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1. Detection of enterovirus RNA in peripheral blood mononuclear cells correlates with the presence of the predisposing allele of the type 1 diabetes risk gene IFIH1 and with disease stage

Author

Sioofy-Khojine, Amir-Babak, Richardson, Sarah J., Locke, Jonathan M., Oikarinen, Sami, Nurminen, Noora, Laine, Antti-Pekka, Downes, Kate, Lempainen, Johanna, Todd, John A., Veijola, Riitta, Ilonen, Jorma, Knip, Mikael, Morgan, Noel G., Hyöty, Heikki, Peakman, Mark, and Eichmann, Martin

Published
2022
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3. Associations between deduced first islet specific autoantibody with sex, age at diagnosis and genetic risk factors in young children with type 1 diabetes

Author

Ilonen, Jorma, Laine, Antti Pekka, Kiviniemi, Minna, Härkönen, Taina, Lempainen, Johanna, Knip, Mikael, The Finnish Pediatric Diabetes Register, Tampere University, Department of Paediatrics, CAMM - Research Program for Clinical and Molecular Metabolism, Molecular and Integrative Biosciences Research Programme, HUS Children and Adolescents, Children's Hospital, University of Helsinki, and Research Group Knip

Subjects
Male, demography, Genotype, Insulin Antibodies, Endocrinology, Diabetes and Metabolism, AUTOIMMUNE, SUSCEPTIBILITY, PHENOTYPE, 3121 Internal medicine, DISEASE, Islets of Langerhans, MARKERS, 3123 Gynaecology and paediatrics, Risk Factors, Internal Medicine, Humans, CELL-ANTIBODIES, HLA antigens, genes, Child, Autoantibodies, GENERAL-POPULATION, Glutamate Decarboxylase, HUMAN THYMUS, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Diabetes Mellitus, Type 1, 3121 General medicine, internal medicine and other clinical medicine, Child, Preschool, ONSET, Pediatrics, Perinatology and Child Health, Female, INSULIN AUTOANTIBODIES
Abstract

Objectives: We aimed to further characterize demography and genetic associations of type 1 diabetes “endotypes” defined by the first appearing islet specific autoantibodies. Research Design and Methods: We analyzed 3277 children diagnosed before the age of 10 years from the Finnish Pediatric Diabetes Register. The most likely first autoantibody could be deduced in 1636 cases (49.9%) based on autoantibody combinations at diagnosis. Distribution of age, sex, HLA genotypes and allele frequencies of 18 single nucleotide polymorphisms (SNPs) in non-HLA risk genes were compared between the endotypes. Results: Two major groups with either glutamic acid decarboxylase (GADA) or insulin autoantibodies (IAA) as the deduced first autoantibody showed significant differences in their demographic and genetic features. Boys and children diagnosed at young age had more often IAA-initiated autoimmunity whereas GADA-initiated autoimmunity was observed more frequently in girls and in subjects diagnosed at an older age. IAA as the first autoantibody was also most common in HLA genotype groups conferring high-disease risk while GADA first was seen more evenly and frequently in HLA groups associated with lower type 1 diabetes risk. The risk alleles in IKZF4 and ERBB3 genes were associated with GADA-initiated whereas those in PTPN22, INS and PTPN2 genes were associated with IAA-initiated autoimmunity. Conclusions: The results support the assumption that in around half of the young children the first autoantibody can be deduced based on islet autoantibody combinations at disease diagnosis. Strong differences in sex and age distributions as well as in genetic associations could be observed between GADA- and IAA-initiated autoimmunity. publishedVersion

Published
2022
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5. Detection of enterovirus RNA in peripheral blood mononuclear cells correlates with the presence of the predisposing allele of the type 1 diabetes risk gene IFIH1 and with disease stage

Author

Sioofy-Khojine, Amir-Babak, Richardson, Sarah J, Locke, Jonathan M, Oikarinen, Sami, Nurminen, Noora, Laine, Antti-Pekka, Downes, Kate, Lempainen, Johanna, Todd, John A, Veijola, Riitta, Ilonen, Jorma, Knip, Mikael, Morgan, Noel G, Hyöty, Heikki, Peakman, Mark, Eichmann, Martin, Sioofy-Khojine, Amir-Babak [0000-0001-5538-5153], Richardson, Sarah J [0000-0002-1160-6062], Locke, Jonathan M [0000-0001-9516-5251], Oikarinen, Sami [0000-0003-3901-6774], Nurminen, Noora [0000-0002-6798-7677], Laine, Antti-Pekka [0000-0003-4962-2882], Lempainen, Johanna [0000-0001-9893-1468], Todd, John A [0000-0003-2740-8148], Veijola, Riitta [0000-0002-6557-270X], Ilonen, Jorma [0000-0002-9973-2062], Knip, Mikael [0000-0003-0474-0033], Morgan, Noel G [0000-0003-1537-8113], Hyöty, Heikki [0000-0003-0370-4145], Peakman, Mark [0000-0003-3328-3513], Eichmann, Martin [0000-0002-8675-2822], Apollo - University of Cambridge Repository, Tampere University, BioMediTech, Department of Clinical Microbiology, Department of Paediatrics, HUS Children and Adolescents, Children's Hospital, University of Helsinki, and CAMM - Research Program for Clinical and Molecular Metabolism

Subjects
EXPRESSION, Adult, MDA5, Interferon-Induced Helicase, IFIH1, Endocrinology, Diabetes and Metabolism, Pancreatic islets, Insulins, CHILDREN, Autoimmunity, FUNCTION MUTATIONS, DIAGNOSIS, 3121 Internal medicine, IFIH-1, RIG-I, DEAD-box RNA Helicases, MELLITUS, INFECTION, Internal Medicine, Interferon induced with helicase C domain 1, Enterovirus Infections, Humans, Genetic Predisposition to Disease, Child, Alleles, Autoantibodies, Enterovirus, Genetic risk, CAPSID PROTEIN VP1, Melanoma differentiation-associated protein 5, RECOGNITION, rs1990760, HLA GENOTYPES, Type 1 diabetes, Diabetes Mellitus, Type 1, 3121 General medicine, internal medicine and other clinical medicine, Leukocytes, Mononuclear, RNA, 3111 Biomedicine
Abstract

Funder: Sigrid Juselius foundation, AIMS/HYPOTHESIS: Enteroviral infection has been implicated consistently as a key environmental factor correlating with the appearance of autoimmunity and/or the presence of overt type 1 diabetes, in which pancreatic insulin-producing beta cells are destroyed by an autoimmune response. Genetic predisposition through variation in the type 1 diabetes risk gene IFIH1 (interferon induced with helicase C domain 1), which encodes the viral pattern-recognition receptor melanoma differentiation-associated protein 5 (MDA5), supports a potential link between enterovirus infection and type 1 diabetes. METHODS: We used molecular techniques to detect enterovirus RNA in peripheral blood samples (in separated cellular compartments or plasma) from two cohorts comprising 79 children or 72 adults that include individuals with and without type 1 diabetes who had multiple autoantibodies. We also used immunohistochemistry to detect the enteroviral protein VP1 in the pancreatic islets of post-mortem donors (n=43) with type 1 diabetes. RESULTS: We observed enhanced detection sensitivity when sampling the cellular compartment compared with the non-cellular compartment of peripheral blood (OR 21.69; 95% CI 3.64, 229.20; p

Published
2021

10. Longitudinal Pattern of First-Phase Insulin Response Is Associated With Genetic Variants Outside the Class II HLA Region in Children With Multiple Autoantibodies

Author

Koskinen, Maarit K., primary, Mikk, Mari-Liis, additional, Laine, Antti-Pekka, additional, Lempainen, Johanna, additional, Löyttyniemi, Eliisa, additional, Vähäsalo, Paula, additional, Hekkala, Anne, additional, Härkönen, Taina, additional, Kiviniemi, Minna, additional, Simell, Olli, additional, Knip, Mikael, additional, Veijola, Riitta, additional, Ilonen, Jorma, additional, and Toppari, Jorma, additional

Published
2019
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11. Longitudinal Pattern of First-Phase Insulin Response Is Associated With Genetic Variants Outside the Class II HLA Region in Children With Multiple Autoantibodies.

Author

Koskinen, Maarit K., Mikk, Mari-Liis, Laine, Antti-Pekka, Lempainen, Johanna, Löyttyniemi, Eliisa, Vähäsalo, Paula, Hekkala, Anne, Härkönen, Taina, Kiviniemi, Minna, Simell, Olli, Knip, Mikael, Veijola, Riitta, Ilonen, Jorma, and Toppari, Jorma

Subjects
AUTOANTIBODIES, SINGLE nucleotide polymorphisms, TYPE 1 diabetes, INSULIN, DIABETES, SEROCONVERSION, INSULIN therapy, PROTEINS, HLA-B27 antigen, GENETIC polymorphisms, ALLELES, ISLANDS of Langerhans, GENES, GENOTYPES, DISEASE susceptibility, GLUCOSE tolerance tests, LONGITUDINAL method
Abstract

A declining first-phase insulin response (FPIR) is associated with positivity for multiple islet autoantibodies, irrespective of class II HLA DR-DQ genotype. We examined the associations of FPIR with genetic variants outside the HLA DR-DQ region in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study in children with and without multiple autoantibodies. Association between FPIR and class I alleles A*24 and B*39 and eight single nucleotide polymorphisms outside the HLA region were analyzed in 438 children who had one or more FPIR results available after seroconversion. Hierarchical linear mixed models were used to analyze repeated measurements of FPIR. In children with multiple autoantibodies, the change in FPIR over time was significantly different between those with various PTPN2 (rs45450798), FUT2 (rs601338), CTSH (rs3825932), and IKZF4 (rs1701704) genotypes in at least one of the models. In general, children carrying susceptibility alleles for type 1 diabetes experienced a more rapid decline in insulin secretion compared with children without susceptibility alleles. The presence of the class I HLA A*24 allele was also associated with a steeper decline of FPIR over time in children with multiple autoantibodies. Certain genetic variants outside the class II HLA region may have a significant impact on the longitudinal pattern of FPIR. [ABSTRACT FROM AUTHOR]

Published
2020
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12. Non--Class II Gene Associated With Type 1 Diabetes Maps to the 240-kb Region Near HLA-B

Author

Nejentsev, Sergei, Gombos, Zsofia, Laine, Antti-Pekka, Veijola, Riitta, Knip, Mikael, Simell, Olli, Vaarala, Outi, Akerblom, Hans K., and Ilonen, Jorma

Subjects
Genetic aspects, Type 1 diabetes -- Genetic aspects
Abstract

Several studies provide evidence that in addition to the DQ-DR genes, HLA contains another uncharacterized gene or genes associated with type 1 diabetes. Our aim was to investigate the effect [...]

Published
2000

13. HLA and non-HLA genes and familial predisposition to autoimmune diseases in families with a child affected by type 1 diabetes.

Author

Parkkola, Anna, Laine, Antti-Pekka, Karhunen, Markku, Härkönen, Taina, Ryhänen, Samppa J., Ilonen, Jorma, Knip, Mikael, and Null, Null

Subjects
*DISEASE susceptibility, *AUTOIMMUNE diseases, *HLA histocompatibility antigen genetics, *PATIENTS, *TYPE 1 diabetes, *GENETICS
Abstract

Genetic predisposition could be assumed to be causing clustering of autoimmunity in individuals and families. We tested whether HLA and non-HLA loci associate with such clustering of autoimmunity. We included 1,745 children with type 1 diabetes from the Finnish Pediatric Diabetes Register. Data on personal or family history of autoimmune diseases were collected with a structured questionnaire and, for a subset, with a detailed search for celiac disease and autoimmune thyroid disease. Children with multiple autoimmune diseases or with multiple affected first- or second-degree relatives were identified. We analysed type 1 diabetes related HLA class II haplotypes and genotyped 41 single nucleotide polymorphisms (SNPs) outside the HLA region. The HLA-DR4-DQ8 haplotype was associated with having type 1 diabetes only whereas the HLA-DR3-DQ2 haplotype was more common in children with multiple autoimmune diseases. Children with multiple autoimmune diseases showed nominal association with RGS1 (rs2816316), and children coming from an autoimmune family with rs11711054 (CCR3-CCR5). In multivariate analyses, the overall effect of non-HLA SNPs on both phenotypes was evident, associations with RGS1 and CCR3-CCR5 region were confirmed and additional associations were implicated: NRP1, FUT2, and CD69 for children with multiple autoimmune diseases. In conclusion, HLA-DR3-DQ2 haplotype and some non-HLA SNPs contribute to the clustering of autoimmune diseases in children with type 1 diabetes and in their families. [ABSTRACT FROM AUTHOR]

Published
2017
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14. Two insulin gene single nucleotide polymorphisms associated with type 1 diabetes risk in the Finnish and Swedish populations

Author

Laine, Antti-Pekka, Holmberg, Hanna, Nilsson, Anita, Örtqvist, Eva, Kiviniemi, Minna, Vaarala, Outi, Åkerblom, Hans K, Simell, Olli, Knip, Mikael, Ludvigsson, Johnny, Ivarsson, Sten-A, Larsson, Karin, Lernmark, Åke, Ilonen, Jorma, Laine, Antti-Pekka, Holmberg, Hanna, Nilsson, Anita, Örtqvist, Eva, Kiviniemi, Minna, Vaarala, Outi, Åkerblom, Hans K, Simell, Olli, Knip, Mikael, Ludvigsson, Johnny, Ivarsson, Sten-A, Larsson, Karin, Lernmark, Åke, and Ilonen, Jorma

Abstract

We have developed high-throughput tests for the detection of the insulin gene region SNPs -23HphI and -2221MspI. The potential of these markers to enhance the efficiency of type 1 diabetes risk screening was then evaluated by analyzing them in Finnish and Swedish populations. Blood spots on filter paper were analyzed using PCR followed by sequence-specific hybridization and time-resolved fluorometry reading. Distribution of the genotypes at both positions differed significantly among the affected children compared to the controls. The risk genotypes (CC, AA) were significantly more common in Finland than in Sweden, both among patients and controls. The VNTR genotype homozygous for the protective class III alleles showed a significantly stronger protective effect than the heterozygote (p=0.02). Analyzing both SNPs enabled the detection of VNTR class III subclasses IIIA and IIIB. The observed significance between effects of the protective genotypes was due to the strong protective effect of the IIIA/IIIA genotype. IIIA/IIIA was the only genotype with significant discrepancy between protective effects compared to the other class III genotypes. These observations suggest that heterogeneity between the protective IDDM2 lineages could exist, and analyzing both -23HphI and -2221MspI would thus potentially enhance the sensitivity and specificity of type 1 diabetes risk estimation.

Published
2007
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15. Two Insulin Gene Single Nucleotide Polymorphisms Associated with Type 1 Diabetes Risk in the Finnish and Swedish Populations

Author

Laine, Antti-Pekka, primary, Holmberg, Hanna, additional, Nilsson, Anita, additional, Örtqvist, Eva, additional, Kiviniemi, Minna, additional, Vaarala, Outi, additional, Åkerblom, Hans K., additional, Simell, Olli, additional, Knip, Mikael, additional, Ludvigsson, Johnny, additional, Ivarsson, Sten-A., additional, Larsson, Karin, additional, Lernmark, Åke, additional, and Ilonen, Jorma, additional

Published
2007
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