| 1. |
- Ahlgren, Kerstin. M, et al.
(författare)
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Diabetes mellitus in dog - : No evidence for a type-1-like phenotype
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Aims/hypothesis Diabetes mellitus (DM) is one of the most common endocrine disorders in dogs, and is commonly proposed to be of autoimmune origin. Although the clinical symptoms of human type 1 diabetes (T1D) and canine DM are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported. Methods Sera from 121 diabetic dogs representing 38 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs from 40 breeds. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immunoprecipitation. Results None of the canine sera analyzed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Conclusions/interpretations Based on sera from 121 diabetic dogs from 38 different breeds were tested for humoral autoreactivity using four different assays, contrary to previous observations, we find no support for an autoimmune aetiology in canine diabetes.
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| 2. |
- Ahlgren, Kerstin M, et al.
(författare)
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Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e105473-
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS:Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.METHODS:Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.RESULTS:None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.CONCLUSIONS/INTERPRETATIONS:Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.
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| 3. |
- Andersson, C, et al.
(författare)
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The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes
- 2011
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Ingår i: Autoimmunity. - : Taylor & Francis. - 0891-6934 .- 1607-842X. ; 44:5, s. 394-405
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative.Methods: A total of 686 patients diagnosed in 1996–2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes.Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%—a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1*X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA.Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1*X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.
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| 4. |
- Brorsson, Caroline, et al.
(författare)
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Correlations between islet autoantibody specificity and the SLC30A8 genotype with HLA-DQB1 and metabolic control in new onset type 1 diabetes
- 2011
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Ingår i: Autoimmunity. - : Taylor & Francis. - 0891-6934 .- 1607-842X. ; 44:2, s. 107-114
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesised that the correlation between autoantibody specificity for the ZnT8 Arg325Trp isoforms and the type 2 diabetes-associated rs13266634 may affect beta-cell function at type 1 diabetes (T ID) onset. To study this, we tested 482 newly diagnosed diabetic probands and 478 healthy siblings from the Danish population-based T1D registry for autoantibodies to ZnT8 (ZnT8A) in addition to GAD65 and IA-2. The prevalence and titres of autoantibodies were correlated with genotypes for rs13266634 and HLA-DQB1, age at diagnosis (AAD) and insulin dose-adjusted HbA1c (IDAA1c), as a proxy for residual beta-cell function. We replicated the correlation between rs13266634 genotypes and specificity for the ZnT8-Argenine (ZnT8R) and ZnT8-Tryptophan (ZnT8W) isoforms previously reported. ZnT8A overlapped substantially with autoantibodies to glutamate decarboxylase 65 (GADA) and IA-2 (IA-2A) and correlated significantly with IA-2A prevalence (p < 2e-16). No effect on IDAA1c was demonstrated for ZnT8A or rs13266634. We found a correlation between ZnT8R positivity and HLA-DQB1*0302 genotypes (p = 0.016), which has not been shown previously. Furthermore, significantly lower ZnT8R and GADA prevalence and titres was found among probands with AAD < 5 years (prevalence: p = 0.004 and p = 0.0001; titres: p = 0.002 and p = 0.001, respectively). The same trend was observed for IA-2A and ZnT8W; however, the difference was non-significant. Our study confirms ZnT8 as a major target for autoantibodies at disease onset in our Danish T1D cohort of children and adolescents, and we have further characterised the relationship between autoantibody specificity for the ZnT8 Arg325Trp epitopes and rs13266634 in relation to established autoantibodies, AAD, measures of beta-cell function and HLA-DQB1 genotypes in T1D.
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| 5. |
- Daka, Bledar, 1976, et al.
(författare)
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Low agreement between radio binding assays in analyzing glutamic acid decarboxylase (GAD65Ab) autoantibodies in patients classified with type 2 diabetes.
- 2009
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Ingår i: Autoimmunity. - : Informa UK Limited. - 1607-842X .- 0891-6934. ; 42:6, s. 507-14
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Tidskriftsartikel (refereegranskat)abstract
- Autoantibodies against glutamic acid decarboxylase (GAD65Ab) are used in the classification of diabetes in adults. We assessed the concordance in GAD65 autoantibody levels within subjects between three different GAD65Ab radio binding assays (RBA). Plasma samples from 112 diabetes patients (median age 50 years) initially classified with type 2 diabetes was randomly selected from a local diabetes registry. Coded samples were analyzed with two RBA employing (35)S-labeled GAD65. The first used the pEx9 plasmid (pEx9 RBA), the second employed the pThGAD65 plasmid (pThGAD65 RBA) to label GAD65 by in vitro transcription translation. We also used a commercial kit employing plasmid pGAD17 labelled with (125)I (pGAD17 RBA). Subsequent analyses followed standard procedures. Two different cut-offs for GAD65Ab positivity were used in all three assays. We calculated the correlation, concordance, and agreement between the assays. The proportion of GAD65Ab positivity differed between assays when low cut-offs were used (pEx9 RBA 25%, pThGAD65 RBA 17.9%, and pGAD17 RBA 12.5%, respectively). When high cut-offs were applied, the concordance between the pEx9 RBA and the pThGAD65 RBA was 97.3 while their concordance to the pGAD17 RBA was lower (88.4 and 87.4, respectively). There was a low agreement between both pEx9 RBA and pGAD17 RBA (0.45, 95% CI 0.20-0.70) and between pThGAD65 RBA and pGAD17 RBA (0.43, 95% CI 0.18-0.68). We found discrepancies in determining the GAD65Ab positivity, which constitutes a problem when GAD65Ab are used clinically. Further methodological GAD65Ab assays studies are warranted.
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| 6. |
- Haghighi, Mona, et al.
(författare)
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A Comparison of Rule-based Analysis with Regression Methods in Understanding the Risk Factors for Study Withdrawal in a Pediatric Study
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Regression models are extensively used in many epidemiological studies to understand the linkage between specific outcomes of interest and their risk factors. However, regression models in general examine the average effects of the risk factors and ignore subgroups with different risk profiles. As a result, interventions are often geared towards the average member of the population, without consideration of the special health needs of different subgroups within the population. This paper demonstrates the value of using rule-based analysis methods that can identify subgroups with heterogeneous risk profiles in a population without imposing assumptions on the subgroups or method. The rules define the risk pattern of subsets of individuals by not only considering the interactions between the risk factors but also their ranges. We compared the rule-based analysis results with the results from a logistic regression model in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Both methods detected a similar suite of risk factors, but the rule-based analysis was superior at detecting multiple interactions between the risk factors that characterize the subgroups. A further investigation of the particular characteristics of each subgroup may detect the special health needs of the subgroup and lead to tailored interventions.
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| 7. |
- Jensen, Richard A., et al.
(författare)
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Multiple factors affect the loss of measurable C-peptide over 6 years in newly diagnosed 15- to 35-year-old diabetic subjects
- 2007
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Ingår i: Journal of diabetes and its complications. - : Elsevier BV. - 1056-8727 .- 1873-460X. ; 21:4, s. 205-213
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study is to identify risk factors for the loss of measurable plasma C-peptide in newly diagnosed 15- to 35-year-old diabetic subjects. Methods: This Swedish study included 778 subjects. C-peptide levels were obtained each year for 6 years after diagnosis. Loss of measurable C-peptide was defined as a level at or below the lower detection limit of the local assay (0.13 nmol/l). In addition to C-peptide, other baseline covariates included gender, age, body mass index, HLA genotype, and autoantibody levels. Results: Compared with autoantibody-negative subjects, autoantibody-positive subjects had lower median baseline C-peptide (0.27 vs. 0.50, P<001), their levels declined over the study period, and the risk of losing measurable C-peptide was significantly higher when more than one autoantibody was present [odds ratio (OR), 4.0; 95% confidence interval (CI), 2.13-7.54]. Among autoantibody-positive individuals, the presence of GAD65Ab (OR, 1.8; 95% Cl, 1.24-2.51) and islet cell antibodies (OR, 1.6; 95% CI, 1.19-2.18) conferred a higher risk for loss of measurable C-peptide as did female gender (OR, 1.6; 95% CI, 1.17-2.11) and time after diagnosis (OR, 1.5 for each additional year postdiagnosis; 95% CI, 1.41-1.57). Higher baseline C-peptide levels were protective (OR, 0.5 for each additional log nanomoles per liter; 95% CI, 0.36-0.58). Conclusions: This study identified autoantibody status, gender, and baseline C-peptide levels as factors that will be useful for predicting the disease course of 15- to 35-year-old diabetic individuals.
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| 8. |
- Jensen, R., et al.
(författare)
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Islet cell autoantibody levels after the diagnosis of young adult diabetic patients
- 2007
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Ingår i: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 24:11, s. 1221-1228
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Tidskriftsartikel (refereegranskat)abstract
- Aims The aim was to determine the course of islet cell antibodies [glutamate decarboxylase (GADA), tyrosine phosphatase-like islet antigen 2 (IA-2A) and islet cell (ICA)] after the diagnosis of the diabetic patient. Methods The Diabetes Incidence Study in Sweden (DISS) attempted to prospectively enrol all newly diagnosed diabetic patients aged 15–34 years during 1992 and 1993. C-peptide and autoantibody levels were determined from venous blood samples at diagnosis and again at yearly intervals for 6 years. Results After the first year, the odds of remaining GADA positive decreased by 9% per year [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.85–0.96] while the mean GADA index remained unchanged ( = 0.8, P = 0.37). There was no change in the percentage of subjects testing IA-2A positive after the first year ( = 0.1, P = 0.75). However, the mean index decreased 0.04 per year (95% CI: 0.03–0.05)—a 7.9% decline (95% CI: 5.4–10.4%). The odds of a subject testing positive for ICA decreased by 24% per year (OR = 0.76, 95% CI = 0.70–0.82). The mean ICA levels decreased 0.75 per year (95% CI: 0.66–0.84)—a 16.4% decline (95% CI: 14.1–18.6%). The rate of change in titres for all three autoantibodies was independent of gender, human leucocyte antigen genotype and C-peptide status. Conclusions GADA levels remained high while ICA levels declined. In contrast to a previous study, we found that the proportion of IA-2A subjects remaining positive did not decrease after the first year, while the average index decreased slightly.
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| 9. |
- Kanatsuna, N, et al.
(författare)
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Doubly reactive INS-IGF2 autoantibodies in children with newly diagnosed autoimmune (type 1) diabetes
- 2015
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Ingår i: Scandinavian Journal of Immunology. - : Wiley-Blackwell. - 0300-9475 .- 1365-3083. ; 82:4, s. 361-369
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Tidskriftsartikel (refereegranskat)abstract
- The splice variant INS-IGF2 entails the preproinsulin signal peptide, the insulin B-chain, eight amino acids of the C-peptide and 138 unique amino acids from an ORF in the IGF2 gene. The aim of this study was to determine whether levels of specific INS-IGF2 autoantibodies (INS-IGF2A) were related to age at diagnosis, islet autoantibodies, HLA-DQ or both, in patients and controls with newly diagnosed type 1 diabetes. Patients (n = 676), 0-18 years of age, diagnosed with type 1 diabetes in 1996-2005 and controls (n = 363) were analysed for specific INS-IGF2A after displacement with both cold insulin and INS-IGF2 to correct for non-specific binding and identify double reactive sera. GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, ZnT8QA and HLA-DQ genotypes were also determined. The median level of specific INS-IGF2A was higher in patients than in controls (P < 0.001). Irrespective of age at diagnosis, 19% (126/676) of the patients had INS-IGF2A when the cut-off was the 95th percentile of the controls (P < 0.001). The risk of INS-IGF2A was increased among HLA-DQ2/8 (OR = 1.509; 95th CI 1.011, 2.252; P = 0.045) but not in 2/2, 2/X, 8/8, 8/X or X/X (X is neither 2 nor 8) patients. The association with HLA-DQ2/8 suggests that this autoantigen may be presented on HLA-DQ trans-heterodimers, rather than cis-heterodimers. Autoantibodies reactive with both insulin and INS-IGF2A at diagnosis support the notion that INS-IGF2 autoimmunity contributes to type 1 diabetes.
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| 10. |
- Larsson, Helena, et al.
(författare)
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Relationship between increased relative birthweight and infections during pregnancy in children with a high-risk diabetes HLA genotype.
- 2007
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 50:6, s. 1161-1169
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Children with high-risk type 1 diabetes HLA genotype have increased risk of high relative birthweight (HrBW), while cord blood islet autoantibodies decrease the risk. As gestational infections may affect offspring type 1 diabetes risk, the aims were to test whether: (1) children of mothers reporting gestational infections have increased HrBW; (2) gestational infections explain islet autoantibody reduction of HrBW; and (3) gestational infections affect the association between HLA and HrBW. Subjects and methods HLA genotypes and autoantibodies to glutamic acid decarboxylase, insulinoma-associated protein 2 and insulin were determined in cord blood of children born to non-diabetic mothers in the Diabetes Prediction in Skane (DiPiS) study. Mothers reported gestational infections when the child was 2 months old. Results Fever or gastroenteritis during pregnancy was reported by 2,848/19,756 mothers (14%); 339 in more than one trimester. Children whose mothers reported infections had increased risk of HrBW (p=0.0003), particularly in the absence of cord blood islet autoantibodies (interaction between HrBW, islet autoantibodies and infections, p=0.0005). The effect on HrBW by high-risk HLA-DQ2/8 was aggravated by infections in more than one trimester (odds ratio [OR]=5.24; p=0.003) (interaction; p=0.022). When infections were reported, cord blood islet autoantibodies decreased HrBW (OR=0.34; p=0.0002). Conclusions/intrepretation This study revealed that: (1) gestational fever, gastroenteritis, or both, increased the risk of HrBW; (2) cord blood islet autoantibodies decreased the risk of HrBW only in combination with infections; and (3) infections aggravated the association between HLA-DQ2/8 and HrBW. These data suggest an interaction between HLA, gestational infections, islet autoantibodies and fetal growth.
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| 11. |
- Larsson, K, et al.
(författare)
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Genetic and perinatal factors as risk for childhood type 1 diabetes
- 2004
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Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552. ; 20:6, s. 429-437
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Forskningsöversikt (refereegranskat)abstract
- The mechanisms by which gestational infections, blood incompatibility, birth weight, mother's age and other prenatal or neonatal events increase the risk for type 1 diabetes are not understood. Studies so far have been retrospective, and there is a lack of population-based prospective studies. The possibility identifying children at type 1 diabetes risk among first-degree relatives has resulted in prospective studies aimed at identifying postnatal events associated with the appearance of autoantibody markers for type 1 diabetes and a possible later onset of diabetes. However, the majority (85%) of new onset type 1 diabetes children do not have a first-degree relative with the disease. Population-based studies are therefore designed to prospectively analyse pregnant mothers and their offspring. One such study is DiPiS (Diabetes Prediction in Skane), which is examining a total of about 10 000 pregnancies expected every year in the Skane (Scania) region of Sweden that has 1.1 million inhabitants. Blood samples from all mothers in this region are obtained during pregnancy and at the time of delivery. Cord blood is analysed for HLA high-risk alleles and for autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GADA), the protein tyrosine phosphatase-related IA-2 antigen (IA-2A) and insulin (IAA) as a measure of prenatal autoimmune exposure. Identifying high-risk children by genetic, autoimmune and gestational risk factors followed by prospective analyses will make it possible to test the hypothesis that gestational events may trigger beta cell autoimmunity as a prerequisite for childhood type 1 diabetes. Copyright (C) 2004 John Wiley Sons, Ltd.
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| 12. |
- Lernmark, Barbro, et al.
(författare)
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Cord blood islet autoantibodies are related to stress in the mother during pregnancy.
- 2006
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923. ; 1079:1079, s. 345-349
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Tidskriftsartikel (refereegranskat)abstract
- A 2-month psychological questionnaire concerning pregnancy was answered by 20,920 nondiabetic mothers of singletons. Retrospective analysis showed increased levels of islet autoantibodies (1A) in 290 (1.4%) newborns. High IA levels in the child's cord blood correlated strongly with IA levels in the mother (GADA r = 0.91, P < 0.0001; IA-2A r = 0.75, P = 0.0001). High IA levels were found in newborns whose mothers during pregnancy had been more worried than usual (P = 0.04), had worried that the child would be sick (P = 0.01) or not survive (P = 0.002), or had experienced serious life events, like "serious accident in the family" (P < 0.0001) or "experienced violence" (P = 0.02). Associations with increased worries by the mother remained in newborns with high type 1 diabetes mellitus (T1DM)-human leukocyte antigen (HLA) risk, but not in non-HLA risk children. ne prospective follow-up of these children will determine the importance of this early 1A for postnatal islet autoimmunity, type I diabetes, or both.
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| 13. |
- Lynch, Kristian, et al.
(författare)
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Cord blood islet autoantibodies and seasonal association with the type 1 diabetes high-risk genotype.
- 2008
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Ingår i: Journal of Perinatology. - : Springer Science and Business Media LLC. - 0743-8346 .- 1476-5543. ; 28:3, s. 211-217
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Tidskriftsartikel (refereegranskat)abstract
- Objective:Human leukocyte antigen DQ (HLA-DQ) genetic factors and islet autoantibodies are strongly associated with type 1 diabetes (T1D) and are currently used to predict T1D. This study examined whether islet autoantibodies in the cord blood of newborns to nondiabetic mothers were associated with the (T1D) high-risk genotype HLA-DQ2/8, gestational infections or both.Study Design:Cord blood samples were taken from 33 683 newborns and used for HLA typing and analyses of islet autoantibodies. Parents completed questionnaires when the child was 2 months of age.Result:The prevalence of newborn islet autoantibodies consistently varied with season over 4 years (P<0.0001); lowest in first quarter (1.2%) and highest in third (2.4%). Cord blood islet autoantibodies were associated with HLA-DQ2/8 in the second (OR, 2.30; P=0.02), third (OR, 2.12; P=0.008) and fourth quarters (OR, 2.49; P=0.007), but not in the first (OR, 1.13). Reported gastroenteritis was additionally associated with islet autoantibodies in the third quarter (OR, 1.80, P=0.04).Conclusion:An association between HLA and islet autoimmunity may depend on environmental exposure during pregnancy. Follow-up of mothers and children will determine risk of T1D.Journal of Perinatology (2008) 28, 211-217; doi:10.1038/sj.jp.7211912; published online 14 February 2008.
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| 14. |
- Nilsson, Anna-Lena, et al.
(författare)
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Relationship between Ljungan virus antibodies, HLA-DQ8, and insulin autoantibodies in newly diagnosed type 1 diabetes children
- 2013
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Ingår i: Viral immunology. - : Mary Ann Liebert, Inc.. - 0882-8245 .- 1557-8976. ; 26:3, s. 207-215
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Tidskriftsartikel (refereegranskat)abstract
- Environmental factors, including viral infections, may explain an increasing and fluctuating incidence of childhood type 1 diabetes (T1D). Ljungan virus (LV) isolated from bank voles have been implicated, but it is unclear whether LV contributes to islet autoimmunity, progression to clinical onset, or both, of T1D. The aim was to test whether LV antibodies (LVAb) were related to HLA-DQ and islet autoantibodies in newly diagnosed T1D patients (n = 676) and controls (n = 309). Patients, 0-18 years of age, diagnosed with T1D in 1996-2005 were analyzed for LVAb, HLA-DQ genotypes, and all seven known islet autoantibodies (GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, and ZnT8QA). LVAb at 75th percentile, defined as cut off, was 90 (range 6-3936) U/mL and 4th quartile LVAb were found in 25% (170/676) of which 64% were < 10 (n = 108, p < 0.0001), and 27% were < 5 (n = 45; p < 0.0001) years old. The 4th quartile LVAb in children < 10 years of age correlated to HLA DQ2/8, 8/8, and 8/X (p < 0.0001). Furthermore, in the group with 4th quartile LVAb, 55% were IAA positive (p = 0.01) and correlation was found between 4th quartile LVAb and IAA in children < 10 years of age (p = 0.035). It is concluded that 1) LVAb were common among the young T1D patients and LVAb levels were higher in the younger age groups; 2) 4th quartile LVAb correlated with IAA; and 3) there was a correlation between 4th quartile LVAb and HLA-DQ8, particularly in the young patients. The presence of LVAb supports the notion that prior exposure to LV may be associated with T1D.
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| 15. |
- Papadopoulou, Anastasia, et al.
(författare)
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The type 1 diabetes protective HLA DQB1*0602 allele is less frequent in gestational diabetes mellitus.
- 2009
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 52, s. 1339-1342
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: We tested whether gestational diabetes mellitus (GDM) is associated with HLA-DQ genotypes. METHODS: A total of 764 mothers with non-autoimmune (GAD65, insulinoma-associated protein 2 [IA-2] and insulin autoantibody-negative) GDM were ascertained between September 2000 and August 2004 in the population-based Diabetes Prediction in Skåne (DiPiS) study. HLA-DQB1 genotypes were determined in these mothers and in 1191 randomly selected non-diabetic control mothers also negative for islet autoantibodies. The data were analysed in relation to maternal age, country of birth, number of pregnancies/siblings and pregnancy weight gain. RESULTS: The frequency of type 1 diabetes high-risk HLA-DQ alleles (DQB1*0201, DQB1*0302) did not differ between GDM mothers and controls. In contrast, the low-risk DQB1*0602 allele was less prevalent (OR 0.64, 95% CI = 0.51-0.80, p = 0.0006) in GDM than in control mothers. The difference in DQB1*0602 frequency between GDM mothers and controls remained after multiple logistic regression analysis correcting for maternal age, country of birth, number of pregnancies/siblings and weight gain during pregnancy (OR 0.67, 95% CI 0.51-0.88, p = 0.009). CONCLUSIONS/INTERPRETATION: The negative association between mothers who have non-autoimmune GDM and HLA-DQ*0602 suggest that this allele may protect not only from type 1 diabetes but also from GDM.
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| 16. |
- Rewers, Marian, et al.
(författare)
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The Environmental Determinants of Diabetes in the Young (TEDDY) Study
- 2008
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 1150, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- The etiology of type 1 diabetes (T1D) remains unknown, but a growing body of evidence points to infectious agents and/or components of early childhood diet. The National Institutes of Health has established the TEDDY Study consortium of six clinical centers in the United States and Europe and a data coordinating center to identify environmental factors predisposing to, or protective against, islet autoimmunity and T1D. From 2004-2009, TEDDY will screen more than 360,000 newborns from both the general population and families already affected by T1D to identify an estimated 17,804 children with high-risk HLA-DR,DQ genotypes. Of those, 7,801 (788 first-degree relatives and 7,013 newborns with no family history of T1D) will be enrolled in prospective follow-up beginning before the age of 4.5 months. As of May 2008, TEDDY has screened more than 250,000 newborns and enrolled nearly 5,000 infants--approximately 70% of the final cohort. Participants are seen every 3 months up to 4 years of age, with subsequent visits every 6 months until the subject is 15 years of age. Blood samples are collected at each visit for detection of candidate infectious agents and nutritional biomarkers; monthly stool samples are collected for infectious agents. These samples are saved in a central repository. Primary endpoints include (1) appearance of one or more islet autoantibodies (to insulin, GAD65 or IA-2) confirmed at two consecutive visits; (2) development of T1D. By age 15, an estimated 800 children will develop islet autoimmunity and 400 will progress to T1D; 67 and 27 children have already reached these endpoints.
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| 17. |
- Skärstrand, H, et al.
(författare)
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Neuropeptide Y autoantibodies in patients with long-term type 1 and type 2 diabetes and neuropathy
- 2013
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Ingår i: Journal of diabetes and its complications. - : Elsevier. - 1056-8727 .- 1873-460X. ; 27:6, s. 609-617
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The neurotransmitter Neuropeptide Y (NPY) was previously reported as a minor autoantigen in newly diagnosed type 1 diabetes (T1D) patients. The single nucleotide polymorphism at rs16139 (T1128C, L7P) in the NPY gene was associated with an increased risk for the development of type 2 diabetes (T2D). We aimed to develop a radiobinding assay for NPY-L (Leucine) and NPY-P (Proline) autoantibodies (A) to study the levels and the association with other islet autoantibodies and neuropathy. Methods: Autoantibodies against NPY-L, NPY-P, ZnT8, GAD65 and IA-2 were studied in T1D (n = 48) and T2D (n = 26) patients with duration up to 42 and 31 years. A subgroup of T1D (n = 32) patients re-examined, 5-8 years after first visit, was tested for peripheral (Z-score) and autonomic neuropathy (E/I ratio). Results: NPY-LA and NPY-PA were detected in 23% and 19% in T1D (p<0.001), and 12% and 23% in T2D patients (p<0.001) compared to 2.5% controls (n = 398). The levels of NPYA declined during follow-up in the T1D patients (p < 0.001). The neuropathy was not related to the NPYA or the other islet autoantibodies. Conclusions: Regardless of the absence of an association between NPYA and neuropathy, NPY may contribute to the pathogenesis of T1D and T2D as a minor autoantigen.
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| 18. |
- TEDDY study group, The, et al.
(författare)
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The environmental determinants of diabetes in the young (TEDDY) study: Study design
- 2007
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 8:5, s. 286-298
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Tidskriftsartikel (refereegranskat)abstract
- The primary objective of this multicenter, multinational, epidemiological study is the identification of infectious agents, dietary factors, or other environmental exposures that are associated with increased risk of autoimmunity and type 1 diabetes mellitus (T1DM). Factors affecting specific phenotypic manifestations such as early age of onset or rate of progression or with protection from the development of T1DM will also be identified. The Environmental Determinants of Diabetes in the Young (TEDDY) is an observational cohort study in which newborns who are younger than 4 months and have high-risk human leukocyte antigen alleles in the general population or are first-degree relatives (FDRs) of patients affected with T1DM will be enrolled. Six clinical centers in the USA and Europe will screen 361 588 newborns, of which it is anticipated that 17 804 will be eligible for enrollment with just over 7800 followed. Recruitment will occur over 5 yr, with children being followed to the age of 15 yr. Identification of such factors will lead to a better understanding of disease pathogenesis and result in new strategies to prevent, delay, or reverse T1DM.
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| 19. |
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| 20. |
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| 21. |
- Agardh, Carl-David, et al.
(författare)
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Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes.
- 2005
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Ingår i: Journal of Diabetes and its Complications. - : Elsevier BV. - 1873-460X .- 1056-8727. ; 19:4, s. 238-246
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this Phase II study was to evaluate if alum-formulated human recombinant GAD65 is safe and does not compromise beta cell function. The study was conducted as a randomized, double blind, placebo-controlled, dose-escalation clinical trial in a total of 47 Latent Autoimmune Diabetes in Adults (LADA) patients who received either placebo or 4, 20, 100, or 500 μg Diamyd subcutaneously at Weeks 1 and 4. Safety evaluations, including neurology, beta cell function tests, diabetes status assessment, hematology, biochemistry, and cellular and humoral immunological markers, were repeatedly assessed over 24 weeks. None of the patients had significant study-related adverse events (AE). Fasting c-peptide levels at 24 weeks were increased compared with placebo (P=.0015) in the 20 μg but not in the other dose groups. In addition, both fasting (P=.0081) and stimulated (P=.0236) c-peptide levels increased from baseline to 24 weeks in the 20 μg dose group. GADA log levels clearly increased (P=.0002) in response to 500 μg Diamyd. The CD4+CD25+/CD4+CD25− cell ratio increased (P=.0128) at 24 weeks in the 20 μg group. No sudden increase in HbA1c or plasma glucose or decrease in beta cell function was observed in any of the dose groups. These positive findings for clinical safety further support the clinical development of Diamyd as a therapeutic to prevent autoimmune diabetes.
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| 22. |
- Agardh, Carl-David, et al.
(författare)
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GAD65 vaccination: 5 years of follow-up in a randomised dose-escalating study in adult-onset autoimmune diabetes.
- 2009
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 52, s. 1363-1368
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: The aim of this study was to ascertain whether treatment of GAD65 autoantibody (GADA)-positive diabetic patients with alum-formulated recombinant GAD65 (GAD-alum) is safe and does not compromise beta cell function. METHODS: This Phase 2, placebo-controlled, dose-escalation clinical trial, which was randomized through a central office, was performed in 47 GADA-positive type 2 diabetic patients, who received subcutaneous injections of GAD-alum (4 [n = 9], 20 [n = 8], 100 [n = 9] or 500 [n = 8] mug) or placebo (n = 13) at weeks 1 and 4 of the trial. Participants and caregivers were blinded to group assignments. The primary outcome was safety as assessed by neurological tests, medications and beta cell function evaluated over 5 years, representing the end of the trial. RESULTS: No severe study-related adverse events occurred during the 5 year follow-up. None of the dose groups was associated with an increased risk of starting insulin treatment compared with the placebo group. The use of oral hypoglycaemic agents did not differ between the dose groups. After 5 years, fasting C-peptide levels declined in the placebo group (-0.24; 95% CI -0.41 to -0.07 log(10) nmol/l; p = 0.01) and the 500 microg dose group (-0.37; 95% CI -0.57 to -0.17 log(10) nmol/l; p = 0.003), but not in the 4 microg (-0.10; 95% CI -0.28 to 0.07 log(10) nmol/l; p = 0.20), 20 microg (0.04; 95% CI -0.12 to 0.19 log(10) nmol/l; p = 0.58) and 100 microg (0.00; 95% CI -0.20 to -0.20 log(10) nmol/l; p = 0.98) dose groups. CONCLUSIONS/INTERPRETATION: The primary outcome of safety was achieved, since no severe study-related adverse events occurred. TRIAL REGISTRATION: Because the study was initiated before 1 July 2005, the protocol was not registered in a registry. FUNDING: This trial was funded by the National Institutes of Health (grant numbers DK26190 and DK53004), the Swedish Research Council (grant number 72X-14064) and Diamyd Therapeutics (Stockholm, Sweden).
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| 23. |
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| 24. |
- Agardh, Daniel, et al.
(författare)
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Autoantibodies Against Soluble and Immobilized Human Recombinant Tissue Transglutaminase in Children with Celiac Disease.
- 2005
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Ingår i: Journal of Pediatric Gastroenterology and Nutrition - Jpgn. - : Ovid Technologies (Wolters Kluwer Health). - 1536-4801 .- 0277-2116. ; 41:3, s. 322-327
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The conformation of tissue transglutaminase might influence the performance of immunoassays to detect autoantibodies from patients with celiac disease. The present study investigated how the exposure of tissue transglutaminase kept in a liquid phase and fixed to a solid support affected the binding of immunoglobulin (Ig)A and IgG autoantibodies in children with untreated and treated celiac disease. Methods: Included were 73 untreated celiac disease children, 50 controls and 80 children with treated celiac disease. IgA and IgG antitissue transglutaminase were measured with solid phase enzyme-linked immunoassay (ELISA) and liquid phase radioligand binding assays. For IgG antitissue transglutaminase detection with radioligand binding assays antihuman IgG and protein A were used. IgA endomysial autoantibodies were measured by indirect immunofluorescence. Results: Both ELISA and radioligand binding assays detected IgA antitissue transglutaminase in 65 of 73 untreated celiac disease children and in 2 of 50 controls. One additional control child was detected with radioligand binding assays. Endomysial autoantibodies were present in 62 of 73 celiac disease children and in 2 of 50 controls. IgG antitissue transglutaminase was detected with both ELISA and radioligand binding assays in 40 of 73 untreated celiac disease children and in 2 of 50 controls. Radioligand binding assays using protein A detected 20 of 73 additional untreated celiac disease children and one control child with increased IgG antitissue transglutaminase. In treated celiac disease children, 21 of 80 were IgA antitissue transglutaminase positive with radioligand binding assays, 3 of 80 with ELISA, whereas none had endomysial autoantibodies. Conclusions: No qualitative differences between radioligand binding assays and ELISA in IgA or IgG antitissue transglutaminase binding from untreated celiac disease children was demonstrated. However, discrepancies in the binding of IgA antitissue transglutaminase from a subgroup of treated celiac disease children indicated that alterations of tissue transglutaminase might occur on fixation of the antigen. Protein A used for radioligand binding assays seemed not to assess IgG autoantibodies exclusively. IgA antitissue transglutaminase detection in screening of childhood celiac disease can be performed either by ELISA or radioligand binding assays because the two assays are interchangeable.
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| 25. |
- Agardh, Daniel, et al.
(författare)
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Calcium activation of tissue transglutaminase in radioligand binding and enzyme-linked autoantibody immunoassays in childhood celiac disease.
- 2005
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Ingår i: Clinica Chimica Acta. - : Elsevier BV. - 0009-8981. ; 358:1-2, s. 95-103
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Tidskriftsartikel (refereegranskat)abstract
- Background Conflicting data have been published concerning the effect of calcium on binding of autoantibodies to tissue transglutaminase (tTG) in celiac disease (CD). Methods IgA-tTG and IgG-tTG were measured with radioligand binding assays (RBA) using human recombinant (hr) 35S-tTG produced in lysate of rabbit reticulocytes and with guinea pig (gp) tTG ELISA in 51 CD children (median: 5.7 years) and 35 controls (median: 2.2 years). Assays were performed with and without calcium. Results In hr-tTG RBA, IgA-tTG levels remained unchanged after calcium detecting 50/51 CD children and 1/35 controls (p < 0.0001). IgG-tTG levels decreased with calcium (p < 0.0001) in CD children and detected 48/51 with and 49/51 without calcium as compared to 1/35 controls (p < 0.0001). In gp-tTG ELISA, levels increased with calcium (p < 0.0001) making it possible to detect an additional three to a total of 50/51 with IgA-tTG and 13 to 39/51 CD children with IgG-tTG compared to 4/35 and 8/35 controls (respectively, p < 0.0001). Rabbit reticulocytes displayed calcium-dependent tTG activity. Conclusions Calcium increased binding of IgA-tTG and IgG-tTG in the ELISA test. The reverse effect observed in RBA may be explained by competitive binding between calcium activated native rabbit reticulocyte tTG and hr 35S-tTG. tTG autoantibody assays may need taking calcium into account for accurate diagnostic sensitivity and specificity for CD.
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| 26. |
- Agardh, Daniel, et al.
(författare)
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HLA-DQB1*0201/0302 is associated with severe retinopathy in patients with IDDM
- 1996
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 39:11, s. 1313-1317
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Tidskriftsartikel (refereegranskat)abstract
- Some insulin-dependent diabetic (IDDM) patients develop severe forms of retinopathy. Putative risk factors such as hypertension, poor metabolic control, nephropathy and growth hormone levels do not fully explain the progress of retinopathy in these patients. It has been discussed whether there is a genetic marker, since some diabetic patients without any known predisposing risk factors develop severe retinopathy and others do not. In the present study, HLA-DR and DQ were compared in two patient groups with IDDM. One group consisted of patients with early-onset diabetes, with severe non-proliferative or proliferative retinopathy; the other group had no or only mild signs of retinopathy. High resolution HLA typing was carried out by polymerase chain reaction (PCR) and hybridization with allele specific probes. Alleles on the DR3-DQ2 haplotype, DRB1*0301, DQA1*0501 and DQB1*0201, were more frequent in patients with severe retinopathy. A difference was seen when combining certain alleles in the genotypes of DQA1*03/0501 (p > 0.05) and DQB1*0201/0302 (p < 0.01). The findings of the present study suggest that DQB1*0201/0302 is the strongest genetic marker for severe retinopathy and DRB1*0301/0401 only has a secondary influence when combined with this genotype. It seems as if IDDM patients who are positive for the genotype DR3-DQ2/DR4-DQ8 (DRB1*0301-DQA1*0501-DQB1*0201/DRB1*0401 -DQA1*03-DQB1*0302) are at greater risk of developing severe retinopathy.
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| 27. |
- Agardh, Daniel, et al.
(författare)
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Inverse relationship between GAD65 antibody levels and severe retinopathy in younger type 1 diabetic patients
- 1998
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Ingår i: Diabetes Research and Clinical Practice. - 1872-8227. ; 40:1, s. 9-14
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Tidskriftsartikel (refereegranskat)abstract
- Several risk factors for severe non-proliferative and proliferative retinopathy in type 1 diabetes mellitus have been proposed without explaining the rapid progression of retinopathy in some patients. Since GAD65 autoantibodies (GAD65Abs) are detected against glutamic acid decarboxylase (GAD), which is mainly expressed in islets and nervous tissue in type 1 diabetic patients, the aim of the present investigation was to test the hypothesis whether GAD65Abs are associated with rapidly progressing severe retinopathy. Patients with severe non-proliferative or proliferative retinopathy (n = 27) were compared with another group, which in spite of long diabetes duration had no or only mild signs of retinopathy (n = 28). GAD65Abs were analysed in a radioimmunoassay using in vitro translated human GAD65, and the levels were expressed as an index in relation to positive and negative reference samples. Using a cut-off level representing the 99th percentile of normals, 6/27 (22%) with and 9/28 (32%) without severe retinopathy were considered GAD65Ab positive. Although there was no difference in the number of GAD65Ab positive patients, the GAD65Ab levels were lower in patients with (0.30; 0.11-0.64) than without (0.68; 0.34-1.12) severe retinopathy (P = 0.03). The patients were also subjected to HLA-DR and DQ typing by PCR and hybridization with oligospecific probes. DQ2/8 was more common in patients with (56%) than without (29%) severe retinopathy (P = 0.05), but DQ2/8 could not account for the lower GAD65Ab levels in patients with severe retinopathy. It is concluded that GAD65Ab levels are inversely correlated with severe retinopathy in young type 1 diabetic patients.
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| 28. |
- Agardh, Daniel, et al.
(författare)
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Prediction of silent celiac disease at diagnosis of childhood type 1 diabetes by tissue transglutaminase autoantibodies and HLA
- 2001
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X. ; 2:2, s. 58-65
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The aims were to estimate the diagnostic sensitivity and specificity of autoantibodies to tissue transglutaminase (IgA- and IgG-tTG), gliadin (AGA) and endomysium (EMA) in relation to human leukocyte antigen (HLA)-DQB1 alleles to identify silent celiac disease at diagnosis of type 1 diabetes. Methods: IgA- and IgG-tTG were measured in radioligand binding assays in 165 type 1 diabetic patients. Data on HLA-DQB1 were available for 148 patients and on both AGA and EMA for 164 patients. For patients considered positive for AGA or EMA, or both, an intestinal biopsy was suggested. HLA-DQB1 typing was carried out by polymerase chain reaction and hybridization with allele specific probes. Results: Three patients, left out from further study of antibodies, but not from HLA-DQB1 analysis, had treated celiac disease at diagnosis. Out of the other 162 type 1 diabetic patients tested, nine had IgA-tTG, six IgG-tTG, eight EMA, and 11 AGA. Biopsy was suggested for nine patients, of whom six showed villous atrophy, one did not and two refused to participate. Thus, silent celiac disease was probable in 8/162 and biopsy-verified in 6/162, where five patients were AGA-positive and six either EMA-, IgA-tTG- or IgG-tTG-positive. Of the 11 patients with celiac disease (three with treated and eight with silent celiac disease), 10 were HLA-DQB1-typed, of whom 65% (13/20) had the DQB1*02 allele, compared with 36% (100/276; p = 0.011) of those without celiac disease. IgA-tTG levels were higher in patients having either *02 or *0302 (0.6; −1.3–112.4 RU) compared with those not having these alleles (0.4; −0.7–3.4 RU; p = 0.023). Conclusion: IgA-tTG are HLA-DQB1*02-associated autoantibodies with high sensitivity and specificity for silent celiac disease at diagnosis of type 1 diabetes.
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| 29. |
- Agardh, Daniel, et al.
(författare)
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Tissue transglutaminase immunoglobulin isotypes in children with untreated and treated celiac disease
- 2003
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Ingår i: Journal of Pediatric Gastroenterology and Nutrition - Jpgn. - 1536-4801. ; 36:1, s. 77-82
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Tissue transglutaminase (tTG) autoantibodies are serologic markers for celiac disease (CD). The aim was to determine the diagnostic sensitivity and specificity of different immunoglobulin isotypes against tTG. Methods: Immunoglobulin A (IgA)-tTG, IgG-tTG, and IgGl-tTG were measured in radioligand binding assays in 67 children with untreated and 89 children with treated CD and compared with 48 biopsy controls. IgM-tTG was measured in children with untreated CD and in biopsy controls. IgA endomysial autoantibodies (EMA) were analyzed in all children using an immunofluorescence method. Results: The sensitivity of IgA-tTG and IgG-tTG was 85.1% (57 of 67) and 83.6% (56 of 67), respectively, which both increased to 93.8% (45 of 48) in children diagnosed at age 2 years or older. Both had a specificity of 93.8% (45 of 48). IgA-EMA had a sensitivity of 80.6% (54 of 67) and a specificity of 91.7% (44 of 48). In treated CD, IgA-tTG and IgG-tTG were detected in 21.3% (19 of 89) and in 14.6% (13 of 89), respectively, despite negative EMA titers. IgGl-tTG was correlated to age (r = -0.47, P = 0.0005) and detected in 50.7% (34 of 67) with untreated CD compared with 11.2% (10 of 89) with treated CD and with 4.2% (2 of 48) of biopsy controls (P < 0.0001, respectively). IgM-tTG was detected in 1.5% (1 of 67) with untreated CD and in none of biopsy controls. Conclusion: IgA-tTG and IgG-tTG analyzed in radioligand binding assays are equivalent to IgA-EMA as screening tests for CD during childhood, but an intestinal biopsy is still the method of choice to establish the diagnosis. Although IgGl-tTG was more common at young age of diagnosis, both IgGl-tTG and IgM-tTG had low specificity and sensitivity and may not be useful as screening tests for CD.
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| 30. |
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| 31. |
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| 32. |
- Ahlqvist, Emma, et al.
(författare)
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Novel subgroups of adult-onset diabetes and their association with outcomes : a data-driven cluster analysis of six variables
- 2018
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Ingår i: The Lancet Diabetes and Endocrinology. - 2213-8587 .- 2213-8595. ; 6:5, s. 361-369
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDiabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis.MethodsWe did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA1c, and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations.FindingsWe identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes.InterpretationWe stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.
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| 33. |
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| 34. |
- Andersen, Marie Louise M., et al.
(författare)
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Association between autoantibodies to the Arginine variant of the Zinc transporter 8 (ZnT8) and stimulated C-peptide levels in Danish children and adolescents with newly diagnosed type 1 diabetes
- 2012
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 13:6, s. 454-462
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Tidskriftsartikel (refereegranskat)abstract
- Background The zinc transporter 8 (ZnT8) was recently identified as a common autoantigen in type 1 diabetes (T1D) and inclusion of ZnT8 autoantibodies (ZnT8Ab) was found to increase the diagnostic specificity of T1D. Objectives The main aims were to determine whether ZnT8Ab vary during follow-up 1 year after diagnosis, and to relate the reactivity of three types of ZnT8Ab to the residual stimulated C-peptide levels during the first year after diagnosis. Subjects A total of 129 newly diagnosed T1D patients <15 years was followed prospectively 1, 3, 6, and 12 months after diagnosis. Methods Hemoglobin A1c, meal-stimulated C-peptide, ZnT8Ab, and other pancreatic autoantibodies were measured at each visit. Patients were genotyped for the rs13266634 variant at the SLC30A8 gene and HLA-DQ alleles. Results The levels of all ZnT8Ab [ZnT8Arg (arginine), ZnT8Trp (tryptophan), ZnT8Gln (glutamine)] tended to decrease during disease progression. A twofold higher level of ZnT8Arg and ZnT8Gln was associated with 4.6%/5.2% (p = 0.02), 5.3%/8.2% (p = 0.02) and 8.9%/9.7% (p = 0.004) higher concentrations of stimulated C-peptide 3, 6, and 12 months after diagnosis. The TT genotype carriers of the SLC30A8 gene had 45.8% (p = 0.01) and 60.1% (p = 0.002) lower stimulated C-peptide 6 and 12 months after diagnosis compared to the CC and the CT genotype carriers in a recessive model. Conclusions The levels of the Arg variant of the ZnT8 autoantibodies are associated with higher levels of stimulated C-peptide after diagnosis of T1D and during follow-up. Carriers of the TT genotype of the SLC30A8 gene predict lower stimulated C-peptide levels 12 months after diagnosis.
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| 35. |
- Andersson, Cecilia K, et al.
(författare)
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Glucose tolerance and beta-cell function in islet autoantibody-positive children recruited to a secondary prevention study.
- 2013
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 14:5, s. 341-349
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Children with type 1 diabetes (T1D) risk and islet autoantibodies are recruited to a secondary prevention study. The aims were to determine metabolic control in relation to human leukocyte antigen (HLA) genetic risk and islet autoantibodies in prepubertal children. METHODS: In 47 healthy children with GADA and at least one additional islet autoantibody, intravenous glucose tolerance test (IvGTT) and oral glucose tolerance test (OGTT) were performed 8-65 d apart. Hemoglobin A1c, plasma glucose as well as serum insulin and C-peptide were determined at fasting and during IvGTT and OGTT. RESULTS: All children aged median 5.1 (4.0-9.2) yr had autoantibodies to two to six of the beta-cell antigens GAD65, insulin, IA-2, and the three amino acid position 325 variants of the ZnT8 transporter. In total, 20/47 children showed impaired glucose metabolism. Decreased (≤30 μU/mL insulin) first-phase insulin response (FPIR) was found in 14/20 children while 11/20 had impaired glucose tolerance in the OGTT. Five children had both impaired glucose tolerance and FPIR ≤30 μU/mL insulin. Number and levels of autoantibodies were not associated with glucose metabolism, except for an increased frequency (p = 0.03) and level (p = 0.01) of ZnT8QA in children with impaired glucose metabolism. Among the children with impaired glucose metabolism, 13/20 had HLA-DQ2/8, compared to 9/27 of the children with normal glucose metabolism (p = 0.03). CONCLUSION: Secondary prevention studies in children with islet autoantibodies are complicated by variability in baseline glucose metabolism. Evaluation of metabolic control with both IvGTT and OGTT is critical and should be taken into account before randomization. All currently available autoantibody tests should be analyzed, including ZnT8QA.
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| 36. |
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| 37. |
- Andersson, Cecilia K, et al.
(författare)
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The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes.
- 2011
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 44, s. 394-405
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative. Methods: A total of 686 patients diagnosed in 1996-2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes. Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%-a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1(*)X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA. Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1(*)X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.
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| 38. |
- 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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| 39. |
- Andersson Svärd, Agnes, et al.
(författare)
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Characterization of plasma lipidomics in adolescent subjects with increased risk for type 1 diabetes in the DiPiS cohort
- 2020
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Ingår i: Metabolomics. - : Springer Science and Business Media LLC. - 1573-3882 .- 1573-3890. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Type 1 diabetes (T1D) is caused by the destruction of pancreatic islet beta cells resulting in total loss of insulin production. Recent studies have suggested that the destruction may be interrelated to plasma lipids.OBJECTIVES: Specific lipids have previously been shown to be decreased in children who develop T1D before four years of age. Disturbances of plasma lipids prior to clinical diagnosis of diabetes, if true, may provide a novel way to improve prediction, and monitor disease progression.METHODS: A lipidomic approach was utilized to analyze plasma from 67 healthy adolescent subjects (10-15 years of age) with or without islet autoantibodies but all with increased genetic risk for T1D. The study subjects were enrolled at birth in the Diabetes Prediction in Skåne (DiPiS) study and after 10-15 years of follow-up we performed the present cross-sectional analysis. HLA-DRB345, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1 genotypes were determined using next generation sequencing. Lipidomic profiles were determined using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. Lipidomics data were analyzed according to genotype.RESULTS: Variation in levels of several specific phospholipid species were related to level of autoimmunity but not development of T1D. Five glycosylated ceramides were increased in insulin autoantibody (IAA) positive adolescent subjects compared to adolescent subjects without this autoantibody. Additionally, HLA genotypes seemed to influence levels of long chain triacylglycerol (TG).CONCLUSION: Lipidomic profiling of adolescent subjects in high risk of T1D may improve sub-phenotyping in this high risk population.
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| 40. |
- Andersson Svärd, Agnes, et al.
(författare)
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Decreased HLA-DQ expression on peripheral blood cells in children with varying number of beta cell autoantibodies
- 2020
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Ingår i: Journal of Translational Autoimmunity. - : Elsevier BV. - 2589-9090. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- The risk for type 1 diabetes is strongly associated with HLA-DQ and the appearance of beta cell autoantibodies against either insulin, glutamate decarboxylase (GAD65), insulinoma-associated protein-2 (IA-2), or zinc transporter 8 (ZnT8). Prolonged exposure to autoantibodies may be related to T cell exhaustion known to occur in chronic infections or autoimmune disorders. It was hypothesized that autoantibody exposure may affect HLA-DQ expression on peripheral blood cells and thereby contribute to T cell exhaustion thought to be associated with the pathogenesis of type 1 diabetes. The aim of this study was to determine whether autoantibody exposure as an expression of autoimmunity burden was related to peripheral blood cell HLA-DQ cell surface expression in either 1) a cross-sectional analysis or 2) cumulative as area under the trajectory of autoantibodies during long term follow-up in the Diabetes Prediction in Skåne (DiPiS) study. Children (n = 67), aged 10-15 years were analyzed for complete blood count, HLA-DQ cell surface median fluorescence intensity (MFI), autoantibody frequency, and HLA genotypes by Next Generation Sequencing. Decreased HLA-DQ cell surface MFI with an increasing number of autoantibodies was observed in CD16+, CD14+CD16-, CD4+ and CD8+ cells but not in CD19+ cells and neutrophils. HLA-DQ cell surface MFI was associated with HLA-DQ2/8 in CD4+ T cells, marginally in CD14+CD16- monocytes and CD8+ T cells. These associations appeared to be related to autoimmunity burden. The results suggest that HLA-DQ cell surface expression was related to HLA and autoimmunity burden.
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| 41. |
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| 42. |
- Asad, Samina, et al.
(författare)
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HTR1A a Novel Type 1 Diabetes Susceptibility Gene on Chromosome 5p13-q13
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: We have previously performed a genome-wide linkage study in Scandinavian Type 1 diabetes (T1D) families. In the Swedish families, we detected suggestive linkage (LOD less than= 2.2) to the chromosome 5p13-q13 region. The aim of our study was to investigate the linked region in search for possible T1D susceptibility genes. Methodology/Principal Findings: Microsatellites were genotyped in the Scandinavian families to fine-map the previously linked region. Further, SNPs were genotyped in Swedish and Danish families as well as Swedish sporadic cases. In the Swedish families we detected genome-wide significant linkage to the 5-hydroxytryptamine receptor 1A (HTR1A) gene (LOD 3.98, pless than9.8x10(-6)). Markers tagging two separate genes; the ring finger protein 180 (RNF180) and HTR1A showed association to T1D in the Swedish and Danish families (pless than0.002, pless than0.001 respectively). The association was not confirmed in sporadic cases. Conditional analysis indicates that the primary association was to HTR1A. Quantitative PCR show that transcripts of both HTR1A and RNF180 are present in human islets of Langerhans. Moreover, immunohistochemical analysis confirmed the presence of the 5-HTR1A protein in isolated human islets of Langerhans as well as in sections of human pancreas. Conclusions: We have identified and confirmed the association of both HTR1A and RFN180, two genes in high linkage disequilibrium (LD) to T1D in two separate family materials. As both HTR1A and RFN180 were expressed at the mRNA level and HTR1A as protein in human islets of Langerhans, we suggest that HTR1A may affect T1D susceptibility by modulating the initial autoimmune attack or either islet regeneration, insulin release, or both.
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| 43. |
- Auchtung, Thomas A, et al.
(författare)
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Temporal changes in gastrointestinal fungi and the risk of autoimmunity during early childhood : the TEDDY study
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Fungal infections are a major health problem that often begin in the gastrointestinal tract. Gut microbe interactions in early childhood are critical for proper immune responses, yet there is little known about the development of the fungal population from infancy into childhood. Here, as part of the TEDDY (The Environmental Determinants of Diabetes in the Young) study, we examine stool samples of 888 children from 3 to 48 months and find considerable differences between fungi and bacteria. The metagenomic relative abundance of fungi was extremely low but increased while weaning from milk and formula. Overall fungal diversity remained constant over time, in contrast with the increase in bacterial diversity. Fungal profiles had high temporal variation, but there was less variation from month-to-month in an individual than among different children of the same age. Fungal composition varied with geography, diet, and the use of probiotics. Multiple Candida spp. were at higher relative abundance in children than adults, while Malassezia and certain food-associated fungi were lower in children. There were only subtle fungal differences associated with the subset of children that developed islet autoimmunity or type 1 diabetes. Having proper fungal exposures may be crucial for children to establish appropriate responses to fungi and limit the risk of infection: the data here suggests those gastrointestinal exposures are limited and variable.
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| 44. |
- Aydemir, O, et al.
(författare)
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Genetic Variation Within the HLA-DRA1 Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes
- 2019
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 68:7, s. 1523-1527
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes (T1D) involves the interaction of multiple gene variants, environmental factors, and immunoregulatory dysfunction. Major T1D genetic risk loci encode HLA-DR and -DQ. Genetic heterogeneity and linkage disequilibrium in the highly polymorphic HLA region confound attempts to identify additional T1D susceptibility loci. To minimize HLA heterogeneity, T1D patients (N = 365) and control subjects (N = 668) homozygous for the HLA-DR3 high-risk haplotype were selected from multiple large T1D studies and examined to identify new T1D susceptibility loci using molecular inversion probe sequencing technology. We report that risk for T1D in HLA-DR3 homozygotes is increased significantly by a previously unreported haplotype of three single nucleotide polymorphisms (SNPs) within the first intron of HLA-DRA1. The homozygous risk haplotype has an odds ratio of 4.65 relative to the protective homozygous haplotype in our sample. Individually, these SNPs reportedly function as “expression quantitative trait loci,” modulating HLA-DR and -DQ expression. From our analysis of available data, we conclude that the tri-SNP haplotype within HLA-DRA1 may modulate class II expression, suggesting that increased T1D risk could be attributable to regulated expression of class II genes. These findings could help clarify the role of HLA in T1D susceptibility and improve diabetes risk assessment, particularly in high-risk HLA-DR3 homozygous individuals.
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| 45. |
- Battaglia, Manuela, et al.
(författare)
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Understanding and preventing type 1 diabetes through the unique working model of TrialNet
- 2017
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 60:11, s. 2139-2147
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes is an autoimmune disease arising from the destruction of pancreatic insulin-producing beta cells. The disease represents a continuum, progressing sequentially at variable rates through identifiable stages prior to the onset of symptoms, through diagnosis and into the critical periods that follow, culminating in a variable depth of beta cell depletion. The ability to identify the very earliest of these presymptomatic stages has provided a setting in which prevention strategies can be trialled, as well as furnishing an unprecedented opportunity to study disease evolution, including intrinsic and extrinsic initiators and drivers. This niche opportunity is occupied by Type 1 Diabetes TrialNet, an international consortium of clinical trial centres that leads the field in intervention and prevention studies, accompanied by deep longitudinal bio-sampling. In this review, we focus on discoveries arising from this unique bioresource, comprising more than 70,000 samples, and outline the processes and science that have led to new biomarkers and mechanistic insights, as well as identifying new challenges and opportunities. We conclude that via integration of clinical trials and mechanistic studies, drawing in clinicians and scientists and developing partnership with industry, TrialNet embodies an enviable and unique working model for understanding a disease that to date has no cure and for designing new therapeutic approaches.
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| 46. |
- Bekris, LM, et al.
(författare)
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Glutamate cysteine ligase catalytic subunit promoter polymorphisms and associations with type 1 diabetes age-at-onset and GAD65 autoantibody levels.
- 2007
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Ingår i: Exp Clin Endocrinol Diabetes. - : Georg Thieme Verlag KG. ; 115:4, s. 221-228
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to test the hypothesis that glutamate cysteine ligase catalytic subunit (GCLC) promoter polymorphisms are susceptibility factors for type 1 diabetes (T1D), T1D age-at-onset and T1D autoantibodies. T1D patients and control subjects from the Swedish Childhood Diabetes Registry and the Swedish Diabetes Incidence Study registry were genotyped for two GCLC promoter polymorphisms; the GCLC -129 C to T single nucleotide polymorphism (GCLC -129 SNP) and the GCLC GAG trinucleotide repeat polymorphism (GCLC TNR). Glutamate decarboxylase antibody (GAD65Ab) positive T1D patients with the GCLC -129 SNP C/T genotype have increased GAD65Ab levels (p-value, <0.05) compared to the GCLC -129 SNP C/C genotype. T1D patients with an age-at-onset of 14-35 years who possess the GCLC -129 SNP T/T genotype have a higher GAD65Ab index than T1D patients with the GCLC -129 SNP C/C genotype (p-value <0.05). In addition, T1D patients with an age-at-onset of 14-35 years possess the GCLC TNR 7/8 genotype at a lower frequency than the control subjects (OR, 0.33, 95% CI, 0.13-0.82). The GCLC -129 SNP and GCLC TNR appear to be in linkage disequilibrium (p-value<0.0001). These results suggest that GCLC promoter polymorphisms may influence GAD65Ab levels and may influence the age at which T1D is diagnosed.
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| 47. |
- Bekris, L. M., et al.
(författare)
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GAD65 autoantibody epitopes in adult patients with latent autoimmune diabetes following GAD65 vaccination
- 2007
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Ingår i: Diabetic Medicine. - : Wiley. - 1464-5491 .- 0742-3071. ; 24:5, s. 521-526
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Tidskriftsartikel (refereegranskat)abstract
- Aims Subcutaneous injection of recombinant human GAD65 (rhGAD65) in patients with latent autoimmune diabetes in adults (LADA) correlates with an increase in C-peptide levels. In this study we analysed the effect of rhGAD65 administration on the GAD65-specific autoimmune response. Methods Longitudinal serum samples obtained from LADA patients (n = 47) who received 4, 20, 100 or 500 mu g alum-formulated rhGAD65 or placebo by subcutaneous injection twice (4 weeks apart) were analysed for their epitope recognition using GAD65-specific recombinant Fab and GAD65/67 fusion proteins. Results Overall, minor changes in the epitope pattern were observed using either approach. Only in the 500-mu g dosage group was an increase in GAD65Ab level associated with a significant increase in the binding to a conformational epitope located at the middle part of GAD65. Conclusions Our data suggest that the apparent beneficial effects of 20 mu g alum-formulated recombinant human GAD65 is not explained by changes in the GAD65Ab epitope pattern.
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| 48. |
- Bekris, L M, et al.
(författare)
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Targeting type 1 diabetes before and at the clinical onset of disease.
- 2006
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Ingår i: Endocrine, Metabolic & Immune Disorders - Drug Targets. - : Bentham Science Publishers Ltd.. - 2212-3873 .- 1871-5303. ; 6:1, s. 103-124
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune type 1 diabetes is strongly associated with a number of immune abnormalities that manifest themselves before and at the time of clinical diagnosis. The clinical onset is associated with a major loss of the pancreatic islet beta cells. Insulin treatment is the only treatment option since numerous trials with agents that suppress or modulate immune function have failed to preserve beta cell function long term. Recent studies suggest that it is possible to predict clinical onset of diabetes by combining genetic with autoantibody testing. In this review we will summarize current and future drug targets for subjects at risk for type 1 diabetes as well as for subjects with recent onset disease. We will also discuss the possible importance of initiating as well as contributing factors such as reactive oxygen species and modified autoantigens. It is speculated that drug targets of factors important to disease pathogenesis may provide safe and effective adductive treatment to preserve beta cell function in autoantibody positive subjects who are at maximum risk for disease.
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| 49. |
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| 50. |
- Beyan, Huriya, et al.
(författare)
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Guthrie card methylomics identifies temporally stable epialleles that are present at birth in humans
- 2012
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 22:11, s. 2138-2145
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Tidskriftsartikel (refereegranskat)abstract
- A major concern in common disease epigenomics is distinguishing causal from consequential epigenetic variation. One means of addressing this issue is to identify the temporal origins of epigenetic variants via longitudinal analyses. However, prospective birth-cohort studies are expensive and time consuming. Here, we report DNA methylomics of archived Guthrie cards for the retrospective longitudinal analyses of in-utero-derived DNA methylation variation. We first validate two methodologies for generating comprehensive DNA methylomes from Guthrie cards. Then, using an integrated epigenomic/genomic analysis of Guthrie cards and follow-up samplings, we identify interindividual DNA methylation variation that is present both at birth and 3 yr later. These findings suggest that disease-relevant epigenetic variation could be detected at birth, i.e., before overt clinical disease. Guthrie card methylomics offers a potentially powerful and cost-effective strategy for studying the dynamics of interindividual epigenomic variation in a range of common human diseases.
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