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- 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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- 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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- Gyllenberg, A, et al.
(författare)
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Variability in the CIITA gene interacts with HLA in multiple sclerosis.
- 2014
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Ingår i: Genes and immunity. - Stockholm : Springer Science and Business Media LLC. - 1476-5470 .- 1466-4879. ; 15, s. 162-167
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Tidskriftsartikel (refereegranskat)abstract
- The human leukocyte antigen (HLA) is the main genetic determinant of multiple sclerosis (MS) risk. Within the HLA, the class II HLA-DRB1*15:01 allele exerts a disease-promoting effect, whereas the class I HLA-A*02 allele is protective. The CIITA gene is crucial for expression of class II HLA molecules and has previously been found to associate with several autoimmune diseases, including MS and type 1 diabetes. We here performed association analyses with CIITA in 2000 MS cases and up to 6900 controls as well as interaction analysis with HLA. We find that the previously investigated single-nucleotide polymorphism rs4774 is associated with MS risk in cases carrying the HLA-DRB1*15 allele (P=0.01, odds ratio (OR): 1.21, 95% confidence interval (CI): 1.04-1.40) or the HLA-A*02 allele (P=0.01, OR: 1.33, 95% CI: 1.07-1.64) and that these associations are independent of the adjacent confirmed MS susceptibility gene CLEC16A. We also confirm interaction between rs4774 and HLA-DRB1*15:01 such that individuals carrying the risk allele for rs4774 and HLA-DRB1*15:01 have a higher than expected risk for MS. In conclusion, our findings support previous data that variability in the CIITA gene affects MS risk, but also that the effect is modulated by MS-associated HLA haplotypes. These findings further underscore the biological importance of HLA for MS risk.Genes and Immunity advance online publication, 16 January 2014; doi:10.1038/gene.2013.71.
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- Andersson, C, et al.
(författare)
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Triple specificity of ZnT8 autoantibodies in relation to HLA and other islet autoantibodies in childhood and adolescent type 1 diabetes
- 2013
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Ingår i: Pediatric Diabetes. - : Wiley-Blackwell. - 1399-543X .- 1399-5448. ; 14:2, s. 97-105
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Tidskriftsartikel (refereegranskat)abstract
- Andersson C, Vaziri-Sani F, Delli AJ, Lindblad B, Carlsson A, Forsander G, Ludvigsson J, Marcus C, Samuelsson U, Ivarsson SA, Lernmark A, Elding Larsson H, the BDD Study group. Triple specificity of ZnT8 autoantibodies in relation to HLA and other islet autoantibodies in childhood and adolescent type 1 diabetes. Pediatric Diabetes 2013: 14: 97-105. Objective To establish the diagnostic sensitivity of and the relationships between autoantibodies to all three Zinc transporter 8 (Zinc transporter 8 autoantibody to either one, two, or all three amino acid variants at position 325, ZnT8A) variants to human leukocyte antigen (HLA)-DQ and to autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A), and insulin (IAA). Methods We analyzed 3165 patients with type 1 diabetes (T1D) in the Better Diabetes Diagnosis study for HLA-DQ genotypes and all six autoantibodies (ZnT8RA, arginine 325 Zinc transporter 8 autoantibody; ZnT8WA, tryptophan 325 Zinc transporter 8 autoantibody; ZnT8QA, glutamine 325 Zinc transporter 8 autoantibody; GADA, IA-2A, and IAA). Results ZnT8A was found in 65% of the patients and as many as 108 of 3165 (3.4%) had 13 ZnT8A alone. None had ZnT8QA alone. Together with GADA (56%), IA-2A (73%), and IAA (33%), 93% of the T1D patients were autoantibody positive. All three ZnT8A were less frequent in children below 2 yr of age (pandlt;0.0001). All three ZnT8A were associated with DQA1-B1*X-0604 (DQ6.4) and DQA1-B1*03-0302 (DQ8). ZnT8WA and ZnT8QA were negatively associated with DQA1-B1*05-02 (DQ2). Conclusions Analysis of ZnT8A increased the diagnostic sensitivity of islet autoantibodies for T1D as only 7% remained islet autoantibody negative. The association between DQ6.4 and all three ZnT8A may be related to ZnT8 antigen presentation by the DQ6.4 heterodimer.
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- Lindehammer, Sabina Resic, et al.
(författare)
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Viruses, diabetes, and autoimmunity : Studies of subjects at genetic risk for type 1 diabetes
- 2013
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Ingår i: Diabetes and Viruses. - New York, NY : Springer New York. - 9781461440505 - 9781461440512 ; 9781461440512, s. 187-194
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Bokkapitel (refereegranskat)abstract
- The possible importance of virus infections before the development of islet autoimmunity and then for the appearance of clinical type 1 diabetes is reviewed. There is a lack of specific data on the role of virus to induce islet autoimmunity. There is also a paucity of data to demonstrate that virus infections may contribute to an accelerated disease process resulting in clinical onset of type 1 diabetes. In contrast, there is a plethora of studies on virus infections at the time of clinical onset. However, these studies have made the understanding of virus in type 1 diabetes less easy. Future studies need to address further gestational infections and the risk of the offspring for islet autoimmunity. Such studies should also investigate the mechanisms by which gestational infections may alter the ability of the offspring to respond to future virus infections related to the development of islet autoimmunity or accelerator of the clinical onset of diabetes.
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- Moralejo, Daniel H., et al.
(författare)
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BB rat Gimap gene expression in sorted lymphoid T and B cells
- 2011
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Ingår i: Life Sciences. - : Elsevier BV. - 1879-0631 .- 0024-3205. ; 89:19-20, s. 748-754
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The Gimap gene family has been shown to be integral to T cell survival and development. A frameshift mutation in Gimap5, one of seven members of the Gimap family, results in lymphopenia and is a prerequisite for spontaneous type 1 diabetes (T1D) in the BioBreeding (BB) rat. While not contributing to lymphopenia, the Gimap family members proximal to Gimap5, encompassed within the Iddm39 quantitative trait locus (QTL), have been implicated in T1D. We hypothesized that expression of the Gimap family members within the Iddm39 QTL, during thymocyte development as well as in peripheral T and B cells contribute to T1D. Main methods: Cell sorted subpopulations were analyzed by quantitative real time (qRT) PCR. Key findings: Gimap4 expression was reduced in DR.(lyp/lyp) rat double negative, double positive and CD8 single positive (SP) thymocytes while expression of Gimap8, Gimap6, and Gimap7 was reduced only in CD8 SP thymocytes. Interestingly, expression of the entire Gimap gene family was reduced in DR.(lyp/lyp) rat peripheral T cells compared to non-lymphopenic, non-diabetic DR.(+/+) rats. With the exception of Gimap6. the Gimap family genes were not expressed in B cells from spleen and mesenteric lymph node (MLN). Expression of Gimap9 was only detected in hematopoietic cells of non B cell lineage such as macrophage, dendritic or NK cells. Significance: These results suggest that lack of the Gimap5 protein in the DR.(lyp/lyp) congenic rat was associated with impaired expression of the entire family of Gimap genes and may regulate T cell homeostasis in the peripheral lymphoid organs. (C) 2011 Elsevier Inc. All rights reserved.
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