| 1. |
- Andersson Svärd, Agnes, et al.
(författare)
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Possible Relationship between the HLA-DRA1 Intron Haplotype of Three Single-Nucleotide Polymorphisms in Intron 1 of the HLA-DRA1 Gene and Autoantibodies in Children at Increased Genetic Risk for Autoimmune Type 1 Diabetes
- 2022
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Ingår i: ImmunoHorizons. - : The American Association of Immunologists. - 2573-7732. ; 6:8, s. 614-629
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Tidskriftsartikel (refereegranskat)abstract
- Recently, a haplotype of three single-nucleotide polymorphisms (tri-SNP) in intron 1 of the HLA-DRA1 gene was found to be strongly associated with type 1 diabetes risk in HLA-DR3/3 individuals. The tri-SNP reportedly function as “expression quantitative trait loci,” modulating HLA-DR and -DQ expression. The aim was to investigate HLA-DRA1 tri-SNPs in relation to extended HLA class II haplotypes and human peripheral blood cell HLA-DQ cell-surface median fluorescence intensity (MFI), the first-appearing islet autoantibody, and autoimmunity burden. A total of 67 healthy subjects (10–15 y) at increased HLA risk for type 1 diabetes and with (n = 54) or without (n = 13) islet autoantibodies were followed longitudinally in the Diabetes Prediction in Skåne study. Among four tri-SNPs, AGG (n = 67), GCA (n = 47), ACG (n = 11), and ACA (n = 9), HLA-DQ cell-surface MFI on CD4+ T cells was lower in AGG than GCA (p = 0.030) subjects. Cumulative autoimmunity burden was associated with reduced HLA-DQ cell-surface MFI in AGG compared with GCA in CD16+ cells (p = 0.0013), CD4+ T cells (p = 0.0018), and CD8+ T cells (p = 0.016). The results suggest that HLA-DRA1 tri-SNPs may be related to HLA-DQ cell-surface expression and autoimmunity burden.
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| 2. |
- Bediaga, Naiara G, et al.
(författare)
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Simplifying prediction of disease progression in pre-symptomatic type 1 diabetes using a single blood sample
- 2021
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 64:11, s. 2432-2444
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw.METHODS: Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial-Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da.RESULTS: Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M60, M90 and M120, based on sampling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood samples. In TEDDY, where only 120 min blood sampling had been performed, the M120 AUC was 0.865. In Fr1da, the M120 AUC of 0.742 was significantly greater than the M60 AUC of 0.615.CONCLUSIONS/INTERPRETATION: Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M120, its validity across different at-risk populations and the requirement for 120 min sampling to stage type 1 diabetes suggest M120 could be readily applied to decrease the cost and complexity of risk stratification.
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| 3. |
- Jahoor, Farook, et al.
(författare)
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Metabolomics Profiling of Patients With A-β+ Ketosis-Prone Diabetes During Diabetic Ketoacidosis
- 2021
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 70:8, s. 1898-1909
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Tidskriftsartikel (refereegranskat)abstract
- When stable and near-normoglycemic, patients with "A-β+" ketosis-prone diabetes (KPD) manifest accelerated leucine catabolism and blunted ketone oxidation, which may underlie their proclivity to develop diabetic ketoacidosis (DKA). To understand metabolic derangements in A-β+ KPD patients during DKA, we compared serum metabolomics profiles of adults during acute hyperglycemic crises, without (n = 21) or with (n = 74) DKA, and healthy control subjects (n = 17). Based on 65 kDa GAD islet autoantibody status, C-peptide, and clinical features, 53 DKA patients were categorized as having KPD and 21 type 1 diabetes (T1D); 21 nonketotic patients were categorized as having type 2 diabetes (T2D). Patients with KPD and patients with T1D had higher counterregulatory hormones and lower insulin-to-glucagon ratio than patients with T2D and control subjects. Compared with patients withT2D and control subjects, patients with KPD and patients with T1D had lower free carnitine and higher long-chain acylcarnitines and acetylcarnitine (C2) but lower palmitoylcarnitine (C16)-to-C2 ratio; a positive relationship between C16 and C2 but negative relationship between carnitine and β-hydroxybutyrate (BOHB); higher branched-chain amino acids (BCAAs) and their ketoacids but lower ketoisocaproate (KIC)-to-Leu, ketomethylvalerate (KMV)-to-Ile, ketoisovalerate (KIV)-to-Val, isovalerylcarnitine-to-KIC+KMV, propionylcarnitine-to-KIV+KMV, KIC+KMV-to-C2, and KIC-to-BOHB ratios; and lower glutamate and 3-methylhistidine. These data suggest that during DKA, patients with KPD resemble patients with T1D in having impaired BCAA catabolism and accelerated fatty acid flux to ketones-a reversal of their distinctive BCAA metabolic defect when stable. The natural history of A-β+ KPD is marked by chronic but varying dysregulation of BCAA metabolism.
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| 4. |
- Stene, Lars C., et al.
(författare)
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Epidemiology and Pathogenesis of Type 1 Diabetes
- 2023. - 2
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Ingår i: Transplantation of the Pancreas. - 9783031209987 - 9783031209994 ; , s. 13-39
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Bokkapitel (refereegranskat)abstract
- Type 1 diabetes is an autoimmune disease that affects 0.1 to nearly 1% of the population, dependent on the country, with its highest incidence around 10–15 years of age. The incidence has increased over time, approximately doubling over the past 2–3 decades. The incidence varies across the world, with the highest among populations of (Northern) European origin and the lowest in Japan. Most diabetic patients do not have affected first-degree relatives, but genetic predispostion encoded in the HLA class II DR- and DQ loci is proabably necessary, albeit not sufficient, for developing disease. Exposure to environmental factors in early life appears to also impact the risk of disease development, but available evidence does not allow for strong conclusions to be drawn. The past decade has brought new data from human pancreatic donors. Hoewever, the timing between etiological triggers and the pathogenesis is poorly defined, and the disease mechanisms need to be elucidated. It is still not possible to prevent or cure type 1 diabetes. The latter can currently only be achieved using invasive beta-cell repacement therapies through transplantation.
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| 5. |
- Vehik, Kendra, et al.
(författare)
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Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study
- 2020
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 43:9, s. 2066-2073
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The first-appearing β-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the risk of autoantibody spreading to the second-appearing autoantibody and further progression to clinical disease in the Environmental Determinants of Diabetes in the Young study.RESEARCH DESIGN AND METHODS: Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or IA2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (ZnT8A) was measured in children who developed another autoantibody.RESULTS: There were 608 children who developed a single first-appearing autoantibody (IAA, n = 282 or GADA, n = 326) with a median follow-up of 12.5 years from birth. The risk of a second-appearing autoantibody was independent of GADA versus IAA as a first-appearing autoantibody (adjusted hazard ratio [HR] = 1.12, 95% CI = 0.88-1.42, P = 0.36). Second-appearing GADA, IAA, IA-2A, or ZnT8A conferred an increased risk of T1D compared with children who remained positive for a single autoantibody, e.g., IAA or GADA second (adjusted HR 6.44; 95% CI 3.78-10.98), IA-2A second (adjusted HR 16.33; 95% CI 9.10-29.29; P < 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61-10.95; P < 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR = 3.08; 95% CI = 2.04-4.65; P < 0.0001) conferred a greater risk of progression to T1D as compared with GADA or IAA. Additionally, both a younger initial age at seroconversion and shorter time to the development of the second-appearing autoantibody increased the risk for T1D.CONCLUSIONS: The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D.
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| 6. |
- Zhao, Lue Ping, et al.
(författare)
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Motifs of Three HLA-DQ Amino Acid Residues (alpha 44, beta 57, beta 135) Capture Full Association With the Risk of Type 1 Diabetes in DQ2 and DQ8 Children
- 2020
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Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 69:7, s. 1573-1587
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Tidskriftsartikel (refereegranskat)abstract
- HLA-DQA1 and -DQB1 are strongly associated with type 1 diabetes (T1D), and DQ8.1 and DQ2.5 are major risk haplotypes. Next-generation targeted sequencing of HLA-DQA1 and -DQB1 in Swedish newly diagnosed 1- to 18 year-old patients (n= 962) and control subjects (n= 636) was used to construct abbreviated DQ haplotypes, converted into amino acid (AA) residues, and assessed for their associations with T1D. A hierarchically organized haplotype (HOH) association analysis allowed 45 unique DQ haplotypes to be categorized into seven clusters. The DQ8/9 cluster included two DQ8.1 risk and the DQ9 resistant haplotypes, and the DQ2 cluster included the DQ2.5 risk and DQ2.2 resistant haplotypes. Within each cluster, HOH found residues alpha 44Q (odds ratio [OR] 3.29,P= 2.38 * 10(-85)) and beta 57A (OR 3.44,P= 3.80 * 10(-84)) to be associated with T1D in the DQ8/9 cluster representing all ten residues (alpha 22, alpha 23, alpha 44, alpha 49, alpha 51, alpha 53, alpha 54, alpha 73, alpha 184, beta 57) due to complete linkage disequilibrium (LD) of alpha 44 with eight such residues. Within the DQ2 cluster and due to LD, HOH analysis found alpha 44C and beta 135D to share the risk for T1D (OR 2.10,P= 1.96 * 10(-20)). The motif "QAD" of alpha 44, beta 57, and beta 135 captured the T1D risk association of DQ8.1 (OR 3.44,P= 3.80 * 10(-84)), and the corresponding motif "CAD" captured the risk association of DQ2.5 (OR 2.10,P= 1.96 * 10(-20)). Two risk associations were related to GAD65 autoantibody (GADA) and IA-2 autoantibody (IA-2A) but in opposite directions. CAD was positively associated with GADA (OR 1.56,P= 6.35 * 10(-8)) but negatively with IA-2A (OR 0.59,P= 6.55 * 10(-11)). QAD was negatively associated with GADA (OR 0.88;P= 3.70 * 10(-3)) but positively with IA-2A (OR 1.64;P= 2.40 * 10(-14)), despite a single difference at alpha 44. The residues are found in and around anchor pockets 1 and 9, as potential T-cell receptor contacts, in the areas for CD4 binding and putative homodimer formation. The identification of three HLA-DQ AAs (alpha 44, beta 57, beta 135) conferring T1D risk should sharpen functional and translational studies.
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