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Evaluating risk of developing type 1 diabetes (T1D) depends on determining an individual's HLA type, especially of the HLA DRB1 and DQB1 alleles. Individuals positive for HLA-DRB1*03 (DR3) or HLA-DRB1*04 (DR4) with DQB1*03:02 (DQ8) have the highest risk of developing T1D. Currently, HLA typing methods are relatively expensive and time consuming. We sought to determine the minimum number of single nucleotide polymorphisms (SNPs) that could rapidly define the HLA-DR types relevant to T1D, namely, DR3/4, DR3/3, DR4/4, DR3/X, DR4/X, and DRX/X (where X is neither DR3 nor DR4), and could distinguish the highest-risk DR4 type (DR4-DQ8) as well as the nonT1D-associated DR4-DQB 1*03:01 type. We analyzed 19,035 SNPs of 10,579 subjects (7,405 from a discovery set and 3,174 from a validation set) from the Type 1 Diabetes Genetics Consortium and developed a novel machine learning method to select as few as three SNPs that could define the HLA-DR and HLA-DQ types accurately. The overall accuracy was 99.3%, area under curve was 0.997, true-positive rates were >0.99, and false-positive rates were <0.001. We confirmed the reliability of these SNPs by 10-fold cross-validation. Our approach predicts HLA-DR/DQ types relevant to T1D more accurately than existing methods and is rapid and cost-effective. Diabetes 62:2135-2140, 2013
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Type 1 diabetes (T1D) is an autoimmune disease with both genetic and environmental components. More than 60 genes have been identified to affect the risk of T1D, with the HLA loci having the greatest impact on susceptibility (1,2). The association of T1D with alleles at HLA loci, especially the HLA class Π genes DR and DQ, is well-validated (3). The DR-DQ types contributing the most risk are HLA-DRB1*03 (DR3), typically observed in haplotypic association with DQA1*05:01DQB1*02:01 (DQ2), and HLA-DRB1*04 (DR4) in haplotypic association with DQA1*03-DQB 1*03:02 (DQ8). The highest risk is seen in individuals who are heterozygous for these types. In contrast, HLA-DRB1*04 (DR4) in haplotypic association with DQA1*03-DQB1*03:01 (DQ7) is not associated with a high risk for T1D.
HLA allele typing assists in determining risk for T1D and in studies to understand the pathogenesis of T1D. It is particularly useful in prevention and intervention trials that test potential preventative treatments in high-risk subjects (4). HLA typing also is required in genetic studies aimed at determining the...