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A new genetic risk score for Type 1 diabetes could improve newborn screenings and allow for better classification of adult incident diabetes type.
Type 1 diabetes (T1D) is prominent in childhood, and with its high genetic heritability there is a potential for powerful diagnostic discrimination if the majority of genetic risk for T1D can be captured. Early identification of T1D risk can minimize morbidity, reduce medical costs at clinical onset, and possibly facilitate prevention therapy.
Measurement of islet autoantibodies (AAb) in venous blood can reveal active T1D years before clinical diagnosis, but AAb surveillance is expensive and difficult in young children. Cost-effectiveness could be greatly improved with the ability to more accurately select infants who require screening.
Unlike previously generated genetic risk scores (GRSs), the researchers in this study aimed to more completely incorporate HLA alleles, their interactions, and recently discovered non-HLA loci to create an improved GRS. Termed “T1D GRS2,” the new tool is intended to more accurately predict T1D in newborn screening studies and to better discriminate diabetes subtypes. The study was led by Seth A. Sharp of the Institute of Biomedical and Clinical Science at the University of Exeter Medical School in the U.K. and was published in Diabetes Care.
In 6,481 cases and 9,247 control subjects from the Type 1 Diabetes Genetics Consortium, researchers analyzed variants associated with T1D both in the HLA region and across the genome. The study modeled interactions between variants marking strongly associated HLA haplotypes and generated odds ratios to create the T1D GRS2.
Newborn screening simulations demonstrate that the T1D GRS2 is nearly twice as efficient as HLA genotyping alone and 50 percent better than current genetic scores in general population T1D prediction. Additionally, when directly compared with genetic scores used previously, the T1D GRS2 significantly improved discrimination of T1D from Type 2 diabetes and control subjects.
The T1D GRS2 is potentially limited by its dependence on genetic information from European Caucasian cohorts, as there is currently a lack of large, well-described, case-control cohorts of varied ethnicity. While there is currently little evidence for strong gene-environment effects in T1D, it is also possible that even in populations of similar ethnic background different environments might mediate different genetic associations, requiring score adjustment.
Still, the T1D GRS2 is highly useful for improving newborn screenings and classifying adult indecent diabetes type. “While it is difficult to envisage a whole-genome sequencing approach to population-wide screening,” the researchers write, “the falling cost of [single nucleotide polymorphism (SNP)] typing and the very strong association of T1D with SNPs in the HLA region make a more comprehensive GRS a practical choice for use in such population-based research and public health settings.”
Sharp S, Rich S, Wood A, et al. “Development and Standardization of an Improved Type 1 Diabetes Genetic Risk Score for Use in Newborn Screening and Incident Diagnosis.” Diabetes Care. Published online February 2019. DOI: 10.2337/dc18-1785