Two Single Nucleotide Polymorphisms Identify Highest-Risk Diabetes Human Leukocyte Antigen Genotype: Potential for Rapid Screening

Abstract

OBJECTIVE: People with the human leukocyte antigen (HLA) genotype DRB1*0301-DQA1*0501-DQB1*0201/DRB1*04-DQA1*0301-DQB1*0302 (DR3/4-DQ8) 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 publically available data of 5019 subjects from the Type 1 Diabetes Genetic Consortium (T1DGC). Additionally, we analyzed these SNPs in samples from 143 HLA-typed children of 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% (1173/1191) sensitive and 99.7% (3815/3828) specific for DR3/4-DQ8. In the DAISY population the test was 100% (69/69) sensitive and 100% (74/74) specific. Overall, the sensitivity for the test was 98.57% and was 99.67% specific.

CONCLUSIONS: A two SNP screening test can identify the highest risk heterozygous genotype for type 1 diabetes, in a time- and cost-effective manner.