Next Generation Sequencing Identifies the HLA-DQA1*03:03 Allele in the Type 1 Diabetes Risk-Associated HLA-DQ8 Serotype
Abstract
:1. Introduction
2. Materials and Methods
2.1. Donor Characteristics
2.2. HLA Typing
2.3. Calculations and Statistics
3. Results
3.1. Identification of the HLA-DQA1*03:03 Allele in the Type 1 Diabetes DQ8 Risk Haplotype
3.2. HLA-DQA1*03:03 Characteristics
3.3. DR4 Haplotypes Containing HLA-DQA1*03:03
3.4. Comparison of HLA-DQA1*03:03 Containing Type 1 Diabetes Risk Haplotypes between Healthy Controls and Individuals with Type 1 Diabetes
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Noble, J.A.; Erlich, H.A. Genetics of type 1 diabetes. Cold Spring Harb. Perspect. Med. 2012, 2, a007732. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Noble, J.A. Immunogenetics of type 1 diabetes: A comprehensive review. J. Autoimmun. 2015, 64, 101–112. [Google Scholar] [CrossRef] [PubMed]
- Erlich, H.; Valdes, A.M.; Noble, J.; Carlson, J.A.; Varney, M.; Concannon, P.; Mychaleckyj, J.C.; Todd, J.A.; Bonella, P.; Fear, A.L.; et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: Analysis of the type 1 diabetes genetics consortium families. Diabetes 2008, 57, 1084–1092. [Google Scholar] [CrossRef] [Green Version]
- Noble, J.A.; Valdes, A.M. Genetics of the HLA region in the prediction of type 1 diabetes. Curr. Diab. Rep. 2011, 11, 533–542. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Regnell, S.E.; Lernmark, A. Early prediction of autoimmune (type 1) diabetes. Diabetologia 2017, 60, 1370–1381. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Undlien, D.E.; Friede, T.; Rammensee, H.G.; Joner, G.; Dahl-Jørgensen, K.; Søvik, O.; Akselsen, H.E.; Knutsen, I.; Rønningen, K.S.; Thorsby, E. HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection. Diabetes 1997, 46, 143–149. [Google Scholar] [CrossRef] [PubMed]
- Mellet, J.; Gray, C.M.; Pepper, M.S. HLA typing: Conventional techniques v. next-generation sequencing. S. Afr. Med. J. 2015, 106, 88–91. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mychaleckyj, J.C.; Noble, J.A.; Moonsamy, P.V.; Carlson, J.A.; Varney, M.D.; Post, J.; Helmberg, W.; Pierce, J.J.; Bonella, P.; Fear, A.L.; et al. HLA genotyping in the international Type 1 Diabetes Genetics Consortium. Clin. Trials 2010, 7, S75–S87. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Teng, S.; Srivastava, A.K.; Schwartz, C.E.; Alexov, E.; Wang, L. Structural assessment of the effects of amino acid substitutions on protein stability and protein protein interaction. Int. J. Comput. Biol. Drug Des. 2010, 3, 334–349. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rammensee, H.G.; Friede, T.; Stevanoviic, S. MHC ligands and peptide motifs: First listing. Immunogenetics 1995, 41, 178–228. [Google Scholar] [CrossRef] [PubMed]
- Bondinas, G.P.; Moustakas, A.K.; Papadopoulos, G.K. The spectrum of HLA-DQ and HLA-DR alleles, 2006: A listing correlating sequence and structure with function. Immunogenetics 2007, 59, 539–553. [Google Scholar] [CrossRef] [PubMed]
- Reich, Z.; Boniface, J.J.; Lyons, D.S.; Borochov, N.; Wachtel, E.J.; Davis, M.M. Ligand-specific oligomerization of T-cell receptor molecules. Nature 1997, 387, 617–620. [Google Scholar] [CrossRef] [PubMed]
- Lindstedt, R.; Monk, N.; Lombardi, G.; Lechler, R. Amino acid substitutions in the putative MHC class II “dimer of dimers” interface inhibit CD4+ T cell activation. J. Immunol. 2001, 166, 800–808. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Klitz, W.; Maiers, M.; Spellman, S.; Baxter-Lowe, L.A.; Schmeckpeper, B.; Williams, T.M.; Fernandez-Viña, M. New HLA haplotype frequency reference standards: High-resolution and large sample typing of HLA DR-DQ haplotypes in a sample of European Americans. Tissue Antigens 2003, 62, 296–307. [Google Scholar] [CrossRef] [PubMed]
- Zhao, L.P.; Papadopoulos, G.K.; Kwok, W.W.; Moustakas, A.K.; Bondinas, G.P.; Larsson, H.E.; Ludvigsson, J.; Marcus, C.; Samuelsson, U.; Wang, R.; et al. Motifs of Three HLA-DQ Amino Acid Residues (α44, β57, β135) Capture Full Association With the Risk of Type 1 Diabetes in DQ2 and DQ8 Children. Diabetes 2020, 69, 1573–1587. [Google Scholar] [CrossRef] [PubMed]
Erlich et al., 2008 Noble et al., 2012 Noble et al., 2015 | Enczmann et al., 2021 | |||||
---|---|---|---|---|---|---|
Haplotype | DRB1 | DQA1 | DQB1 | DRB1 | DQA1 | DQB1 |
DR3/DQ2 | 03:01 | 05:01 | 02:01 | 03:01 | 05:01 | 02:01 |
DR4/DQ8 | 04:01 | 03:01 | 03:02 | 04:01 | 03:01 | 03:02 |
04:01 | 03:03 | 03:02 | ||||
04:02 | 03:01 | 03:02 | 04:02 | 03:01 | 03:02 | |
04:04 | 03:01 | 03:02 | 04:04 | 03:01 | 03:02 | |
04:05 | 03:01 | 03:02 | ||||
04:05 | 03:03 | 03:02 |
DRB1 | DQA1 | DQB1 | Haplotype Counts | Proportion of DQA1*03:03 within DR04:x [%] |
---|---|---|---|---|
04:01 | 03:01 | 03:02 | 18 | |
04:01 | 03:03 | 03:02 | 3 | 14.3 |
04:02 | 03:01 | 03:02 | 38 | 0 |
04:03 | 03:01 | 03:02 | 26 | 0 |
04:04 | 03:01 | 03:02 | 38 | 0 |
04:05 | 03:03 | 03:02 | 22 | 100 |
04:06 | 03:01 | 03:02 | 29 | 0 |
04:07 | 03:01 | 03:02 | 27 | |
04:07 | 03:03 | 03:02 | 7 | 20.6 |
04:08 | 03:01 | 03:02 | 3 | |
04:08 | 03:03 | 03:02 | 8 | 72.7 |
04:10 | 03:03 | 03:02 | 1 | 100 |
04:11 | 03:01 | 03:02 | 7 | 0 |
04:13 | 03:01 | 03:02 | 17 | 0 |
04:14 | 03:01 | 03:02 | 16 | 0 |
04:15 | 03:01 | 03:02 | 7 | 0 |
04:21 | 03:01 | 03:02 | 2 | 0 |
04:26 | 03:01 | 03:02 | 3 | 0 |
04:28 | 03:01 | 03:02 | 2 | 0 |
04:36 | 03:01 | 03:02 | 1 | 0 |
04:38 | 03:01 | 03:02 | 1 | 0 |
04:50 | 03:01 | 03:02 | 3 | 0 |
Haplotype | DRB1 | DQA1 | DQB1 | Haplotype Counts (Frequencies, %) of Controls | Haplotype Counts (Frequencies, %) of T1D Patients | Odds Ratio (95% CI) | p-Value |
---|---|---|---|---|---|---|---|
DR3/DQ2 | 03:01 | 05:01 | 02:01 | 2049 (10.5) | 147 (32.1) | 4.04 (3.31–4.95) | <0.0001 |
DR4/DQ8 | 04:01 | 03:01 | 03:02 | 696 (3.6) | 85 (18.6) | 6.18 (4.85–9.94) | <0.0001 |
04:01 | 03:03 | 03:02 | 116 (0.6) | 13 (2.8) | 4.90 (2.80–8.62) | <0.0001 | |
04:02 | 03:01 | 03:02 | 192 (1.0) | 22 (4.8) | 5.09 (3.27–7.97) | <0.0001 | |
04:04 | 03:01 | 03:02 | 429 (2.2) | 18 (3.9) | 1.83 (1.13–2.91) | 0.023 | |
04:05 | 03:03 | 03:02 | 49 (0.3) | 17 (3.7) | 15.36 (8.62–26.52) | <0.0001 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Enczmann, J.; Balz, V.; Hoffmann, M.; Kummer, S.; Reinauer, C.; Döing, C.; Förtsch, K.; Welters, A.; Mayatepek, E.; Meissner, T.; et al. Next Generation Sequencing Identifies the HLA-DQA1*03:03 Allele in the Type 1 Diabetes Risk-Associated HLA-DQ8 Serotype. Genes 2021, 12, 1879. https://doi.org/10.3390/genes12121879
Enczmann J, Balz V, Hoffmann M, Kummer S, Reinauer C, Döing C, Förtsch K, Welters A, Mayatepek E, Meissner T, et al. Next Generation Sequencing Identifies the HLA-DQA1*03:03 Allele in the Type 1 Diabetes Risk-Associated HLA-DQ8 Serotype. Genes. 2021; 12(12):1879. https://doi.org/10.3390/genes12121879
Chicago/Turabian StyleEnczmann, Jürgen, Vera Balz, Maximilian Hoffmann, Sebastian Kummer, Christina Reinauer, Carsten Döing, Katharina Förtsch, Alena Welters, Ertan Mayatepek, Thomas Meissner, and et al. 2021. "Next Generation Sequencing Identifies the HLA-DQA1*03:03 Allele in the Type 1 Diabetes Risk-Associated HLA-DQ8 Serotype" Genes 12, no. 12: 1879. https://doi.org/10.3390/genes12121879