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- Lernmark, Åke
(författare)
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Etiology of Autoimmune Islet Disease : Timing Is Everything
- 2021
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 70:7, s. 1431-1439
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Tidskriftsartikel (refereegranskat)abstract
- Life is about timing.-Carl LewisThe understanding of autoimmune type 1 diabetes is increasing, and examining etiology separate from pathogenesis has become crucial. The components to explain type 1 diabetes development have been known for some time. The strong association with HLA has been researched for nearly 50 years. Genome-wide association studies added another 60+ non-HLA genetic factors with minor contribution to risk. Insulitis has long been known to be present close to clinical diagnosis. T and B cells recognizing β-cell autoantigens are detectable prior to diagnosis and in newly diagnosed patients. Islet autoantibody tests against four major autoantigens have been standardized and used as biomarkers of islet autoimmunity. However, to clarify the etiology would require attention to time. Etiology may be defined as the cause of a disease (i.e., type 1 diabetes) or abnormal condition (i.e., islet autoimmunity). Timing is everything, as neither the prodrome of islet autoimmunity nor the clinical onset of type 1 diabetes tells us much about the etiology. Rather, the islet autoantibody that appears first and persists would mark the diagnosis of an autoimmune islet disease (AID). Events after the diagnosis of AID would represent the pathogenesis. Several islet autoantibodies without (stage 1) or with impaired glucose tolerance (stage 2) or with symptoms (stage 3) would define the pathogenesis culminating in clinical type 1 diabetes. Etiology would be about the timing of events that take place before the first-appearing islet autoantibody.
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| 2. |
- Li, Qian, et al.
(författare)
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Longitudinal Metabolome-Wide Signals Prior to the Appearance of a First Islet Autoantibody in Children Participating in the TEDDY Study
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 69:3, s. 465-476
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Tidskriftsartikel (refereegranskat)abstract
- Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children's plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and γ-aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D.
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| 3. |
- Li, Qian, et al.
(författare)
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Plasma Metabolome and Circulating Vitamins Stratified Onset Age of an Initial Islet Autoantibody and Progression to Type 1 Diabetes : the TEDDY Study
- 2021
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 70:1, s. 282-292
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Tidskriftsartikel (refereegranskat)abstract
- Children's plasma metabolome, especially lipidome reflects gene regulation and dietary exposures, heralding the development of islet autoantibodies (IA) and type 1 diabetes (T1D). The TEDDY study enrolled 8676 newborns by screening HLA-DR-DQ genotypes at six clinical centers in four countries; profiled metabolome and measured concentrations of ascorbic acid, 25-hydroxyvitamin D (25(OH)D), erythrocyte membrane fatty acids following birth until IA seroconversion under nested case-control design. We grouped children having an initial autoantibody only against insulin (IAA-first) or glutamic acid decarboxylase (GADA-first) by unsupervised clustering of temporal lipidome, identifying a subgroup of children having early onset of each initial autoantibody, i.e., IAA-first by 12 months and GADA-first by 21 months, consistent with population-wide early seroconversion age. Differential analysis showed that infants having reduced plasma ascorbic acid and cholesterol experienced IAA-first earlier, while early onset of GADA-first was preceded by reduced sphingomyelins at infancy. Plasma 25(OH)D prior to either autoantibody was lower in T1D progressors compared to non-progressors, with simultaneous lower diglycerides, lysophosphatidylcholines, triglycerides, alanine before GADA-first. Plasma ascorbic acid and 25(OH)D at infancy were lower in HLA-DR3/DR4 children among IA cases but not in matched controls, implying gene expression dysregulation of circulating vitamins as latent signals for IA or T1D progression.
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| 4. |
- Zhao, Lue Ping, et al.
(författare)
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Motifs of Three HLA-DQ Amino Acid Residues (α44, β57, β135) Capture Full Association With the Risk of Type 1 Diabetes in DQ2 and DQ8 Children
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 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 α44Q (odds ratio [OR] 3.29, P = 2.38 * 10-85) and β57A (OR 3.44, P = 3.80 * 10-84) to be associated with T1D in the DQ8/9 cluster representing all ten residues (α22, α23, α44, α49, α51, α53, α54, α73, α184, β57) due to complete linkage disequilibrium (LD) of α44 with eight such residues. Within the DQ2 cluster and due to LD, HOH analysis found α44C and β135D to share the risk for T1D (OR 2.10, P = 1.96 * 10-20). The motif "QAD" of α44, β57, and β135 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 α44. 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 (α44, β57, β135) conferring T1D risk should sharpen functional and translational studies.
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| 5. |
- Zhao, Lue Ping, et al.
(författare)
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Next-Generation HLA Sequence Analysis Uncovers Seven HLA-DQ Amino Acid Residues and Six Motifs Resistant to Childhood Type 1 Diabetes
- 2020
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Ingår i: Diabetes. - Arlington, VA, United States : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 69:11, s. 2523-2535
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Tidskriftsartikel (refereegranskat)abstract
- HLA-DQA1 and -DQB1 genes have significant and potentially causal associations with autoimmune type 1 diabetes (T1D). To follow up on the earlier analysis on high-risk HLA-DQ2.5 and DQ8.1, the current analysis uncovers seven residues (alpha a1, alpha 157, alpha 196, beta 9, beta 30, beta 57, and beta 70) that are resistant to T1D among subjects with DQ4-, 5-, 6-, and7-resistant DQ haplotypes. These 7 residues form 13 common motifs: 6 motifs are significantly resistant, 6 motifs have modest or no associations (Pvalues >0.05), and 1 motif has 7 copies observed among control subjects only. The motifs "DAAFYDG," "DAAYHDG," and "DAAYYDR" have significant resistance to T1D (odds ratios [ORs] 0.03, 0.25, and 0.18;P= 6.11 x 10(-24), 3.54 x 10(-15), and 1.03 x 10(-21), respectively). Remarkably, a change of a single residue from the motif "DAAYHDG" to "DAAYHSG" (D to S at beta 57) alters the resistance potential, from resistant motif (OR 0.15;P= 3.54 x 10(-15)) to a neutral motif (P= 0.183), the change of which was significant (FisherPvalue = 0.0065). The extended set of linked residues associated with T1D resistance and unique to each cluster of HLA-DQ haplotypes represents facets of all known features and functions of these molecules: antigenic peptide binding, peptide-MHC class II complex stability, beta 167-169 RGD loop, T-cell receptor binding, formation of homodimer of alpha-beta heterodimers, and cholesterol binding in the cell membrane rafts. Identification of these residues is a novel understanding of resistant DQ associations with T1D. Our analyses endow potential molecular approaches to identify immunological mechanisms that control disease susceptibility or resistance to provide novel targets for immunotherapeutic strategies.
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