMS/HYPOTHESIS: Evidence for the role of infant feeding in the development of beta cell autoimmunity is inconsistent. We set out to study the effects of breastfeeding and of age at introduction of supplementary foods on the development of beta cell autoimmunity. SUBJECTS AND METHODS: A prospective birth cohort of 3,565 infants with HLA-DQB1-conferred susceptibility to type 1 diabetes was recruited between 1996 and 2001 from two university hospital areas in Finland. Blood samples were collected at 3- to 12-month intervals to measure antibodies against islet cells, insulin, glutamate dehydroxylase and islet antigen 2. The families kept a record on the age at introduction of new foods, and for each visit completed a structured dietary questionnaire. The endpoint was repeated positivity for islet cell antibodies together with at least one of the other three antibodies. RESULTS: The overall or exclusive duration of breastfeeding was not associated with the risk of developing the endpoint. An early age at introduction of fruits and berries (< or =4 months) was related to increased risk of developing positivity for the endpoint (hazard ratio [95% CI] for earliest tertile 2.02 [1.03-3.95] and for midtertile 1.97 [1.06-3.64] compared with latest tertile >4 months). Also, introducing roots between 3 and 3.9 months (midtertile) was related to increased risk of the endpoint (hazard ratio [95% CI] for the earliest tertile 1.04 [0.57-1.90] and for midtertile 1.82 [1.19-2.79] compared with latest tertile). These associations were independent of several putative socio-demographic and perinatal confounding factors. CONCLUSIONS/INTERPRETATION: Our findings suggest that an early age at introduction of fruits and berries and roots associates independently with beta cell autoimmunity, contradicting earlier findings from smaller birth cohort studies.

Age Factors↗
PubMed2006

Evidence for linkage to and association with type 1 diabetes at the 3q21 region in the Finnish population.

IDDM9-region on chromosome 3q has shown suggestive evidence for linkage to type 1 diabetes in some but not all genome scans. We analyzed 22 microsatellite markers in 121 Finnish type 1 diabetes multiplex families across the IDDM9-region. Two-point maximum LOD scores of 3.4 and 2.5 were detected with markers D3S1589 and D3S3606, respectively. Two markers were further tested for association using the transmission disequilibrium test in 384 Finnish type 1 diabetes simplex families. Marker AFM203wd10 showed association with type 1 diabetes (P = 0.0002 for allele R16). Association was present in families with children carrying the HphI-23 AA risk genotype at IDDM2 but not in families with children carrying protective AT or TT genotypes implying interaction between the two loci. Our data gives credence to earlier findings of linkage in this region and suggests a location for a polymorphism affecting type 1 diabetes susceptibility in the area surrounding AFM203wd10.

Adolescent↗
PubMed2006

IA-2 antibody isotypes and epitope specificity during the prediabetic process in children with HLA-conferred susceptibility to type I diabetes.

The natural history of preclinical diabetes is partly characterized, but there is still limited information on the dynamics of the immune response to beta-cell autoantigens during the course of preclinical disease. The aim of this work was to assess the maturation of the humoral immune response to the protein tyrosine phosphatase(PTP)-related proteins (IA-2 and IA-2beta) in preclinical type I diabetes (TID). Forty-five children participating in the Finnish Type I Diabetes Prediction and Prevention (DIPP) Study who had seroconverted to IA-2 antibody positivity were analysed. Specific radiobinding assays were used to determine IA-2/IA-2beta epitope-specific antibodies (the juxtamembrane (JM) region of IA-2, PTP-like domain and betaPTP-like domain) and isotype-specific IA-2 antibodies. Individual areas under the curve (AUC) over the observation period were calculated for total IA-2 antibodies, each isotype and specific epitope responses. The children who progressed to TID tended to have an initial IA-2 JM epitope response more frequently (P = 0.06), and this response was more often dominant during the observation period (P < 0.05). The children who did not progress to TID had IgE-IA-2 more frequently (70%; versus progressors 27%; P < 0.05), and had higher integrated titres of IgE-IA-2 antibodies (P < 0.05). The occurrence of IgE-IA-2 antibodies was protective even when combined with positivity for IA-2 JM antibodies (P = 0.002). IgE-IA-2 antibody reactivity may be a marker of a regulatory immune response providing protection against or delaying progression to TID among IA-2 antibody-positive young children with HLA-conferred disease susceptibility.

Autoantibodies↗
PubMed2006

The association of CTLA-4 and HLA class II autoimmune risk genotype with regulatory T cell marker expression in 5-year-old children.

Regulatory T cells (Treg) are involved in the maintenance of peripheral tolerance by suppression of autoreactive lymphocytes that have avoided thymic depletion. The defective function of Treg cells has recently attracted attention in autoimmune diseases such as type 1 diabetes (T1D), rheumatoid arthritis and multiple sclerosis. Susceptibility to these diseases is associated with specific human leucocyte antigen (HLA) class II and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene polymorphisms. This study aimed to investigate the relationship between HLA class II and CTLA +49 A/G polymorphisms associated with susceptibility to T1D and the number and characteristics of Treg cells in children. Samples from 47 5-year-old children who participated in the All Babies in South-east Sweden (ABIS) follow-up study were grouped according to the presence of the T1D risk-associated HLA genotype (DQA1*0501-DQB1*0201, DQA1*0301-DQB1*0302) or neutral HLA genotypes. Lower percentages of CD4+ T cells (P = 0.03) and CD4+ CD25high cells (P = 0.06) expressing intracellular CTLA-4 were detected in samples from children with CTLA-4 +49GG compared to children with the +49AA genotype. Similarly, lower percentages of CD4+ (P = 0.002) and CD4+ CD25high (P = 0.002) cells expressing CTLA-4 were observed in children positive for HLA DQA1*0501-DQB1*0201 and DQA1*0301-DQB1*0302 (P = 0.04 for CD4+ and P = 0.02 for CD4+ CD25high) risk haplotypes when compared to children without these alleles. The percentage of CD25high cells among CD4+ cells was correlated inversely with CTLA-4 mRNA expression in PBMC (r = -0.56, P = 0.03). Decreased levels of CTLA-4 in CD4+ and CD4+ CD25high cells in individuals with CTLA-4 and HLA class II alleles associated with T1D may contribute to the initiation and/or progression of autoimmune response.

Antigens, CD↗
PubMed2006

Rotavirus-specific T cell responses and cytokine mRNA expression in children with diabetes-associated autoantibodies and type 1 diabetes.

Rotavirus infections have been implicated as a possible trigger of type 1 diabetes. We elucidated this connection by comparing peripheral blood T cell responses to rotavirus between children with newly diagnosed type 1 diabetes (n = 43), healthy children with multiple diabetes-associated autoantibodies (n = 36) and control children carrying human leukocyte antigen (HLA)-conferred susceptibility to type 1 diabetes but without autoantibodies (n = 104). Lymphocyte proliferation assays based on stimulation with an antigen were performed using freshly isolated peripheral blood mononuclear cells (PBMC) and IgG and IgA class rotavirus antibodies were measured using plasma samples collected from the children. The expression of interferon (IFN)-gamma, interleukin (IL)-4, IL-10 and transforming growth factor (TGF)-beta in PBMC was studied with real-time polymerase chain reaction (PCR) in a subgroup of 38 children. No differences were observed in the strength or frequency of positive T cell responses to rotavirus between children with overt diabetes, children with multiple autoantibodies and control children. Children with diabetes-associated autoantibodies had, instead, stronger T cell responses to purified coxsackie B4 virus than control children. Rotavirus-stimulated lymphocytes from autoantibody-positive children produced more IL-4 and phytohaemagglutinin (PHA)-stimulated lymphocytes more IL-4 and IFN-gamma than lymphocytes from control children. PHA-stimulated lymphocytes from children with diabetes also produced more IL-4 and purified protein derivative (PPD)-stimulated lymphocytes less TGF-beta than lymphocytes from autoantibody-negative control children. In conclusion, our lymphocyte proliferation studies did not provide evidence supporting an association between rotavirus infections and the development of type 1 diabetes or diabetes-associated autoantibodies in young children.

Antigens, Viral↗
PubMed2005

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

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-lymphocyte-associated 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 [IA-2A]). Those who developed beta-cell-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.

Antibody Formation↗
PubMed2005

Dietary manipulation of beta cell autoimmunity in infants at increased risk of type 1 diabetes: a pilot study.

AIMS/HYPOTHESIS: We aimed to assess the feasibility of a dietary intervention trial with weaning to hydrolysed formula in infants at increased risk of type 1 diabetes and to study the effect of the intervention on the emergence of diabetes-associated autoantibodies in early childhood. METHODS: We studied 242 newborn infants who had a first-degree relative with type 1 diabetes and carried risk-associated HLA-DQB1 alleles. After exclusive breastfeeding, the infants underwent a double-blind, randomised pilot trial of either casein hydrolysate (Nutramigen; Mead Johnson) or conventional cow's milk-based formula until the age of 6-8 months. During a mean observation period of 4.7 years, autoantibodies to insulin, anti-glutamic acid decarboxylase and insulinoma-associated antigen-2 were measured by radiobinding assays, and islet cell antibodies (ICA) by immunofluorescence. RESULTS: The feasibility of screening and identifying a cohort of first-degree relatives with HLA-conferred disease susceptibility, enrolling them in a dietary intervention trial and following them for seroconversion to autoantibody positivity is established. The cumulative incidence of autoantibodies was somewhat smaller in the casein hydrolysate vs control formula group, suggesting the need for a larger well-powered study. After adjustment for duration of study formula feeding, life-table analysis showed a significant protection by the intervention from positivity for ICA (p=0.02) and at least one autoantibody (p=0.03). CONCLUSIONS/INTERPRETATION: The present study provides the first evidence ever in man, despite its limited power, that it may be possible to manipulate spontaneous beta cell autoimmunity by dietary intervention in infancy.

Autoantibodies↗
PubMed2005

Dynamics of diabetes-associated autoantibodies in young children with human leukocyte antigen-conferred risk of type 1 diabetes recruited from the general population.

This study characterized the dynamics of islet cell antibodies (ICA), insulin antibodies (IAA), glutamic acid decarboxylase antibodies (GADA), and IA-2 antibodies (IA-2A) in 1006 children recruited from the general population due to human leukocyte antigen (HLA) DQB1-conferred risk for type 1 diabetes (T1D). By the age of 5 yr, 13.8% of the children had had one or more autoantibodies in at least one sample drawn at 3- to 12-month intervals from birth, whereas 6.1% had had one or more of the three autoantibodies to biochemically defined antigens in at least two consecutive samples. The cumulative frequencies of positivity for at least two antibodies ranged from 3.2-4.4%. Seventy-five children (7.5%) had at least once ICA, 83 (8.3%) had IAA, 46 (4.6%) had GADA, and 33 (3.3%) had IA-2A. IAA were transient more frequently than the other antibodies (P < or = 0.03) and fluctuated between positivity and negativity more often than ICA (P = 0.001). The genetically high risk children were positive for each autoantibody reactivity more often (P < or = 0.03) than the moderate risk subjects. Thirteen of the 1006 children (1.3%) presented with T1D by the age of 5 yr. The most sensitive predictors of T1D were ICA and IAA, whereas the most specific predictor was IA-2A. Positivity for at least two autoantibodies of IAA, GADA, and IA-2A had the highest positive predictive value for T1D (34%). We conclude that the frequency of various diabetes-associated autoantibodies increases at a relatively stable rate at least up to the age of 5 yr. Persistent positivity for two or more autoantibodies appears to reflect destructive progressive beta-cell autoimmunity, whereas positivity for a single autoantibody may represent harmless nonprogressive or even regressive beta-cell autoimmunity.

Autoantibodies↗
PubMed2004

Recombination in uveitis-causing enterovirus strains.

The complete nucleotide sequences of three human echovirus (EV) 11 strains and one EV19 strain, all of which caused outbreaks of enterovirus uveitis (EU), a new infant disease first identified in 1980 in Siberia, were determined. One EV11 strain which caused an outbreak of sepsis-like disease in Hungary was also sequenced. All four EV11 strains were mosaic recombinants of the prototype EV11 strain Gregory, with their non-structural coding regions and 5' NTRs being more similar to other prototype enteroviruses (EV1, EV9). However, this finding is probably a feature of all circulating enterovirus strains and may not be related to their altered virulence. A full genome sequence comparison of the three subtypes of EU-causing strains excludes the role of recent recombination in their emergence, and points to their independent emergence.

5' Untranslated Regions↗
PubMed2004

Rotavirus-specific T-cell responses in young prospectively followed-up children.

Rotavirus is a major cause of gastroenteritis in young children. Antibodies seem to protect against rotavirus infection but cell-mediated immune responses are probably also important for protection. We evaluated the development of T-cell responses to rotavirus in follow-up samples from 20 healthy children with an increased genetic risk for type 1 diabetes. Blood samples from 16 healthy adults were also available for the study. T-cell proliferation was analysed at 3-6 month intervals from the age of 3 months to the age of 4-5 years using the Wa strain of human rotavirus and the NCDV strain of bovine rotavirus as antigens. IgG and IgA antibodies to rotavirus were studied from simultaneously drawn plasma samples with EIA method using NCDV as an antigen. A total of 24 infections were revealed by antibody analysis. Sixteen children showed diagnostic increases in both IgG and IgA antibodies to rotavirus, while 5 children showed increases in IgA antibodies only and 3 in IgG only. Antibody rises were accompanied by T-cell responses to rotavirus (SI > 3) in 9 of the 24 cases. T-cell responses to purified or lysed human rotavirus were stronger after a rise in rotavirus antibodies than the responses before infection (P = 0.017 and 0.027, respectively). There was a correlation between T-cell responses to purified and lysed human rotavirus and NCDV. Strong T-cell responses to rotavirus were transient and the ability to respond usually disappeared in one year, but in all adults T-cell responses to rotavirus were strong implicating that several infections are needed to develop consistent, strong T-cell responsiveness.

Adult↗
PubMed2004

Type 1 diabetes is insulin -2221 MspI and CTLA-4 +49 A/G polymorphism dependent.

BACKGROUND: Several studies have demonstrated an association of type 1 diabetes with specific alleles of HLA class II molecules, as with polymorphisms of insulin gene region. The aim of our study was to evaluate the interaction of insulin -2221 MspI polymorphism to type 1 diabetes susceptibility in connection with autoimmunity associated gene--CTLA-4 polymorphism. MATERIALS AND METHODS: Insulin -2221 MspI C/T and CTLA-4 +49 A/G polymorphisms were detected by restriction fragment-length polymorphism analysis or oligonucleotide hybridization in type 1 (n = 69), type 2 diabetes (n = 301) patients and 158 healthy controls. Regression model adjusted for age, gender and gene polymorphisms was studied. RESULTS: C-allele of insulin -2221 MspI and G-allele of +49 CTLA-4 were significant risk factors for type 1 diabetes (crude OR 3.53 and 1.59, respectively) and this impact increased in the homozygous form of both alleles. The regression model supported the idea of insulin CC and CTLA-4 GG genotypes for an independent and clearly significant risk for developing type 1 diabetes. We could not detect any significant correlation between investigated polymorphisms and type 2 diabetes. CONCLUSIONS: There exists a significant association between the C-allele of -2221 MspI in the insulin gene and type 1 diabetes. The CTLA-4 G-allele is also positively correlated with type 1 diabetes. According to the regression model the investigated gene polymorphisms are independent risk factors for development of type 1 diabetes in the Estonian population. We propose that -2221 MspI is a good marker for evaluation of risk of insulin gene haplotype in type 1 diabetes patients.

Aged↗
PubMed2004

The human leukocyte antigen genotype has a modest effect on the insulin gene polymorphism-associated susceptibility to type 1 diabetes in the Finnish population.

In addition to the known human leukocyte antigen (HLA)-associated risk, polymorphisms of insulin gene region show association with type 1 diabetes. We analyzed possible interactions between the HLA class II genotypes and -2221 MspI (insulin) INS gene polymorphism in Finnish population, using a series of 1331 diabetic children and 2222 healthy newborns. C/C genotype was increased among diabetic children compared to the controls (83.2 vs 70.1%). This genotype was slightly more common in diabetic children with low or moderate HLA-associated risk than in those with high risk, but INS gene effect was clear in all major HLA-risk genotypes and, thus, can be used as an additional risk prediction marker, irrespective of HLA genotypes.

Child↗
PubMed2004

Isolation of enterovirus strains from children with preclinical Type 1 diabetes.

AIMS: To develop methods for isolation of enterovirus strains from subjects with preclinical Type 1 diabetes and evaluate if their presence in stools is associated with beta-cell damage. METHODS: The study subjects were participants of the Finnish Type 1 Diabetes Prediction and Prevention Study (DIPP). The prospectively followed birth cohort comprised 12 children who turned positive for diabetes-associated autoantibodies during the follow-up (case children) and 53 controls matched for date of birth, sex and HLA-DQB1 alleles. Altogether, 878 stool samples were analysed for the presence of enterovirus RNA by RT-PCR followed by virus isolation and partial sequencing of viral genome. Enterovirus antibodies and RNA were simultaneously analysed from serum. RESULTS: Eleven enterovirus infections were diagnosed in case children and 42 infections in control children by the presence of viral RNA in stools. The proportion of children who were repeatedly enterovirus RNA-positive stools was higher among case than control children (42% vs. 11% of children; P=0.02). Combined serum (antibody and RT-PCR) and stool analyses indicated at least one enterovirus infection in 83% of the case children before the appearance of autoantibodies, while only 42% of the control children had infection by the same age (P=0.006). Twelve enterovirus strains were isolated from case children and 38 strains from control children. CONCLUSIONS: This protocol makes it possible to isolate a large number of enterovirus strains from prediabetic subjects. The findings suggest that enterovirus infections may be associated with the beta-cell damaging process.

Autoantibodies↗
PubMed2004

HLA-DR-DQ haplotypes and genotypes in Finnish patients with rheumatoid arthritis.

OBJECTIVES: To elucidate the contribution of HLA-DR-DQ haplotypes and their genotypic combinations to susceptibility to rheumatoid arthritis, and to evaluate the various models for HLA associated risk for the disease in a series of Finnish patients. METHODS: 322 Finnish patients with rheumatoid arthritis were typed for common north European HLA-DR-DQ haplotypes and compared with a series of 1244 artificial family based control haplotypes. RESULTS: The association of the so called shared epitope (SE) haplotypes (DRB1*0401, *0404, *0408, and *01) with rheumatoid arthritis was confirmed. The DRB1*0401 haplotypes carried a far stronger risk for the disease than the (DRB1*01/10)-(DQA1*01)-DQB1*0501 haplotypes. Seven protective HLA haplotypes--(DRB1*15)-(DQA1*01)-DQB1*0602; (DRB1*08)-(DQA1*04)-DQB1*04; (DRB1*11/12)-DQA1*05-DQB1*0301; (DRB1*1301)-(DQA1*01)-DQB1*0603; (DRB1*1302)-(DQA1*01)-DQB1*0604; (DRB1*07)-DQA1*0201-DQB1*0303; and (DRB1*16)- (DQA1*01)-DQB1*0502--were identified. In accordance with the reshaped shared epitope hypothesis, all the protective DRB1 alleles in these haplotypes share either isoleucine at position 67 or aspartic acid at position 70 in their third hypervariable region motif. However, differences in the disease risk of haplotypes carrying the same DR but different DQ alleles were also found: (DRB1*07)-DQA1*0201-DQB1*0303 was protective, while (DRB1*07)-DQA1*0201-DQB1*02 was neutral. The same haplotypes carried different risks for rheumatoid arthritis depending on their combination in genotypes. CONCLUSIONS: When assessing the influence of HLA genes on the susceptibility to rheumatoid arthritis, not only should the HLA-DR or -DQ alleles or haplotypes be unravelled but also the genotype. The effect of HLA class II region genes is more complicated than any of the existing hypotheses can explain.

Arthritis, Rheumatoid↗
PubMed2003

Temporal changes in the frequencies of HLA genotypes in patients with Type 1 diabetes--indication of an increased environmental pressure?

AIMS/HYPOTHESIS: The incidence of Type 1 diabetes has increased 2.5 times during the time period from 1966 to 2000 in Finland-a general trend seen in almost all developed countries that can only be explained by environmental factors. The aim of this study was to test the possible effect of a changing environment on distribution of genotypes associated with disease susceptibility. METHODS: HLA DRB1-DQA1-DQB1 genes and two diabetes-associated polymorphisms at IDDM2 and IDDM12 were analyzed. The frequencies of genotypes were compared between cases diagnosed with childhood-onset Type 1 diabetes during the period of 1939-1965 (n=367) and those diagnosed between 1990 and 2001 (n=736). Chi-square statistics or the Fisher's Exact test were used for the comparison of frequencies of analyzed haplotypes and genotypes in the two groups. RESULTS: The frequencies of (DR3) -DQA1*05-DQB1*02 and (DR4) -DQB1*0302 risk haplotypes and the high risk (DR3) -DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 genotype were higher while proportion of patients carrying protective haplotypes-(DR15) -DQB1*0602 and (DR1301) -DQB1*0603-or protective genotypes was lower in patients diagnosed before 1965 as compared to those who developed disease after 1990. No temporal variation was found in the frequencies of genotypes at IDDM2 and IDDM12. CONCLUSION/INTERPRETATION: Our data suggest that the need for genetic susceptibility to develop Type 1 diabetes has decreased over time due to an increasing environmental pressure and this results in a higher disease progression rate especially in subjects with protective HLA genotypes.

Child↗