Two Single Nucleotide Polymorphisms Identify the Highest-Risk Diabetes HLA Genotype : Potential for Rapid Screening

• Published in: Diabetes (New York, N.Y.) Vol. 57; no. 11; pp. 3152 - 3155
• Main Authors: BARKER, Jennifer M, TRIOLO, Taylor M, ALY, Theresa A, BASCHAL, Erin E, BABU, Sunanda R, KRETOWSKI, Adam, REWERS, Marian J, EISENBARTH, George S
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.11.2008
• Subjects: Biological and medical sciences; Consortia; Development and progression; Diabetes; Diabetes Mellitus, Type 1 - diagnosis; Diabetes Mellitus, Type 1 - genetics; Diabetes. Impaired glucose tolerance; Diagnosis; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzymes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene Frequency; Genetic aspects; Genetics; Genotype; Genotype & phenotype; Genotypes; HLA-D Antigens - genetics; HLA-DQ Antigens - genetics; HLA-DR Antigens - genetics; Humans; Hybridization; Medical sciences; Physiological aspects; Polymorphism, Single Nucleotide; Prevention; Research design; Review boards; Risk Factors; Siblings; Type 1 diabetes; United States; Endocrinopathy; HLA-System; Genotype; Diabetes mellitus; Risk factor; Polymorphism
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db08-0605

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