Sex as a determinant of type 1 diabetes at diagnosis

Turtinen, Maaret; Härkönen, Taina; Parkkola, Anna; Ilonen, Jorma; Knip, Mikael

doi:10.1111/pedi.12697

Cited by 26 publications

(24 citation statements)

References 44 publications

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“…However, the risk of bias as to the family history of FDRs may have been smaller than if the extended family had also been included. Another source of selection bias is the inclusion criterion requiring sample availability for autoantibody and HLA analyses, although the frequency of children with familial and sporadic disease did not differ between those included and excluded [20].…”

Section: Discussionmentioning

confidence: 99%

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Characteristics of familial type 1 diabetes: effects of the relationship to the affected family member on phenotype and genotype at diagnosis

et al. 2019

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Aims/hypothesisIn previous studies, the risk of developing familial type 1 diabetes has been reported to be more than two times higher in the offspring of affected fathers than in those of affected mothers. We tested the hypothesis that index children with an affected father may have a more aggressive disease process at diagnosis than those with other affected first-degree relatives.MethodsA cross-sectional, observational study was performed using the Finnish Pediatric Diabetes Register. Clinical and metabolic characteristics, beta cell autoantibodies and HLA class II genetics were analysed from index children in Finland diagnosed before the age of 15 years between January 2003 and December 2016. Information on the presence of type 1 diabetes in first-degree relatives was collected at diagnosis using a structured questionnaire.ResultsOut of 4993 newly diagnosed index children, 519 (10.4%) had familial type 1 diabetes. More than 5% (n = 253, 5.1%) had an affected father, 2.8% (n = 141) had an affected mother, 1.9% (n = 95) had an affected sibling and 0.6% (n = 30) had two or more affected family members. All clinical and metabolic variables were markedly poorer in children with sporadic vs familial diabetes. The index children with an affected father or mother were younger than those with an affected sibling (median age 7.59 vs 6.74 vs 10.73 years, respectively; p < 0.001). After age- and sex-adjusted analyses, index children with an affected father presented more often with ketoacidosis (9.7% vs 3.6%; p = 0.033) and had greater weight loss before diagnosis (3.2% vs 0%; p = 0.006) than those with an affected mother. Children with familial disease tested negative for all autoantibodies more often (3.5% vs 2.1%; p = 0.041) and had insulin autoantibodies more frequently (49.8% vs 42.2%; p = 0.004) than those with sporadic disease. Both major HLA risk haplotypes (DR3-DQ2 and DR4-DQ8) were more often lacking among children with sporadic vs familial disease (15.9% vs 11.2%; p = 0.006). The DR4-DQ8 haplotype was more frequent in the familial vs the sporadic group (75.7% vs 68.5%; p = 0.001) and especially among children with an affected father when compared with children with sporadic disease (77.5% vs 68.5%; p < 0.05). When comparing index children with affected parents diagnosed before or after the birth of the index child, a clear male preponderance was seen among the affected parents diagnosed before the birth of the index child (fathers 66.2% vs mothers 33.8%; p = 0.006), whereas the proportion of fathers and mothers was similar if type 1 diabetes was diagnosed after the birth of the index child.Conclusions/interpretationThe more severe metabolic derangement at diagnosis in children with sporadic type 1 diabetes compared with those with familial type 1 diabetes was confirmed. The higher frequency of diabetic ketoacidosis and increased weight loss at diagnosis in index children with an affected father compared with an affected mother support the hypothesis that paternal type 1 diabetes is associated with more severe d...

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Section: Discussionmentioning

confidence: 99%

“…1). A comparison between the included and excluded participants has been presented in our previous work [20]. Only the first diagnosed child per family who fulfilled the inclusion criteria was included as an index child.…”

Section: Methodsmentioning

confidence: 99%

Characteristics of familial type 1 diabetes: effects of the relationship to the affected family member on phenotype and genotype at diagnosis

et al. 2019

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“…Similar assays for autoantibody detection were used in both DIPP and FPDR samples but the analyses for IAA, GADA, and IA‐2A were carried out in different laboratories and thus slightly different cut‐off values were used. Details of the assays are published earlier as well as the results of these laboratories in autoantibody standardization programs 11‐14 …”

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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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. Results: In the DIPP cohort, 621 children developed one single persistent autoantibody, GADA in 284, IAA in 268, and IA-2A in 40 cases. Highly significant differences in the specificity of the first autoantibody were observed between HLA genotypes. Homozygotes for the DR3-DQ2 haplotype had almost exclusively GADA as the first autoantibody, whereas a more even distribution between GADA and IAA was found in DR3-DQ2/DR4-DQ8 as well as DR3-DQ/x and DR4-DQ8/x genotypes (x referring to neutral haplotypes). In DR4-DQ8 positive genotypes with the DRB1*04:01 allele IAA was more often the first autoantibody than in DRB1*04:04 positive genotypes. Various neutral haplotypes also significantly affected the relative proportions of different initial autoantibodies. These findings were confirmed and expanded in a series of 1591 T1D children under the age of 10 years from FPDR. Conclusions: These results emphasize the importance of HLA class II polymorphisms in the recognition of autoantigen epitopes in the initiation of various pathways of the autoimmune response.

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“…Children diagnosed with type 1 diabetes between January 2003 and December 2016 under the age of 15 years with samples available for autoantibody analysis and HLA genotyping were included in this study. The sample collection and characteristics have been described earlier [30]. In brief, 4993 children were included with a male majority (2824/4993, 56.6% boys) and a median age of 8.2 years (ranging from 0.52 to 14.99 years).…”

Section: Methodsmentioning

confidence: 99%

Family history of type 2 diabetes and characteristics of children with newly diagnosed type 1 diabetes

et al. 2020

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Aims/hypothesis Shared aetiopathogenetic factors have been proposed in type 1 diabetes and type 2 diabetes and both diseases have been shown to cluster in families. Characteristics related to type 2 diabetes have been described in patients with type 1 diabetes with a positive family history of type 2 diabetes. We wanted to characterise the family history of type 2 diabetes and its possible effects on the phenotype and genotype of type 1 diabetes in affected children at diagnosis. Methods A total of 4993 children under the age of 15 years with newly diagnosed type 1 diabetes from the Finnish Pediatric Diabetes Register were recruited (56.6% boys, median age of 8.2 years) for a cross-sectional, observational, population-based investigation. The family history of diabetes at diagnosis was determined by a structured questionnaire, and markers of metabolic derangement, autoantibodies and HLA class II genetics at diagnosis were analysed. Results Two per cent of the children had an immediate family member and 36% had grandparents with type 2 diabetes. Fathers and grandfathers were affected by type 2 diabetes more often than mothers and grandmothers. The children with a positive family history for type 2 diabetes were older at the diagnosis of type 1 diabetes (p < 0.001), had higher BMI-for-age (p = 0.01) and more often tested negative for all diabetes-related autoantibodies (p = 0.02). Conclusions/interpretation Features associated with type 2 diabetes, such as higher body weight, older age at diagnosis and autoantibody negativity, are more frequently already present at the diagnosis of type 1 diabetes in children with a positive family history of type 2 diabetes. Graphical abstract

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Sex as a determinant of type 1 diabetes at diagnosis

Cited by 26 publications

References 44 publications

Characteristics of familial type 1 diabetes: effects of the relationship to the affected family member on phenotype and genotype at diagnosis

Characteristics of familial type 1 diabetes: effects of the relationship to the affected family member on phenotype and genotype at diagnosis

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

Family history of type 2 diabetes and characteristics of children with newly diagnosed type 1 diabetes

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