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Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: A prospective study in children.

ABSTRACT: Background: Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes.

Methods and findings: The Environmental Determinants of Diabetes in the Young (TEDDY) study followed genetically at-risk children at 3- to 6-monthly intervals from birth for the development of islet autoantibodies and type 1 diabetes. Infants were enrolled between 1 September 2004 and 28 February 2010 and monitored until 31 May 2016. The risk (positive predictive value) for developing multiple islet autoantibodies (pre-symptomatic type 1 diabetes) and type 1 diabetes was determined in 4,543 children who had no first-degree relatives with type 1 diabetes and either a heterozygous HLA DR3 and DR4-DQ8 risk genotype or a homozygous DR4-DQ8 genotype, and in 3,498 of these children in whom genetic scores were calculated from 41 single nucleotide polymorphisms. In the children with the HLA risk genotypes, risk for developing multiple islet autoantibodies was 5.8% (95% CI 5.0%-6.6%) by age 6 years, and risk for diabetes by age 10 years was 3.7% (95% CI 3.0%-4.4%). Risk for developing multiple islet autoantibodies was 11.0% (95% CI 8.7%-13.3%) in children with a merged genetic score of >14.4 (upper quartile; n = 907) compared to 4.1% (95% CI 3.3%-4.9%, P < 0.001) in children with a genetic score of ?14.4 (n = 2,591). Risk for developing diabetes by age 10 years was 7.6% (95% CI 5.3%-9.9%) in children with a merged score of >14.4 compared with 2.7% (95% CI 1.9%-3.6%) in children with a score of ?14.4 (P < 0.001). Of 173 children with multiple islet autoantibodies by age 6 years and 107 children with diabetes by age 10 years, 82 (sensitivity, 47.4%; 95% CI 40.1%-54.8%) and 52 (sensitivity, 48.6%, 95% CI 39.3%-60.0%), respectively, had a score >14.4. Scores were higher in European versus US children (P = 0.003). In children with a merged score of >14.4, risk for multiple islet autoantibodies was similar and consistently >10% in Europe and in the US; risk was greater in males than in females (P = 0.01). Limitations of the study include that the genetic scores were originally developed from case-control studies of clinical diabetes in individuals of mainly European decent. It is, therefore, possible that it may not be suitable to all populations.

Conclusions: A type 1 diabetes genetic score identified infants without family history of type 1 diabetes who had a greater than 10% risk for pre-symptomatic type 1 diabetes, and a nearly 2-fold higher risk than children identified by high-risk HLA genotypes alone. This finding extends the possibilities for enrolling children into type 1 diabetes primary prevention trials.

SUBMITTER: Bonifacio E

PROVIDER: S-EPMC5882115 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: A prospective study in children.

Bonifacio Ezio E Beyerlein Andreas A Hippich Markus M Winkler Christiane C Vehik Kendra K Weedon Michael N MN Laimighofer Michael M Hattersley Andrew T AT Krumsiek Jan J Frohnert Brigitte I BI Steck Andrea K AK Hagopian William A WA Krischer Jeffrey P JP Lernmark Åke Å Rewers Marian J MJ She Jin-Xiong JX Toppari Jorma J Akolkar Beena B Oram Richard A RA Rich Stephen S SS Ziegler Anette-G AG

PLoS medicine 20180403 4

<h4>Background</h4>Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes.<h4>Methods and findings</h4>The Environmental Determi ...[more]

PMID: 29614081

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Project description:Aims/hypothesisPsychological stress has long been considered a possible trigger of type 1 diabetes, although prospective studies examining the link between psychological stress or life events during pregnancy and the child's type 1 diabetes risk are rare. The objective of this study was to examine the association between life events during pregnancy and first-appearing islet autoantibodies (IA) in young children, conditioned by the child's type 1 diabetes-related genetic risk.MethodsThe IA status of 7317 genetically at-risk The Environmental Determinants of Diabetes in the Young (TEDDY) participants was assessed every 3 months from 3 months to 4 years, and bi-annually thereafter. Reports of major life events during pregnancy were collected at study inception when the child was 3 months of age and placed into one of six categories. Life events during pregnancy were examined for association with first-appearing insulin (IAA) (N = 222) or GAD (GADA) (N = 209) autoantibodies in the child until 6 years of age using proportional hazard models. Relative excess risk due to interaction (RERI) by the child's HLA-DR and SNP profile was estimated.ResultsOverall, 65% of mothers reported a life event during pregnancy; disease/injury (25%), serious interpersonal (28%) and job-related (25%) life events were most common. The association of life events during pregnancy differed between IAA and GADA as the first-appearing autoantibody. Serious interpersonal life events correlated with increased risk of GADA-first only in HLA-DR3 children with the BACH2-T allele (HR 2.28, p < 0.0001), an additive interaction (RERI 1.87, p = 0.0004). Job-related life events were also associated with increased risk of GADA-first among HLA-DR3/4 children (HR 1.53, p = 0.04) independent of serious interpersonal life events (HR 1.90, p = 0.002), an additive interaction (RERI 1.19, p = 0.004). Job-related life events correlated with reduced risk of IAA-first (HR 0.55, p = 0.004), particularly in children with the BTNL2-GG allele (HR 0.48; 95% CI 0.31, 0.76).Conclusions/interpretationSpecific life events during pregnancy are differentially related to IAA vs GADA as first-appearing IA and interact with different HLA and non-HLA genetic factors, supporting the concept of different endotypes underlying type 1 diabetes. However, the mechanisms underlying these associations remain to be discovered. Life events may be markers for other yet-to-be-identified factors important to the development of first-appearing IA.

Project description:Background and purposePancreatic islet autoantibodies (iAb) are the hallmark of autoimmunity in type 1 diabetes. A more comprehensive understanding of the global iAb prevalence could help reduce avertible morbidity and mortality among children and adolescents and contribute to the understanding in the observed differences in the incidence, prevalence and health outcomes of children and adolescents with type 1 diabetes across and within countries. We present the first scoping review that provides a global synthesis of the prevalence of iAb in children and adolescents with type 1 diabetes.Research design and methodsWe searched Ovid MEDLINE® with Daily Update, Embase (Elsevier, embase.com) and PubMed (National Library of Medicine -NCBI), for studies pertaining to prevalence in children and adolescents (0-19) with type 1 diabetes published between 1 Jan 1990 and 18 June 2021. Results were synthesized using Covidence systematic review software and meta-analysis was completed using R v3·6·1. Two reviewers independently screened abstracts with a third reviewer resolving conflicts (k= 0·92).ResultsThe review revealed 125 studies from 48 different countries, with 92 from high-income countries. Globally, in new-onset type 1 diabetes, IA-2A was the most prevalent iAb 0·714 [95% CI (0·71, 0·72)], followed by ICA 0·681 [95% CI (0·67, 0·69)], ZnT8A was 0·654 [95% CI (0·64, 0·66)], GADA 0·636 [95% CI (0·63, 0·66)] and then IAA 0·424 [95% CI (0·42, 0·43)], with substantial variation across world regions. The weighted mean prevalence of IA-2A was more variable, highest in Europe at 0·749 [95% CI (0·74, 0·76)] followed by Northern America 0·662 [95% CI (0·64, 0·69)], Latin America and the Caribbean 0·632 [95% CI (0·54, 0·72)], Oceania 0·603 [95% CI (0·54, 0·67)], Asia 0·466 [95% CI (0·44, 0·50)] and Africa 0·311 [95% CI (0·23, 0·40)]. In established cases of type 1 diabetes, GADA was the most prevalent iAb 0·407 [95% CI (0·39, 0·42)] followed by ZnT8A 0·322 [95% CI (0·29, 0·36)], IA-2A 0·302 [95% CI (0·29, 0·32)], IAA 0·258 [95% CI (0·24, 0·26)] and ICA 0·145 [95% CI (0·13, 0·16)], again with substantial variation across world regions.ConclusionUnderstanding the global prevalence of iAb in children and adolescents with type 1 diabetes could help with earlier identification of those at-risk of developing type 1 diabetes and inform clinical practice, health policies, resource allocation, and targeted healthcare interventions to better screen, diagnose and manage children and adolescents with type 1 diabetes.

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Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: A prospective study in children.

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Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: A prospective study in children.

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