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2. 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

Author

Sanjeevi, Carani B., Sedimbi, Saikiran K., Landin-Olsson, Mona, Kockum, Ingrid, Lernmark, Åke, Aili, M., Bååth, L.E., Carlsson, E., Edenwall, H., Forsander, G., Granström, B.W., Gustavsson, I., Hanås, R., Hellenberg, L., Hellgren, H., Holmberg, E., Hörnell, H., Ivarsson, Sten-A., Johansson, C., Jonsell, G., Kockum, K., Lindblad, B., Lindh, A., Ludvigsson, J., Myrdal, U., Neiderud, J., Segnestam, K., Sjöblad, S., Skogsberg, L., Strömberg, L., Ståhle, U., Thalme, B., Tullus, K., Tuvemo, Torsten, Wallensteen, M., Westphal, O., Dahlquist, G., Åman, J., Sanjeevi, Carani B., Sedimbi, Saikiran K., Landin-Olsson, Mona, Kockum, Ingrid, Lernmark, Åke, Aili, M., Bååth, L.E., Carlsson, E., Edenwall, H., Forsander, G., Granström, B.W., Gustavsson, I., Hanås, R., Hellenberg, L., Hellgren, H., Holmberg, E., Hörnell, H., Ivarsson, Sten-A., Johansson, C., Jonsell, G., Kockum, K., Lindblad, B., Lindh, A., Ludvigsson, J., Myrdal, U., Neiderud, J., Segnestam, K., Sjöblad, S., Skogsberg, L., Strömberg, L., Ståhle, U., Thalme, B., Tullus, K., Tuvemo, Torsten, Wallensteen, M., Westphal, O., Dahlquist, G., and Åman, J.

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.

Published
2008
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3. Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk

Author

Resic-Lindehammer, Sabina, Larsson, K., Örtqvist, E., Carlsson, A., Cederwall, E., Cilio, C. M., Ivarsson, S-A., Jönsson, B. A., Larsson, H. E., Lynch, K., Neiderud, J., Nilsson, A., Sjöblad, S., Lernmark, Å., Aili, M., Bååth, L. E., Carlsson, E., Edenwall, H., Forsander, G., Granstro, B. W., Gustavsson, I., Hanås, R., Hellenberg, L., Hellgren, H., Holmberg, E., Hörnell, H., Ivarsson, Sten-A., Johansson, C., Jonsell, G., Kockum, K., Lindblad, B., Lindh, A., Ludvigsson, J., Myrdal, U., Segnestam, K., Skogsberg, L., Strömberg, L., Ståhle, U., Thalme, B., Tullus, K., Tuvemo, Torsten, Wallensteen, M., Westphal, O., Aman, J., Resic-Lindehammer, Sabina, Larsson, K., Örtqvist, E., Carlsson, A., Cederwall, E., Cilio, C. M., Ivarsson, S-A., Jönsson, B. A., Larsson, H. E., Lynch, K., Neiderud, J., Nilsson, A., Sjöblad, S., Lernmark, Å., Aili, M., Bååth, L. E., Carlsson, E., Edenwall, H., Forsander, G., Granstro, B. W., Gustavsson, I., Hanås, R., Hellenberg, L., Hellgren, H., Holmberg, E., Hörnell, H., Ivarsson, Sten-A., Johansson, C., Jonsell, G., Kockum, K., Lindblad, B., Lindh, A., Ludvigsson, J., Myrdal, U., Segnestam, K., Skogsberg, L., Strömberg, L., Ståhle, U., Thalme, B., Tullus, K., Tuvemo, Torsten, Wallensteen, M., Westphal, O., and Aman, J.

Abstract

The aim of this study was to compare the frequency of human leukocyte antigen (HLA) genotypes in 1-18-year-old patients with type 1 diabetes newly diagnosed in 1986-1987 (n = 430), 1996-2000 (n = 342) and in 2003-2005 (n = 171). We tested the hypothesis that the HLA DQ genotype distribution changes over time. Swedish type 1 diabetes patients and controls were typed for HLA using polymerase chain reaction amplification and allele specific probes for DQ A1* and B1* alleles. The most common type 1 diabetes HLA DQA1*-B1*genotype 0501-0201/0301-0302 was 36% (153/430) in 1986-1987 and 37% (127/342) in 1996-2000, but decreased to 19% (33/171) in 2003-2005 (P \ 0.0001). The 0501-0201/0501-0201 genotype increased from 1% in 1986-1987 to 7% in 1996-2000 (P = 0.0047) and to 5% in 2003-2005 (P > 0.05). This study in 1-18-year-old Swedish type 1 diabetes patients supports the notion that there is a temporal change in HLA risk.

Published
2008
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4. IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5

Author

Shin, J-H, Janer, M, McNeney, B, Blay, S, Deutsch, K, Sanjeevi, C B, Kockum, I, Lernmark, A, Graham, J, Arnqvist, Hans, Björck, Elizabeth, Eriksson, Jan, Nyström, Lennarth, Ohlson, Lars Olof, Scherstén, Bengt, Ostman, Jan, Aili, M, Bååth, L E, Carlsson, E, Edenwall, H, Forsander, G, Granström, B W, Gustavsson, I, Hanås, R, Hellenberg, L, Hellgren, H, Holmberg, E, Hörnell, H, Ivarsson, Sten-A, Johansson, C, Jonsell, G, Kockum, K, Lindblad, B, Lindh, A, Ludvigsson, J, Myrdal, U, Neiderud, J, Segnestam, K, Sjöblad, S, Skogsberg, L, Strömberg, L, Ståhle, U, Thalme, B, Tullus, K, Tuvemo, T, Wallensteen, M, Westphal, O, Aman, J, Shin, J-H, Janer, M, McNeney, B, Blay, S, Deutsch, K, Sanjeevi, C B, Kockum, I, Lernmark, A, Graham, J, Arnqvist, Hans, Björck, Elizabeth, Eriksson, Jan, Nyström, Lennarth, Ohlson, Lars Olof, Scherstén, Bengt, Ostman, Jan, Aili, M, Bååth, L E, Carlsson, E, Edenwall, H, Forsander, G, Granström, B W, Gustavsson, I, Hanås, R, Hellenberg, L, Hellgren, H, Holmberg, E, Hörnell, H, Ivarsson, Sten-A, Johansson, C, Jonsell, G, Kockum, K, Lindblad, B, Lindh, A, Ludvigsson, J, Myrdal, U, Neiderud, J, Segnestam, K, Sjöblad, S, Skogsberg, L, Strömberg, L, Ståhle, U, Thalme, B, Tullus, K, Tuvemo, T, Wallensteen, M, Westphal, O, and Aman, J

Abstract

In a large case-control study of Swedish incident type I diabetes patients and controls, 0–34 years of age, we tested the hypothesis that the GIMAP5 gene, a key genetic factor for lymphopenia in spontaneous BioBreeding rat diabetes, is associated with type I diabetes; with islet autoantibodies in incident type I diabetes patients or with age at clinical onset in incident type I diabetes patients. Initial scans of allelic association were followed by more detailed logistic regression modeling that adjusted for known type I diabetes risk factors and potential confounding variables. The single nucleotide polymorphism (SNP) rs6598, located in a polyadenylation signal of GIMAP5, was associated with the presence of significant levels of IA-2 autoantibodies in the type I diabetes patients. Patients with the minor allele A of rs6598 had an increased prevalence of IA-2 autoantibody levels compared to patients without the minor allele (OR=2.2; Bonferroni-corrected P=0.003), after adjusting for age at clinical onset (P=8.0 10-13) and the numbers of HLA-DQ A1*0501-B1*0201 haplotypes (P=2.4 10-5) and DQ A1*0301-B1*0302 haplotypes (P=0.002). GIMAP5 polymorphism was not associated with type I diabetes or with GAD65 or insulin autoantibodies, ICA, or age at clinical onset in patients. These data suggest that the GIMAP5 gene is associated with islet autoimmunity in type I diabetes and add to recent findings implicating the same SNP in another autoimmune disease.

Published
2007
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5. SUMO4 M55V polymorphism affects susceptibility to type I diabetes in HLA DR3- and DR4-positive Swedish patients

Author

Sedimbi, S K, Luo, X R, Sanjeevi, C B, Lernmark, Ake, Landin-Olsson, Mona, Arnqvist, Hans, Björck, Elizabeth, Nyström, Lennarth, Ohlson, Lars Olof, Scherstén, Bengt, Ostman, Jan, Aili, M, Bååth, L E, Carlsson, E, Edenwall, H, Forsander, G, Granström, B W, Gustavsson, I, Hanås, R, Hellenberg, L, Hellgren, H, Holmberg, E, Hörnell, H, Ivarsson, Sten-A, Johansson, C, Jonsell, G, Kockum, K, Lindblad, B, Lindh, A, Ludvigsson, J, Myrdal, U, Neiderud, J, Segnestam, K, Sjöblad, S, Skogsberg, L, Strömberg, L, Ståhle, U, Thalme, B, Tullus, K, Tuvemo, Torsten, Wallensteen, M, Westphal, O, Dahlquist, Gisela, Aman, J, Sedimbi, S K, Luo, X R, Sanjeevi, C B, Lernmark, Ake, Landin-Olsson, Mona, Arnqvist, Hans, Björck, Elizabeth, Nyström, Lennarth, Ohlson, Lars Olof, Scherstén, Bengt, Ostman, Jan, Aili, M, Bååth, L E, Carlsson, E, Edenwall, H, Forsander, G, Granström, B W, Gustavsson, I, Hanås, R, Hellenberg, L, Hellgren, H, Holmberg, E, Hörnell, H, Ivarsson, Sten-A, Johansson, C, Jonsell, G, Kockum, K, Lindblad, B, Lindh, A, Ludvigsson, J, Myrdal, U, Neiderud, J, Segnestam, K, Sjöblad, S, Skogsberg, L, Strömberg, L, Ståhle, U, Thalme, B, Tullus, K, Tuvemo, Torsten, Wallensteen, M, Westphal, O, Dahlquist, Gisela, and Aman, J

Abstract

SUMO4 M55V, located in IDDM5, has been a focus for debate because of its association to type I diabetes (TIDM) in Asians but not in Caucasians. The current study aims to test the significance of M55V association to TIDM in a large cohort of Swedish Caucasians, and to test whether M55V is associated in those carrying human leukocyte antigen (HLA) class II molecules. A total of 673 TIDM patients and 535 age- and sex-matched healthy controls were included in the study. PCR–RFLP was performed to identify the genotype and allele variations. Our data suggest that SUMO4 M55V is not associated with susceptibility to TIDM by itself. When we stratified our patients and controls based on heterozygosity for HLA-DR3/DR4 and SUMO4 genotypes, we found that presence of SUMO4 GG increased further the relative risk conferred by HLA-DR3/DR4 to TIDM, whereas SUMO4 AA decreased the risk. From the current study, we conclude that SUMO4 M55V is associated with TIDM in association with high-risk HLA-DR3 and DR4, but not by itself., Group Author(s): Swedish Childhood Diabetes

Published
2007
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9. Inskränkt aktiv extension av fingerleder hos juvenila diabetiker.

Author

Ludvigsson, J, Dahlqvist, G, Edenvall, H, Lundmark, KM, Samuelson, Gösta, Skogsberg, L, Thilén, A, Ludvigsson, J, Dahlqvist, G, Edenvall, H, Lundmark, KM, Samuelson, Gösta, Skogsberg, L, and Thilén, A

Abstract

Professor Gösta Samuelson samlade trycksaker; 114

Published
1984

10. Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk.

Author

Resic-Lindehammer S, Larsson K, Ortqvist E, Carlsson A, Cederwall E, Cilio CM, Ivarsson SA, Jönsson BA, Larsson HE, Lynch K, Neiderud J, Nilsson A, Sjöblad S, Lernmark A, Aili M, Bååth LE, Carlsson E, Edenwall H, Forsander G, Granstro BW, Gustavsson I, Hanås R, Hellenberg L, Hellgren H, Holmberg E, Hörnell H, Ivarsson SA, Johansson C, Jonsell G, Kockum K, Lindblad B, Lindh A, Ludvigsson J, Myrdal U, Neiderud J, Segnestam K, Sjöblad S, Skogsberg L, Strömberg L, Ståhle U, Thalme B, Tullus K, Tuvemo T, Wallensteen M, Westphal O, and Aman J

Subjects
Adolescent, Age of Onset, Child, Child, Preschool, Diabetes Mellitus, Type 1 epidemiology, Female, Gene Frequency, HLA-DQ Antigens genetics, HLA-DQ alpha-Chains, HLA-DQ beta-Chains, Humans, Infant, Male, Sweden epidemiology, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 immunology, Genotype, HLA Antigens genetics
Abstract

The aim of this study was to compare the frequency of human leukocyte antigen (HLA) genotypes in 1-18-year-old patients with type 1 diabetes newly diagnosed in 1986-1987 (n = 430), 1996-2000 (n = 342) and in 2003-2005 (n = 171). We tested the hypothesis that the HLA DQ genotype distribution changes over time. Swedish type 1 diabetes patients and controls were typed for HLA using polymerase chain reaction amplification and allele specific probes for DQ A1* and B1* alleles. The most common type 1 diabetes HLA DQA1*-B1*genotype 0501-0201/0301-0302 was 36% (153/430) in 1986-1987 and 37% (127/342) in 1996-2000, but decreased to 19% (33/171) in 2003-2005 (P \ 0.0001). The 0501-0201/0501-0201 genotype increased from 1% in 1986-1987 to 7% in 1996-2000 (P = 0.0047) and to 5% in 2003-2005 (P > 0.05). This study in 1-18-year-old Swedish type 1 diabetes patients supports the notion that there is a temporal change in HLA risk.

Published
2008
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11. Improved treatment satisfaction but no difference in metabolic control when using continuous subcutaneous insulin infusion vs. multiple daily injections in children at onset of type 1 diabetes mellitus.

Author

Skogsberg L, Fors H, Hanas R, Chaplin JE, Lindman E, and Skogsberg J

Subjects
Adolescent, Blood Glucose metabolism, Child, Female, Glycated Hemoglobin metabolism, Humans, Hyperglycemia blood, Hypoglycemia blood, Hypoglycemic Agents administration & dosage, Injections, Subcutaneous, Male, Diabetes Mellitus, Type 1 drug therapy, Insulin administration & dosage, Insulin Infusion Systems, Patient Satisfaction
Abstract

Objective: The aim of this study was to compare safety, metabolic control, and treatment satisfaction in children/adolescents at onset of type 1 diabetes mellitus who were treated with either continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI)., Research Design and Methods: Seventy-two children/adolescents (7-17 yr of age) were enrolled in this open, randomized, parallel, multicenter study. Approximately half of the patients were treated with MDI (natural protamine hagedorn [NPH] insulin twice daily and rapid-acting insulin three to -four times daily, n = 38) by pen, and the other half received CSII (n = 34). The patients were followed for 24 months with clinical visits at the entry of the study and after 1, 6, 12, and 24 months. During these visits, hemoglobin A1c, insulin doses, weight, and height were registered. Severe episodes of hypoglycemia and ketoacidosis as well as technical problems were recorded. In addition, the patients/parents answered the Diabetes Treatment Satisfaction Questionnaire., Results: There was no significant difference in metabolic control between the treatment groups. Treatment satisfaction was significantly higher in the group treated with CSII compared with the MDI group (p

Published
2008
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12. IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5.

Author

Shin JH, Janer M, McNeney B, Blay S, Deutsch K, Sanjeevi CB, Kockum I, Lernmark A, Graham J, Arnqvist H, Björck E, Eriksson J, Nyström L, Ohlson LO, Scherstén B, Ostman J, Aili M, Bååth LE, Carlsson E, Edenwall H, Forsander G, Granström BW, Gustavsson I, Hanås R, Hellenberg L, Hellgren H, Holmberg E, Hörnell H, Ivarsson SA, Johansson C, Jonsell G, Kockum K, Lindblad B, Lindh A, Ludvigsson J, Myrdal U, Neiderud J, Segnestam K, Sjöblad S, Skogsberg L, Strömberg L, Ståhle U, Thalme B, Tullus K, Tuvemo T, Wallensteen M, Westphal O, and Aman J

Subjects
Adolescent, Adult, Autoantibodies blood, Case-Control Studies, Child, Child, Preschool, Diabetes Mellitus, Type 1 metabolism, Female, GTP-Binding Proteins metabolism, Humans, Infant, Infant, Newborn, Male, Polymorphism, Single Nucleotide, Sweden, Autoantibodies immunology, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 immunology, GTP-Binding Proteins genetics
Abstract

In a large case-control study of Swedish incident type I diabetes patients and controls, 0-34 years of age, we tested the hypothesis that the GIMAP5 gene, a key genetic factor for lymphopenia in spontaneous BioBreeding rat diabetes, is associated with type I diabetes; with islet autoantibodies in incident type I diabetes patients or with age at clinical onset in incident type I diabetes patients. Initial scans of allelic association were followed by more detailed logistic regression modeling that adjusted for known type I diabetes risk factors and potential confounding variables. The single nucleotide polymorphism (SNP) rs6598, located in a polyadenylation signal of GIMAP5, was associated with the presence of significant levels of IA-2 autoantibodies in the type I diabetes patients. Patients with the minor allele A of rs6598 had an increased prevalence of IA-2 autoantibody levels compared to patients without the minor allele (OR=2.2; Bonferroni-corrected P=0.003), after adjusting for age at clinical onset (P=8.0 x 10(-13)) and the numbers of HLA-DQ A1*0501-B1*0201 haplotypes (P=2.4 x 10(-5)) and DQ A1*0301-B1*0302 haplotypes (P=0.002). GIMAP5 polymorphism was not associated with type I diabetes or with GAD65 or insulin autoantibodies, ICA, or age at clinical onset in patients. These data suggest that the GIMAP5 gene is associated with islet autoimmunity in type I diabetes and add to recent findings implicating the same SNP in another autoimmune disease.

Published
2007
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13. SUMO4 M55V polymorphism affects susceptibility to type I diabetes in HLA DR3- and DR4-positive Swedish patients.

Author

Sedimbi SK, Luo XR, Sanjeevi CB, Lernmark A, Landin-Olsson M, Arnqvist H, Björck E, Nyström L, Ohlson LO, Scherstén B, Ostman J, Aili M, Bååth LE, Carlsson E, Edenwall H, Forsander G, Granström BW, Gustavsson I, Hanås R, Hellenberg L, Hellgren H, Holmberg E, Hörnell H, Ivarsson SA, Johansson C, Jonsell G, Kockum K, Lindblad B, Lindh A, Ludvigsson J, Myrdal U, Neiderud J, Segnestam K, Sjöblad S, Skogsberg L, Strömberg L, Ståhle U, Thalme B, Tullus K, Tuvemo T, Wallensteen M, Westphal O, Dahlquist G, and Aman J

Subjects
Adolescent, Adult, Alleles, Case-Control Studies, Child, Child, Preschool, Cohort Studies, Diabetes Mellitus, Type 1 immunology, Female, Genetic Predisposition to Disease, Genotype, HLA-DR3 Antigen immunology, HLA-DR4 Antigen immunology, Haplotypes, Humans, Infant, Infant, Newborn, Male, Polymorphism, Single Nucleotide, Small Ubiquitin-Related Modifier Proteins immunology, Sweden, Diabetes Mellitus, Type 1 genetics, HLA-DR3 Antigen genetics, HLA-DR4 Antigen genetics, Small Ubiquitin-Related Modifier Proteins genetics
Abstract

SUMO4 M55V, located in IDDM5, has been a focus for debate because of its association to type I diabetes (TIDM) in Asians but not in Caucasians. The current study aims to test the significance of M55V association to TIDM in a large cohort of Swedish Caucasians, and to test whether M55V is associated in those carrying human leukocyte antigen (HLA) class II molecules. A total of 673 TIDM patients and 535 age- and sex-matched healthy controls were included in the study. PCR-RFLP was performed to identify the genotype and allele variations. Our data suggest that SUMO4 M55V is not associated with susceptibility to TIDM by itself. When we stratified our patients and controls based on heterozygosity for HLA-DR3/DR4 and SUMO4 genotypes, we found that presence of SUMO4 GG increased further the relative risk conferred by HLA-DR3/DR4 to TIDM, whereas SUMO4 AA decreased the risk. From the current study, we conclude that SUMO4 M55V is associated with TIDM in association with high-risk HLA-DR3 and DR4, but not by itself.

Published
2007
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