| 1. |
- Shin, J. H., et al.
(författare)
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IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5
- 2007
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Ingår i: Genes Immun. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 8:6, s. 503-12
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Tidskriftsartikel (refereegranskat)abstract
- In a large case-control study of Swedish incident type I diabetes patients and controls, 0-34 years of age, we tested the hypothesis that the GIMAP5 gene, a key genetic factor for lymphopenia in spontaneous BioBreeding rat diabetes, is associated with type I diabetes; with islet autoantibodies in incident type I diabetes patients or with age at clinical onset in incident type I diabetes patients. Initial scans of allelic association were followed by more detailed logistic regression modeling that adjusted for known type I diabetes risk factors and potential confounding variables. The single nucleotide polymorphism (SNP) rs6598, located in a polyadenylation signal of GIMAP5, was associated with the presence of significant levels of IA-2 autoantibodies in the type I diabetes patients. Patients with the minor allele A of rs6598 had an increased prevalence of IA-2 autoantibody levels compared to patients without the minor allele (OR=2.2; Bonferroni-corrected P=0.003), after adjusting for age at clinical onset (P=8.0 x 10(-13)) and the numbers of HLA-DQ A1*0501-B1*0201 haplotypes (P=2.4 x 10(-5)) and DQ A1*0301-B1*0302 haplotypes (P=0.002). GIMAP5 polymorphism was not associated with type I diabetes or with GAD65 or insulin autoantibodies, ICA, or age at clinical onset in patients. These data suggest that the GIMAP5 gene is associated with islet autoimmunity in type I diabetes and add to recent findings implicating the same SNP in another autoimmune disease.
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| 2. |
- Carlsson, Annelie, et al.
(författare)
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Low risk HLA-DQ and increased body mass index in newly diagnosed type 1 diabetes children in the Better Diabetes Diagnosis study in Sweden
- 2012
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Ingår i: International Journal of Obesity. - : Nature Publishing Group. - 0307-0565 .- 1476-5497. ; 36:5, s. 718-724
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Type 1 diabetes and obesity has increased in childhood. We therefore tested the hypothesis that type 1 diabetes human leukocyte antigen DQ (HLA-DQ) risk genotypes may be associated with increased body mass index (BMI). less thanbrgreater than less thanbrgreater thanDesign: The type 1 diabetes high-risk HLA-DQ A1*05:01-B1*02:01/A1*03:01-B1*03:02 genotype along with lower risk DQ genotypes were determined at the time of clinical onset by PCR and hybridization with allele-specific probes. BMI was determined after diabetes was stabilized. less thanbrgreater than less thanbrgreater thanSubjects: A total of 2403 incident type 1 diabetes children below 18 years of age were ascertained in the Swedish national Better Diabetes Diagnosis (BDD) study between May 2005 to September 2009. All children classified with type 1 diabetes, including positivity for at least one islet autoantibody, were investigated. less thanbrgreater than less thanbrgreater thanResults: Overall, type 1 diabetes HLA-DQ risk was negatively associated with BMI (Pandlt;0.0008). The proportion of the highest risk A1*05:01-B1*02:01/A1*03:01-B1*03:02 genotype decreased with increasing BMI (Pandlt;0.0004). However, lower risk type 1 diabetes DQ genotypes were associated with an increased proportion of patients who were overweight or obese (Pandlt;0.0001). Indeed, the proportion of patients with the low-risk A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype increased with increasing BMI (Pandlt;0.003). The magnitude of association on the multiplicative scale between the A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype and increased BMI was significant (Pandlt;0.006). The odds ratio in patients with this genotype of being obese was 1.80 (95% confidence interval 1.21-2.61; Pandlt;0.006). The increased proportion of overweight type 1 diabetes children with the A1*05:01-B1*02:01 haplotype was most pronounced in children diagnosed between 5 and 9 years of age. less thanbrgreater than less thanbrgreater thanConclusions: Susceptibility for childhood type 1 diabetes was unexpectedly found to be associated with the A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype and an increased BMI. These results support the hypothesis that overweight may contribute to the risk of type 1 diabetes in children positive for HLA-DQ A1*05:01-B1*02:01.
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| 3. |
- Gyllenberg, A, et al.
(författare)
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Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes
- 2012
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Ingår i: Genes and Immunity. - Stockholm : Springer Science and Business Media LLC. - 1476-5470 .- 1466-4879. ; 76:2, s. 202-203
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Tidskriftsartikel (refereegranskat)abstract
- The major histocompatibility complex class II transactivator (CIITA) gene (16p13) has been reported to associate with susceptibility to multiple sclerosis, rheumatoid arthritis and myocardial infarction, recently also to celiac disease at genome-wide level. However, attempts to replicate association have been inconclusive. Previously, we have observed linkage to the CIITA region in Scandinavian type 1 diabetes (T1D) families. Here we analyze five Swedish T1D cohorts and a combined control material from previous studies of CIITA. We investigate how the genotype distribution within the CIITA gene varies depending on age, and the association to T1D. Unexpectedly, we find a significant difference in the genotype distribution for markers in CIITA (rs11074932, P=4 × 10(-5) and rs3087456, P=0.05) with respect to age, in the collected control material. This observation is replicated in an independent cohort material of about 2000 individuals (P=0.006, P=0.007). We also detect association to T1D for both markers, rs11074932 (P=0.004) and rs3087456 (P=0.001), after adjusting for age at sampling. The association remains independent of the adjacent T1D risk gene CLEC16A. Our results indicate an age-dependent variation in CIITA allele frequencies, a finding of relevance for the contrasting outcomes of previously published association studies.
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| 4. |
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| 5. |
- Samuelsson, Ulf, et al.
(författare)
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Residual beta cell function at diagnosis of type 1 diabetes in children and adolescents varies with gender and season
- 2013
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Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley and Sons. - 1520-7552 .- 1520-7560. ; 29:1, s. 85-89
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThere are seasonal variations and gender differences in incidence of type 1 diabetes (T1D), metabolic control and responses to immune interventions at onset of the disease.We hypothesized that there are seasonal and gender differences in residual insulin secretion already at diagnosis of T1D.MethodsIn 2005, a national study, the Better Diabetes Diagnosis, was started to classify all newly diagnosed children and adolescents with diabetes. About 95% (3824/4017) of the patients were classified as T1D, and our analyses are based on the patients with T1D.ResultsC-peptide was lower in younger children, 0–10 years of age (0.23 ± 0.20 nmol/L) than in older children, 11–18 years of age (0.34 ± 0.28 nmol/L) (p < 0.000 ). There was a seasonal variation in non-fasting serum C-peptide, significantly correlated to the seasonal variation of diagnosis (p < 0.01). Most children were diagnosed in January, February and March as well as in October when C-peptide was highest, whereas fewer patients were diagnosed in April and May when serum C-peptide was significantly lower (p < 0.01). The seasonal variation of C-peptide was more pronounced in boys than in girls (p < 0.000 and p < 0.01, respectively). Girls had higher C-peptide than boys (p < 0.05), especially in early puberty.ConclusionsBoth seasonal and gender differences in residual beta cell function exist already at diagnosis of T1D. These observations have consequences for treatment and for randomizing patients in immune intervention clinical trials.
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| 6. |
- Sedimbi, S. K., et al.
(författare)
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SUMO4 M55V polymorphism affects susceptibility to type I diabetes in HLA DR3- and DR4-positive Swedish patients
- 2007
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Ingår i: Genes Immun. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 8:6, s. 518-21
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Tidskriftsartikel (refereegranskat)abstract
- SUMO4 M55V, located in IDDM5, has been a focus for debate because of its association to type I diabetes (TIDM) in Asians but not in Caucasians. The current study aims to test the significance of M55V association to TIDM in a large cohort of Swedish Caucasians, and to test whether M55V is associated in those carrying human leukocyte antigen (HLA) class II molecules. A total of 673 TIDM patients and 535 age- and sex-matched healthy controls were included in the study. PCR-RFLP was performed to identify the genotype and allele variations. Our data suggest that SUMO4 M55V is not associated with susceptibility to TIDM by itself. When we stratified our patients and controls based on heterozygosity for HLA-DR3/DR4 and SUMO4 genotypes, we found that presence of SUMO4 GG increased further the relative risk conferred by HLA-DR3/DR4 to TIDM, whereas SUMO4 AA decreased the risk. From the current study, we conclude that SUMO4 M55V is associated with TIDM in association with high-risk HLA-DR3 and DR4, but not by itself.
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| 7. |
- Svensson, Matilda1, et al.
(författare)
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Antibodies to Influenza Virus A/H1N1 Hemagglutinin in Type 1 Diabetes Children Diagnosed Before, During and After the SWEDISH A(H1N1)pdm09 Vaccination Campaign 2009-2010
- 2014
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 79:2, s. 137-148
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Tidskriftsartikel (refereegranskat)abstract
- We determined A/H1N1-hemagglutinin (HA) antibodies in relation to HLAD-Q genotypes and islet autoantibodies at clinical diagnosis in 1141 incident 0.7 to 18-year-old type 1 diabetes patients diagnosed April 2009-December 2010. Antibodies to S-35-methionine-labelled A/H1N1 hemagglutinin were determined in a radio-binding assay in patients diagnosed before (n = 325), during (n = 355) and after (n = 461) the October 2009-March 2010 Swedish A(H1N1) pdm09 vaccination campaign, along with HLA-DQ genotypes and autoantibodies against GAD, insulin, IA-2 and ZnT8 transporter. Before vaccination, 0.6% patients had A/H1N1-HA antibodies compared with 40% during and 27% after vaccination (P less than 0.0001). In children less than3 years of age, A/H1N1-HA antibodies were found only during vaccination. The frequency of A/H1N1-HA antibodies during vaccination decreased after vaccination among the 3 less than 6 (P = 0.006) and 13 less than 18 (P = 0.001), but not among the 6 less than 13-year-olds. HLA-DQ2/8 positive children less than3 years decreased from 54% (15/28) before and 68% (19/28) during, to 30% (9/30) after vaccination (P = 0.014). Regardless of age, DQ2/2; 2/X (n = 177) patients had lower frequency (P = 0.020) and levels (P = 0.042) of A/H1N1-HA antibodies compared with non-DQ2/2; 2/X (n = 964) patients. GADA frequency was 50% before, 60% during and 51% after vaccination (P = 0.009). ZnT8QA frequency increased from 30% before to 34% during and 41% after vaccination (P = 0.002). Our findings suggest that young (less than3 years) along with DQ2/2; 2/X patients were low responders to Pandemrix (R). As the proportion of DQ2/8 patients less than3 years of age decreased after vaccination and the frequencies of GADA and ZnT8QA were enhanced, it cannot be excluded that the vaccine affected clinical onset of type 1 diabetes.
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| 8. |
- Åkesson, K, et al.
(författare)
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The non-inherited maternal HLA haplotype affects the risk for type 1 diabetes
- 2009
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Ingår i: International journal of immunogenetics. - 1744-3121 .- 1744-313X. ; 36:1, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to test the hypothesis that the human leucocyte antigen (HLA) haplotype that is not inherited from the mother, that is, the non-inherited maternal antigen (NIMA) affects the risk for type 1 diabetes (T1D). A total of 563 children with T1D and 286 non-diabetic control children from Sweden were genotyped for DRB1, DQA1 and DQB1 alleles. The frequency of positively (DR4-DQA1*0301-B1*0302 and DR3-DQA1*0501-B1*0201), negatively (DR15-DQ A1*0102-B1*0602) or neutrally (all other) T1D associated HLA haplotypes were compared between NIMA and non-inherited paternal antigen (NIPA). All comparisons were carried out between HLA-matched patients and controls. The frequency of positively associated NIMA was higher among both DR4/X-positive healthy individuals compared wit DR4/X-positive patients (P < 0.00003) and DR3/X-positive healthy individuals compared with DR3/X-positive patients (P < 0.009). No such difference was observed for NIPA. High-risk NIMA was increased compared to NIPA among healthy DR3/X- and DR4/X-positive children (P < 0.05). There was no difference in frequency of positively associated haplotypes between patient NIMA and NIPA. The NIMA but not the NIPA affects the risk for T1D, suggesting that not only the inherited but also non-inherited maternal HLA haplotypes, perhaps through microchimerism or other mechanisms, may influence the risk for the disease.
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