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

Abstract

Aims/hypothesis: In 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.

Methods: A 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.

Results: Out 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/interpretation: The 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 disease in the offspring than maternal diabetes. The sex difference seen between affected parents diagnosed before and after the birth of the index child supports the hypothesis that maternal insulin treatment protects against type 1 diabetes.

Keywords: Autoantibodies; Clinical characteristics; Family; HLA class II; Type 1 diabetes.

Fig. 1

Flow diagram showing inclusion and exclusion criteria and grouping of the index children according to the relationship to the affected FDR. All children and adolescents were diagnosed between 2003 and 2016, with age at diagnosis ≤15 years

Fig. 2

Median age (interquartile range) at diagnosis of type 1 diabetes in children with different family members with diabetes and children with sporadic type 1 diabetes. **p<0.01, ***p<0.001 (adjusted for sex and age at diagnosis). Significance was evaluated using quantile regression in R

Fig. 3

Frequency of diabetic ketoacidosis (95% CI) at diagnosis of type 1 diabetes in children with different family members with diabetes and children with sporadic type 1 diabetes. *p<0.05, **p<0.01, ***p<0.001 (adjusted for sex and age at diagnosis). Significance was evaluated using logistic regression analysis