Next Generation Sequencing Identifies the HLA-DQA1*03:03 Allele in the Type 1 Diabetes Risk-Associated HLA-DQ8 Serotype.

Abstract

The highest genetic type 1 diabetes risk is conferred by HLA class II haplotypes defined by alleles at the HLA-DR and -DQ loci. The combination of HLA-DQA1*03:01 and DQB1*03:02 alleles (summarized as 'HLA-DQ8') is reported to be among the two most prevalent HLA class II haplotypes in Caucasian type 1 diabetes patients. This classification is based on conventional genotyping of exon 2 of the DQ gene locus and excludes exon 3. In this study, HLA genotyping on the type 1 diabetes susceptibility loci HLA-DRB1, DQA1 and DQB1 was performed using a high-resolution next generation sequencing method. In addition to the routinely examined exon 2, exon 3 was also sequenced. Samples from 229 children with type 1 diabetes were included and compared to a cohort of 9,786 controls. In addition to previously described HLA-DQ haplotypes in type 1 diabetes patients, we found that as well as HLA-DQA1*03:01,HLA-DQA1*03:03 also contributed to HLA-DQ8. HLA-DQA1*03:03 differs from HLA-DQA1*03:01 by one nucleotide substitution in exon 3 at position 160, leading to a single amino acid replacement. DRB1*04:05 was exclusively associated with DQA1*03:03 whereas the DRB1*04:01 haplotype comprised either DQA1*03:01 or DQA1*03:03. Significantly increased type 1 diabetes risk was confirmed for all these haplotypes with only minor differences between DQA1*03:01 and DQA1*03:03 alleles. This study identified the HLA-DQA1*03:03 allele as an addition to the already known type 1 diabetes risk haplotypes, and can contribute to more precise HLA genotyping approaches.

• Authors: Jürgen Enczmann, Vera Balz, Maximilian Hoffmann, Sebastian Kummer, Christina Reinauer, Carsten Döing, Katharina Förtsch, Alena Welters, Ertan Mayatepek, Thomas Meissner, Marc Jacobsen, Julia Seyfarth
• Journal: Genes (Genes (Basel)) Vol. 12 Issue 12 (11 25 2021) ISSN: 2073-4425 [Electronic] Switzerland
• PMID: 34946827 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HLA-DQ Antigens
• HLA-DQ alpha-Chains
• HLA-DQ8 antigen
• HLA-DQA1 antigen
• HLA-DRB1 Chains

Topics

• Adolescent
• Alleles
• Child
• Child, Preschool
• Diabetes Mellitus, Type 1 (genetics)
• Female
• Gene Frequency (genetics)
• Genetic Predisposition to Disease (genetics)
• HLA-DQ Antigens (genetics)
• HLA-DQ alpha-Chains (genetics)
• HLA-DRB1 Chains (genetics)
• Haplotypes (genetics)
• High-Throughput Nucleotide Sequencing (methods)
• Humans
• Infant
• Male
• Serogroup