Virginia PrIMeD Study

The goal of this study was to determine whether screening children (2-16 yrs) in pediatric waiting rooms for genetic risk of type 1 diabetes (T1D) could be applied to diverse (by geography, genetic ancestry) communities, and for those at "high genetic risk," if barriers prevent subsequent screening for presence of islet autoantibodies. A total of 3,818 children were recruited from eight general pediatric and specialty clinics across Virginia. Clinical Research Coordinators were stationed at each clinic and obtained informed consent/assent, a brief medical history, and a saliva sample for DNA extraction and determination of their genetic risk using a T1D Genetic Risk Score (T1D GRS). Children were present in the clinic for a "healthy" visit, although children with and without a history of T1D were recruited into the study. Age, sex, self-reported ancestry/race, T1D history, and other medical history information was obtained. DNA was extracted from the saliva samples and genotyping with a T1D-focused array using 74 SNPs (including 26 SNPs in the HLA region) provided data to generate a T1D GRS for each individual. Of the 3,818 children recruited, there was a slight excess of males (1,959, 51.3%), a majority of white and Hispanic/Latino ancestry (82.8%), and 91 (2.4%) with prevalent T1D. A total of 542 (14.2%) had "high T1D genetic risk" (T1D GRS > 5). Although the T1D GRS included non-HLA genetic variants, 80% of those with "high genetic risk" would have been classified using only those SNPs in the HLA region alone. Of children with "high genetic risk" and without pre-existing T1D (n=494), 7.0% (34/494) consented for islet autoantibody screening. Among children with pre-existing T1D (n=91), 52% (n=48) also had a "high genetic risk." The HLA-focused T1D GRS was not significantly associated with age at onset of T1D. Of those at high genetic risk that consented for autoantibody testing (n=34) and completed the blood collection (n=28), two (2/28, 7.1%) tested positive for multiple autoantibodies and were at significant risk of developing T1D. Follow up of 55% of parents/guardians identified 2 (of 2,096, 0.095%) participants who developed T1D, one at "high genetic risk" and one with a first-degree relative with T1D. A major factor in obtaining islet autoantibody testing was concern over SARS-Cov-2 exposure and an independent non-scheduled blood collection.Individual-level data at each SNP (genotyped and imputed) for T1D genetic risk and affiliated data are provided in dbGaP. ]]>
To be included in the study, participants were required to have parent/guardian consent, provide self-reported medical history information, and a saliva sample for DNA extraction. No restrictions were made for evidence of T1D in the participant. Consent was obtained for subsequent follow-up and participation in future studies related to type 1 diabetes. ]]>
Type 1 diabetes (T1D) is a common autoimmune disease in which the destruction of pancreatic β-cells results in the eventual inability of the body to produce insulin. Without insulin, there is accumulation of glucose in the bloodstream and an inability for glucose to enter cells for production of energy. Progression of glucose accumulation leads to blood vessel and organ damage from dehydration, conversion of tissue to ketones for alternative energy sources, and life-threatening diabetic ketoacidosis, thereby requiring external sources of insulin for survival. T1D has been characterized by three specific stages: stage 1 represents the transition from normal glucose homeostasis in an individual with variable genetic and other risk factors to production of multiple islet autoantibodies but with glucose levels in the normal range; stage 2 includes individuals who have multiple islet autoantibodies but with glucose levels exceeding normal range (e.g., fasting plasma glucose > 100 mg/dL or > 5.6 mmol/L); with stage 3 representing clinically diagnosed T1D. Each of these stages of T1D diabetes may have overlapping, as well as distinct, genetic, and non-genetic risk factors. The Type 1 Diabetes Genetics Consortium (T1DGC) conducted genome-wide association scans (GWAS) and fine-mapping of genomic regions associated with T1D risk to define the single nucleotide polymorphisms (SNPs) most associated with T1D. These data have been used to develop T1D Genetic Risk Scores (T1D GRS) to identify children at genetic risk for developing T1D and consider screening for evidence of islet autoantibodies (and “staging” of disease). As only ~5% of those who develop T1D have a positive family history of T1D, there is need to understand the benefits and barriers to screening communities for prediction of T1D, monitoring for detection of symptoms, and intervention (with FDA approval 17 November, 2022, of the anti-CD3 compound, Tzield, teplizumab-mzwv). ]]>