Association between family history, early growth and the risk of beta cell autoimmunity in children at risk for type 1 diabetes

Abstract

Aims/hypothesis: The aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility.

Methods: In a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were compared in relation to family history of type 1 diabetes (mother vs father vs sibling) in 2074 children from families with a single affected family member.

Results: Multiple autoantibodies (≥2 of 5 measured) developed in 277 (13%) children: 107 (10%), 114 (16%) and 56 (18%) born with a mother, father or sibling with type 1 diabetes, respectively (p < 0.001). The HR for time to multiple autoimmunity was 0.54 (95% CI 0.39, 0.75) in offspring of affected mothers (n = 107/1046, p < 0.001) and 0.81 (95% CI 0.59, 1.11) (n = 114/722, p = 0.19) in offspring of affected fathers, compared with participants with a sibling with type 1 diabetes (comparator group n = 56/306). The time to the first autoantibody present (to insulin, GAD, tyrosine phosphatase-related insulinoma-associated 2 molecules, islet cell or zinc transporter 8) was similar in the three groups. Height velocity (z score/year) in the first 24 months was independently associated with developing multiple antibodies in the total cohort (HR 1.31 [95% CI 1.01, 1.70], p = 0.04). A higher birthweight in children born to an affected mother vs affected father or an affected sibling was not related to the risk of multiple autoimmunity.

Conclusions/interpretation: The risk of developing multiple autoantibodies was lower in children with maternal type 1 diabetes. For the whole group, this risk of developing multiple autoantibodies was independent of birthweight but was greater in those with increased height velocity during the first 2 years of life. However, the risk associated with paternal type 1 diabetes was not linked to differences in birthweight or early growth.

Trial registration: ClinicalTrials.gov NCT00179777 Graphical abstract.

Keywords: Beta cell autoimmunity; Birthweight; Familial risk; Father; Genetic risk; Linear growth; Mother; Proband; Type 1 diabetes.

Fig. 1

Time to presence of autoantibodies by family history (mother vs father vs sibling): multiple autoantibodies defined as two or more antibodies (logrank χ² 16.2, p < 0.001) (a); GADA as first antibody (logrank χ² 4.8, p = 0.090) (b); IAA as first antibody (logrank χ² 5.5, p = 0.064) (c); IA-2A as first antibody (logrank χ² 0.55, p = 0.761) (d); ZnT8A as first antibody (logrank χ² 0.6, p = 0.73) (e); and ICA as first antibody (logrank χ² 1.2, p = 0.55) (f)