Date Published: April 3, 2018
Publisher: Public Library of Science
Author(s): Ezio Bonifacio, Andreas Beyerlein, Markus Hippich, Christiane Winkler, Kendra Vehik, Michael N. Weedon, Michael Laimighofer, Andrew T. Hattersley, Jan Krumsiek, Brigitte I. Frohnert, Andrea K. Steck, William A. Hagopian, Jeffrey P. Krischer, Åke Lernmark, Marian J. Rewers, Jin-Xiong She, Jorma Toppari, Beena Akolkar, Richard A. Oram, Stephen S. Rich, Anette-G. Ziegler, Ronald C. W. Ma
Abstract: BackgroundAround 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 findingsThe 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.ConclusionsA 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.
Partial Text: Precision medicine typically relies on our ability to identify individuals with precise genetic elements that define a disease. These elements may be used not only to select optimal treatment modalities, but also to identify individuals who may benefit from preventative interventions. In pediatric disease, current studies seeking to elucidate disease etiology, as well as clinical trials aimed at prevention, rely on identifying and enrolling infants with increased risk [1–7]. The risk for diseases such as allergy, type 1 diabetes, and celiac disease is often assessed in terms of family history [1–3,7], which, at best, identifies 10% of children who subsequently develop the condition [7,8].
Genetic scores derived from logistic regression of numerous loci associated with type 1 diabetes susceptibility were able to stratify the risk for pre-symptomatic and clinical type 1 diabetes in a prospective cohort of children with high-risk HLA genotypes but no family history of type 1 diabetes. The risks of developing islet autoantibodies, multiple islet autoantibodies, and diabetes increased with each increment in the genetic score. A genetic score that would identify <1% of all newborn infants was associated with a risk for developing multiple islet autoantibodies of >10% by 6 years of age. This compares to a background population risk of around 0.4% . These findings provide a paradigm for identifying infants whose risk for developing type 1 diabetes is more than 25 times that of the general population, twice that of infants identified by the highest-risk HLA genotypes alone, and higher than that of children with a first-degree relative with type 1 diabetes.