CXADR polymorphism rs6517774 modifies islet autoimmunity characteristics and exhibits sex disparity.

Enteroviral infections have been linked to the development of islet autoimmunity (IA) and type 1 diabetes (T1D), and the coxsackie and adenovirus receptor (CXADR) is one of the ligands used by adenoviruses and enteroviruses for cell internalization. Two single nucleotide polymorphisms (SNPs), rs6517774 and rs2824404, were previously associated with an increased susceptibility to IA in the international TEDDY study (The Environmental Determinants of Diabetes in the Young). This study aimed to replicate the results by genotyping 2886 children enrolled in the Finnish Diabetes Prediction and Prevention study (DIPP).

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.

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.

Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes: Phase and Endotype Specific Effects.

The non-HLA loci conferring susceptibility to type 1 diabetes determine approximately half of the genetic disease risk, and several of them have been shown to affect immune-cell or pancreatic β-cell functions. A number of these loci have shown associations with the appearance of autoantibodies or with progression from seroconversion to clinical type 1 diabetes. In the current study, we have re-analyzed 21 of our loci with prior association evidence using an expanded DIPP follow-up cohort of 976 autoantibody positive cases and 1,910 matched controls.

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

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.

Tri-SNP polymorphism in the intron of HLA-DRA1 affects type 1 diabetes susceptibility in the Finnish population.

Genes in the HLA class II region include the most important inherited risk factors for type 1 diabetes (T1D) although also polymorphisms outside the HLA region modulate the predisposition to T1D. This study set out to confirm a recent observation in which a novel expression quantitative trait locus was formed by three single nucleotide polymorphisms (SNP) in the intron of HLA-DRA1 in DR3-DQ2 haplotypes. The SNPs significantly increased the risk for T1D in DR3-DQ2 homozygous individuals and we intended to further explore this association, in the Finnish population, by comparing two DR3-DQ2 positive genotypes.

HLA-DR-DQ haplotypes and specificity of the initial autoantibody in islet specific autoimmunity.

Objective: We aimed to clarify the association of various HLA risk alleles with different types of autoantibodies initiating islet specific autoimmunity.

Methods: Follow-up cohorts from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and children diagnosed with type 1 diabetes (T1D) from the Finnish Pediatric Diabetes Register (FPDR) were analyzed for the presence of autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), IA-2 antigen (IA-2A), and zinc transporter 8 (ZnT8A); and genotyped for HLA DR/DQ alleles. In the DIPP study, autoantibodies were regularly analyzed from birth up to 15 years of age.

Associations Between IFI44L Gene Variants and Rates of Respiratory Tract Infections During Early Childhood.

Background: Genetic heterogeneity in type I interferon (IFN)-related gene IFI44L may account for variable susceptibility to respiratory tract infections (RTIs) in children.

Methods: In 2 prospective, population-based birth cohorts, the STEPS Study and the FinnBrain Birth Cohort Study, IFI44L genotypes for rs273259 and rs1333969 were determined in relation to the development of RTIs until 1 or 2 years of age, respectively. At age 3 months, whole-blood transcriptional profiles were analyzed and nasal samples were tested for respiratory viruses in a subset of children.

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

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 and and eight single nucleotide polymorphisms outside the HLA region were analyzed in 438 children who had one or more FPIR results available after seroconversion.

Characteristics of Slow Progression to Type 1 Diabetes in Children With Increased HLA-Conferred Disease Risk.

Context: Characterization of slow progression to type 1 diabetes (T1D) may reveal novel means for prevention of T1D. Slow progressors might carry natural immunomodulators that delay β-cell destruction and mediate preservation of β-cell function.

Objective: To identify demographic, genetic, and immunological characteristics of slow progression from seroconversion to clinical T1D.

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

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.

Primary islet autoantibody at initial seroconversion and autoantibodies at diagnosis of type 1 diabetes as markers of disease heterogeneity.

Objective: The relationship between patterns of islet autoantibodies at diagnosis and specificity of the first islet autoantibody at the initiation of autoimmunity was analyzed with the aim of identifying patterns informative of the primary autoantibodies.

Methods: Information about a single first autoantibody at seroconversion and autoantibody data at diagnosis were available for 128 children participating in the follow-up cohort of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. Autoantibody data at diagnosis and genotyping results were also obtained from children in the Finnish Pediatric Diabetes Register (FPDR).

Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility.

Aims/hypothesis: In this study, we aimed to characterise rapid progressors to type 1 diabetes among children recruited from the general population, on the basis of HLA-conferred disease susceptibility.

Methods: We monitored 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study for the development of beta cell autoimmunity and type 1 diabetes from birth over a median follow-up time of 16.2 years (range 0.

Non-HLA gene effects on the disease process of type 1 diabetes: From HLA susceptibility to overt disease.

In addition to the HLA region numerous other gene loci have shown association with type 1 diabetes. How these polymorphisms exert their function has not been comprehensively described, however. We assessed the effect of 39 single nucleotide polymorphisms (SNP) on the development of autoantibody positivity, on progression from autoantibody positivity to clinical disease and on the specificity of the antibody initiating the autoimmune process in 521 autoantibody-positive and 989 control children from a follow-up study starting from birth.

GIMAP GTPase family genes: potential modifiers in autoimmune diabetes, asthma, and allergy.

GTPase of the immunity-associated protein (GIMAP) family members are differentially regulated during human Th cell differentiation and have been previously connected to immune-mediated disorders in animal studies. GIMAP4 is believed to contribute to the Th cell subtype-driven immunological balance via its role in T cell survival. GIMAP5 has a key role in BB-DR rat and NOD mouse lymphopenia.

Risk genes and autoantibodies in Egyptian children with type 1 diabetes - low frequency of autoantibodies in carriers of the HLA-DRB1*04:05-DQA1*03-DQB1*02 risk haplotype.

Background: The study aimed to define the frequencies of type 1 diabetes-associated gene polymorphisms and their associations with various diabetes-associated autoantibodies in Egyptian children.

Methods: One hundred and one children with type 1 diabetes and 160 healthy controls from the same region were studied for HLA-DQB1, HLA-DQA1, and HLA-DRB1 (DR4 subtypes) alleles; for INS and protein tyrosine phosphatase, non-receptor type 22 gene polymorphisms (rs689 and rs2476601); and for diabetes-associated autoantibodies.

Results: Most children with diabetes (77.

Circulating concentrations of soluble receptor for AGE are associated with age and AGER gene polymorphisms in children with newly diagnosed type 1 diabetes.

Objective: We analyzed the relationship among soluble receptor for advanced glycation end products (sRAGEs), the clinical phenotype, HLA genotype, and risk-associated single nucleotide polymorphisms (SNPs) in the AGER gene in a large population of Finnish children with newly diagnosed type 1 diabetes.

Research Design And Methods: Samples from 2,115 clinically phenotyped children <15 years of age in whom type 1 diabetes was diagnosed and 316 control subjects were analyzed for sRAGEs. Three SNPs of AGER, previously associated with HLA-DR/DQ haplotype independent diabetes risk (rs2070600, rs9469089, and rs17493811), were analyzed in 1,390 affected subjects.

Patterns of β-cell autoantibody appearance and genetic associations during the first years of life.

We analyzed demographic and genetic differences between children with various diabetes-associated autoantibodies reflecting the autoimmune process. In a prospective birth cohort comprising children with HLA-conferred susceptibility to type 1 diabetes (T1D), the pattern of autoantibody appearance was analyzed in 520 children with advanced β-cell autoimmunity associated with high risk for disease. In 315 cases, a single biochemical autoantibody could be identified in the first positive sample as insulin (insulin autoantibody [IAA]) in 180, as GAD (GAD antibody [GADA]) in 107, and as IA-2 antigen (IA-2 antibody [IA-2A]) in 28.

Association of CTLA4 but not ICOS polymorphisms with type 1 diabetes in two populations with different disease rates.

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and inducible T-cell co-stimulator (ICOS) genes are important mediators of T-cell activation in autoimmune diseases. The aim of the current study was to assess the impact of CTLA-4 and ICOS genes on the susceptibility to type 1 diabetes among two populations with different disease incidence rates. Three single nucleotide polymorphisms (SNPs) within the CTLA-4 region (+49A/G, CT60A/G, CTBC217_1C/T) and two SNPs within the ICOS region (CTIC154_1 C/T, CTIC159 C/G) were genotyped in 955 control subjects and 574 diabetic patients of Estonian and Finnish descent.

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

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.

A linkage study of 12 IDDM susceptibility loci in the Finnish population.

Background: HLA region is the major locus (IDDM1) of type 1 diabetes (T1D) susceptibility. It explains approximately 50% of the genetic background of T1D, indicating additional genetic determinants. Genome scans and candidate gene studies have generated several chromosomal candidate regions that may have a role in T1D development.

Vitamin D receptor polymorphisms: no association with type 1 diabetes in the Finnish population.

Objective: The effect of polymorphisms of the vitamin D receptor (VDR) gene on susceptibility to type 1 diabetes has recently been investigated extensively. Several findings on positive disease associations have been observed and, in addition, a protective effect of vitamin D supplementation has been reported.

Design: We studied the effect of three vitamin D receptor gene polymorphisms (VDRA, VDRB, VDRF) on susceptibility to type 1 diabetes in a large case-control series (more than 2000 controls and about 1000 patients) from the Finnish population.