Two Single Nucleotide Polymorphisms Identify the Highest-Risk Diabetes HLA Genotype

Abstract

are at the highest risk of developing type 1 diabetes. We sought to find an inexpensive, rapid test to identify DR3/4-DQ8 subjects using two single nucleotide polymorphisms (SNPs).RESEARCH DESIGN AND METHODS-SNPs rs2040410 and rs7454108 were associated with DR3-DQB1*0201 and DR4-DQB1*0302. We correlated these SNPs with HLA genotypes and with publicly available data on 5,019 subjects from the Type 1 Diabetes Genetic Consortium (T1DGC). Additionally, we analyzed these SNPs in samples from 143 HLA-typed children who participated in the Diabetes Autoimmunity Study of the Young (DAISY) using Taqman probes (rs7454108) and restriction digest analysis (rs2040410).RESULTS-With a simple combinatorial rule, the SNPs of interest identified the presence or absence of the DR3/4-DQ8 genotype. A wide variety of genotypes were tested for both SNPs. In T1DGC samples, the two SNPs were 98.5% (1,173 of 1,191) sensitive and 99.7% (3,815 of 3,828) specific for DR3/4-DQ8. In the DAISY population, the test was 100% (69 of 69) sensitive and 100% (74 of 74) specific. Overall, the sensitivity and specificity for the test were 98.57 and 99.67%, respectively. CONCLUSIONS-

Feature ranking of type 1 diabetes susceptibility genes improves prediction of type 1 diabetes

“…In the simulated example, we could select children with around 20% risk, and include nearly a quarter of future cases when thresholds were set to select 0.5% of the general population (Table 3). Typing could be achieved with two or three SNPs from the HLA region as recently shown [29,30] and the nine SNPs from the additional genes. True performance will require actual validation, but screening based on these ten genetic markers may provide a more efficient selection of risk children than screening with HLA alone.…”

Novel Gene Associations in Type 1 Diabetes

“…The screening can also be performed stepwise to minimize the need for tests [52]. Use of selected SNPs strongly correlating to the presence of risk haplotypes has also been suggested [53]. However, application of homogeneous hybridization methods to HLA typing eliminates all washing steps and can be made using blood spots as a starting material [52,54,55].…”

The Next Big Idea

“…These discoveries have been translated into improved newborn screening protocols. 15,16 Many of the DAISY contributions to the genetics of T1D have been led by George and his outstanding Fellows. Akane Ide, Terry Aly, Erin Baschal, and Mohamed Jahromi have explored in the DAISY population additional genetic determinants within the major histocompatibility complex (MHC) region.…”