| 1. |
- Sanjeevi, Carani B., et al.
(författare)
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The risk conferred by HLA-DR and DQ for type 1 diabetes in 0-35-year age group are different in different regions of Sweden
- 2008
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. - 9781573317337 ; 1150, s. 106-11
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Tidskriftsartikel (refereegranskat)abstract
- HLA DR4-DQ8 and DR3-DQ2 haplotypes account for 89% of newly diagnosed cases of type 1 diabetes (T1D) in Sweden. The presence of a single copy of DQ6 confers protection. The aim of the present study is to evaluate whether the risk conferred by high risk HLA DR and DQ to T1D is similar in all regions of Sweden and see whether there are any significant regional differences. The subjects comprised 799 consecutively diagnosed T1D patients and 585 age-, sex-, and geography-matched healthy controls in the age group 0-35 years. HLA typing for high-risk haplotypes was previously performed using PCR-SSOP and RFLP. The results showed that HLA DR3-DR4 gave an odds ratio of 8.14 for the whole of Sweden. However, when the study group was divided into six geographical regions, subjects from Stockholm had the highest OR, followed by those from Lund, Linköping, Gothenburg, Umeå, and Uppsala. Absolute protection was conferred by the presence of DQ6 in subjects from the Linköping region, but varied in the other regions. The frequency of DR3 and DQ2, DR4 and DQ8, DR15, and DQ6 in patients showed high linkage for each region, but were different between regions. In conclusion: The risk conferred by high-risk HLA varies in different regions for a homogenous population in Sweden. The results highlight the important role played by the various environmental factors in the precipitation of T1D.
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| 2. |
- Christie, M., et al.
(författare)
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Antibodies to a Mr-64000 islet cell protein in Swedish children with newly diagnosed Type 1 (insulin-dependent) diabetes
- 1988
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Ingår i: Diabetologia. - 0012-186X. ; 31:8, s. 597-602
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Tidskriftsartikel (refereegranskat)abstract
- Sera from 40 Swedish children diagnosed as having Type 1 (insulin-dependent) diabetes mellitus during a one year period along with 40 age and geographically matched control subjects were tested for antibodies to a Mr-64000 islet protein by immunoprecipitation of 35S-methionine-labelled rat islet amphiphilic proteins. Of the 40 diabetic patients, 29 (73%) were found to be positive whereas all 40 control subjects were negative. Samples were also tested for titres of islet cell cytoplasmic antibodies by indirect immunofluorescence on frozen sections of human pancreas. In the diabetic group, 30 of the 40 patients (75%) were positive for islet cell cytoplasmic antibodies compared with 2 of the 40 control subjects (5%). A comparison of levels of antibodies to the Mr-64000 protein with islet cell cytoplasmic antibodies revealed a weak (rs=0.46), but significant (p<0.01) correlation between the two tests. There was no effect of age or sex on levels of antibodies to the Mr-64000 protein. These results in population-based diabetic children and control subjects demonstrate a high frequency of antibodies to the Mr-64000 protein at the time of clinical onset.
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| 3. |
- Graham, J, et al.
(författare)
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Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes
- 2002
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 51:5, s. 1346-1355
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Tidskriftsartikel (refereegranskat)abstract
- Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0–34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3′ end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.
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| 4. |
- Landin-Olsson, M, et al.
(författare)
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Epidemiological and genetic aspects on islet autoimmunity in childhood insulin-dependent diabetes.
- 1988
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Ingår i: Genetic susceptibility to environmental factors : a challenge for public intervention : [First International Ernhold Lundström Symposium, Malmö, Sweden, May 14-16, 1987] - [First International Ernhold Lundström Symposium, Malmö, Sweden, May 14-16, 1987]. - 9122012621 ; , s. 87-93
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Bokkapitel (refereegranskat)
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| 5. |
- Landin-Olsson, M., et al.
(författare)
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Islet cell and other organ-specific autoantibodies in all children developing Type 1 (insulin-dependent) diabetes mellitus in Sweden during one year and in matched control children
- 1989
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Ingår i: Diabetologia. - 0012-186X. ; 32:6, s. 387-395
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Tidskriftsartikel (refereegranskat)abstract
- The majority (about 90%) of children developing Type 1 (insulin-dependent) diabetes mellitus do not have a first-degree relative with the disease. Nearly all (389/405, 96%) children (0-14 years) in Sweden, who developed diabetes during one year, were therefore studied to compare islet cell, thyroid peroxidase, thyroglobulin, and gastric H+, K+-ATPase antibodies with 321 age, sex, and geographically matched, but non-related, control children. Islet cell (cytoplasmic) antibodies were found in 81% (316/389) of the patients and in 3% (9/321) of the control children (p<0.001). The median islet cell antibody levels were 70 (range 3-8200) Juvenile Diabetes Foundation (JDF) Units in the islet cell antibody positive patients, and 27 (range 17-1200) JDF Units in the control children (NS). Autoantibodies against thyroid peroxidase (8%), thyroglobulin (6%), and gastric H+, K+- ATPase (3%) were all increased in the patients compared with the control children, being 2% (p<0.001), 2% (p<0.01), and 0.3% (p<0.01), respectively. During an observation time of 20-34 months, two of the nine islet cell antibody positive control children developed Type 1 diabetes, after 8 and 25 months respectively, while the others remained healthy and became islet cell antibody negative. None of the islet cell antibody negative control children developed diabetes during the same time of observation. This first investigation of an unselected population of diabetic children and matched control children shows: that islet cell antibodies are strongly associated with newly diagnosed childhood diabetes, that other autoantibodies are more frequent among diabetic children than control children, and that the frequency of islet cell antibodies in the background population of children is higher than previously documented, and could also be transient, underlining that factors additional to islet cell antibodies are necessary for the later development of Type 1 diabetes.
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| 6. |
- Landin-Olsson, M, et al.
(författare)
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Predictive value of islet cell and insulin autoantibodies for type 1 (insulin-dependent) diabetes mellitus in a population-based study of newly-diagnosed diabetic and matched control children
- 1992
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Ingår i: Diabetologia. - 0012-186X. ; 35:11, s. 73-1068
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Tidskriftsartikel (refereegranskat)abstract
- Most studies evaluating immune markers for prediction of Type 1 (insulin-dependent) diabetes mellitus have focused on first degree relatives, although only 10% of newly-diagnosed patients have an affected first degree relative. The Swedish Childhood Diabetes Register identifies 99% of all diabetic children at diagnosis. In this population-based study, islet cell antibodies and insulin autoantibodies in 0-14-year-old Swedish consecutively-diagnosed patients and control subjects were analysed to define their sensitivity and specificity. Over 16 months (1986-1987), 515 Swedish children developed diabetes. Plasma samples were obtained from 494 (96%) patients, and 420 matched control children. Among patients, the frequency of islet cell antibodies was 84% (415 of 494), insulin autoantibodies 43% (145 of 334); 40% (135 of 334) were positive for both and 88% (294 of 334) were positive for one or both. Among control children, 3% (14 of 420) had islet cell antibodies, 1% (4 of 390) insulin autoantibodies, and 4% (16 of 390) had either autoantibody marker. The predictive value of finding a patient with the disease was only 7% since 4% of the control children were antibody-positive and the cumulative incidence rate up to 15 years of age is 0.38%. None of the autoantibody-positive (n = 21) or negative control children developed diabetes during 3 to 5 years of follow-up. Longitudinal investigations of islet cell or insulin-autoantibody-positive healthy children are necessary to accurately determine the conversion rate from marker positivity to disease onset.
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| 7. |
- Lowe, Michael R., et al.
(författare)
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The length of the CTLA-4 microsatellite (AT)(N)-repeat affects the risk for type 1 diabetes
- 2000
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 32:3, s. 173-180
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Tidskriftsartikel (refereegranskat)abstract
- CTLA-4 is important to down-regulating T cell responses and has been implicated in type 1 (insulin dependent) diabetes mellitus in both linkage and association studies. The aim of our study was to relate the polymorphic (AT)(n) microsatellite in the 3' untranslated sequence of the CTLA-4 gene to diabetes risk. We studied 616 consecutively diagnosed 0-34 year-old Swedish patients and 502 matched controls by PCR-based genotyping to determine the length of the 3'-end (AT)(n)repeat region of the CTLA-4 gene and categorizing alleles as predominantly monomorphic short (S) or highly polymorphic (in length) long (L) alleles. The odds of type 1 diabetes of subjects with the L/L genotype was estimated to be 1.84 times that of subjects with the S/S genotype (95% CI 1.44-2.73, p=0.002). Further analysis of the long alleles, partitioned into intermediate (I) length and very long (VL) alleles, suggested that L alleles act recessively in conferring diabetes risk (p=0.0009). This study suggests that the 3'-end (AT)(n) repeat region of the CTLA-4 gene represents a recessive risk factor for type 1 diabetes.
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| 8. |
- Madsen, O D, et al.
(författare)
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A two-colour immunofluorescence test with a monoclonal human proinsulin antibody improves the assay for islet cell antibodies
- 1986
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Ingår i: Diabetologia. - : Springer-Verlag New York. - 0012-186X .- 1432-0428. ; 29:2, s. 8-115
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Tidskriftsartikel (refereegranskat)abstract
- The conventional indirect immunofluorescence assay for islet cell antibodies was compared with a two-colour immunofluorescent assay to detect both islet cell antibodies with fluorescein isothiocyanate-labeled rabbit anti-human IgG and pancreatic B cells with a monoclonal human proinsulin antibody and Texas red-labeled sheep anti-mouse IgG. Determinations of end-point titres showed a correlation between the new two-colour immunofluorescent assay and the conventional indirect immunofluorescent assay in 1) selected sera positive for islet cell antibodies and insulin autoantibodies rs = 0.93 (p less than 0.01) or for islet cell antibodies alone rs = 0.99 (p less than 0.005) and 2) sera from children or young adults with newly diagnosed Type 1 (insulin-dependent) diabetes rs = 0.95 (p less than 0.0001). No interference between the monoclonal human proinsulin antibodies and islet cell antibodies with or without insulin autoantibodies or between the two second fluorescent antibodies was detected. It is concluded that the two-colour immunofluorescence assay is advantageous since it is possible to mix the reagents to avoid a more time-consuming and technically complicated assay, the presence of B cells can be confirmed in each section to permit detection of B cell cytoplasmic antibodies and microscopic evaluation is easier and more accurate, particularly in islet cell antibody negative samples.
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| 9. |
- Pundziute-Lycka, A, et al.
(författare)
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The incidence of Type I diabetes has not increased but shifted to a younger age at diagnosis in the 0-34 years group in Sweden 1983 to 1998
- 2002
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 45:6, s. 783-791
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis. To analyse the incidence of Type I (insulin-dependent) diabetes mellitus in the 0-34 years age group in Sweden 1983-1998. Methods. Incidence and cumulative incidence per 100 000 and Poisson regression analysis of age-period effects was carried out using 11 751 cases from two nation-wide prospective registers. Results. Incidence (95%-CI) was 21.4 (20.8-21.9) in men and 17.1 (16.6-17.5) in women between 0 and 34 years of age. In boys aged 0-14 and girls aged 0-12 years the incidence increased over time, but it tended to decrease at older age groups, especially in men. Average cumulative incidence at 35 years was 748 in men and 598 in women. Cumulative incidence in men was rather stable during four 4-year periods (736, 732, 762, 756), while in women it varied more (592, 542, 617, 631). In males aged 0-34 years, the incidence did not vary between the 4-year periods (p=0.63), but time changes among the 3-year age groups differed (p<0.001). In females the incidence between the periods varied (p<0.001), being lower in 1987-1990 compared to 1983-1986, but time changes in the age groups did not differ (p=0.08). For both sexes median age at diagnosis was higher in 1983-1986 than in 1995-1998 (p<0.001) (15.0 and 12.5 years in males, 11.9 and 10.4 in females, respectively). Conclusion/interpretation. During a 16-year period the incidence of Type I diabetes did not increase in the 0-34 years age group in Sweden, while median age at diagnosis decreased. A shift to younger age at diagnosis seems to explain the increasing incidence of childhood Type I diabetes.
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| 10. |
- Sanjeevi, C. B., et al.
(författare)
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Polymorphic amino acid variations in HLA-DQ are associated with systematic physical property changes and occurrence of IDDM
- 1995
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 44:1, s. 125-131
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Tidskriftsartikel (refereegranskat)abstract
- The association between human leukocyte antigen (HLA) insulin-dependent diabetes was studied in a large population-based investigation using genotyping of 425 new-onset patients, 0-14 years of age, and 367 matched control subjects. As many as 97% of patients compared with 75% of control subjects were positive for one or several of DQA1*0301, DQA1*0501, DQB1*0302, or DQB1*0201. Asp-57 DQB was present among 28% of patients, indicating that this residue alone does not confer protection. Combining Asp- 57 DQB1 with either Arg-52 DQA1 or Leu-69 DQA1 did not explain susceptibility or protection either. DQA1*0301-DQB1*0302 (DQS) and DQA1*0301-DQB1*0301 (DQ7) are identical except for four amino acid substitutions in the β- chain, but DQ8 was positively (odds ratio 8.07; P < 0.001) and DQ7 negatively (odds ratio 0.38; P < 0.001) associated with the disease. Molecular modeling was used to determine whether physicochemical properties such as steric factors and surface electrostatic potentials also differ in a systematic way for various DQ molecules. Amino acids were substituted systematically at the four polymorphic sites, and the solvent-accessible surfaces and electrostatic potentials were computed for each molecule. Dramatic alterations in electrostatic potential were seen for double substitutions at position 45 (G45E) and 57 (A57D) of DQB1. The variation of physicochemical properties due to polymorphic substitutions may be significant to the mechanism of HLA-DQ association with insulin-dependent diabetes, via the effect these property variations have on peptide antigen binding selectivity and subsequent interactions with specific T-cell receptors.
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