The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes
Background: HLA-DR4, a common antigen of HLA-DRB1, has multiple subtypes that are strongly associated with risk of type 1 diabetes (T1D); however, some are risk neutral or resistant. The pathobiological mechanism of HLA-DR4 subtypes remains to be elucidated. Methods: We used a population-based case-...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-07-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396421002243 |
| _version_ | 1819102224392912896 |
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| author | Lue Ping Zhao George K Papadopoulos Terry P. Lybrand Antonis K. Moustakas George P. Bondinas Annelie Carlsson Helena Elding Larsson Johnny Ludvigsson Claude Marcus Martina Persson Ulf Samuelsson Ruihan Wang Chul-Woo Pyo Wyatt C. Nelson Daniel E. Geraghty Stephen S. Rich Åke Lernmark |
| author_facet | Lue Ping Zhao George K Papadopoulos Terry P. Lybrand Antonis K. Moustakas George P. Bondinas Annelie Carlsson Helena Elding Larsson Johnny Ludvigsson Claude Marcus Martina Persson Ulf Samuelsson Ruihan Wang Chul-Woo Pyo Wyatt C. Nelson Daniel E. Geraghty Stephen S. Rich Åke Lernmark |
| author_sort | Lue Ping Zhao |
| collection | DOAJ |
| description | Background: HLA-DR4, a common antigen of HLA-DRB1, has multiple subtypes that are strongly associated with risk of type 1 diabetes (T1D); however, some are risk neutral or resistant. The pathobiological mechanism of HLA-DR4 subtypes remains to be elucidated. Methods: We used a population-based case-control study of T1D (962 patients and 636 controls) to decipher genetic associations of HLA-DR4 subtypes and specific residues with susceptibility to T1D. Using a birth cohort of 7865 children with periodically measured islet autoantibodies (GADA, IAA or IA-2A), we proposed to validate discovered genetic associations with a totally different study design and time-to-seroconversions prior to clinical onset of T1D. A novel analytic strategy hierarchically organized the HLA-DRB1 alleles by sequence similarity and identified critical amino acid residues by minimizing local genomic architecture and higher-order interactions. Findings: Three amino acid residues of HLA-DRB1 (β71, β74, β86) were found to be predictive of T1D risk in the population-based study. The “KAG” motif, corresponding to HLA-DRB1×04:01, was most strongly associated with T1D risk ([O]dds [R]atio=3.64, p = 3.19 × 10−64). Three less frequent motifs (“EAV”, OR = 2.55, p = 0.025; “RAG”, OR = 1.93, p = 0.043; and “RAV”, OR = 1.56, p = 0.003) were associated with T1D risk, while two motifs (“REG” and “REV”) were equally protective (OR = 0.11, p = 4.23 × 10−4). In an independent birth cohort of HLA-DR3 and HLA-DR4 subjects, those having the “KAG” motif had increased risk for time-to-seroconversion (Hazard Ratio = 1.74, p = 6.51 × 10−14) after adjusting potential confounders. Interpretations: DNA sequence variation in HLA-DRB1 at positions β71, β74, and β86 are non-conservative (β74 A→E, β71 E vs K vs R and β86 G vs V). They result in substantial differences in peptide antigen anchor pocket preferences at p1, p4 and potentially neighboring regions such as pocket p7. Differential peptide antigen binding is likely to be affected. These sequence substitutions may account for most of the HLA-DR4 contribution to T1D risk as illustrated in two HLA-peptide model complexes of the T1D autoantigens preproinsulin and GAD65. Funding: National Institute of Diabetes and Digestive and Kidney Diseases and the Swedish Child Diabetes Foundation and the Swedish Research Council. |
| first_indexed | 2024-12-22T01:31:10Z |
| format | Article |
| id | doaj.art-298f1a40bf1e4c889622fbd1193abbd1 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-22T01:31:10Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-298f1a40bf1e4c889622fbd1193abbd12022-12-21T18:43:29ZengElsevierEBioMedicine2352-39642021-07-0169103431The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetesLue Ping Zhao0George K Papadopoulos1Terry P. Lybrand2Antonis K. Moustakas3George P. Bondinas4Annelie Carlsson5Helena Elding Larsson6Johnny Ludvigsson7Claude Marcus8Martina Persson9Ulf Samuelsson10Ruihan Wang11Chul-Woo Pyo12Wyatt C. Nelson13Daniel E. Geraghty14Stephen S. Rich15Åke Lernmark16Public Health Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave NE, Seattle, WA 98109, USA; Corresponding authors.Laboratory of Biophysics, Biochemistry, Biomaterials and Bioprocessing, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, Arta GR47100, Greece; Corresponding authors.Department of Chemistry, Department of Pharmacology and Center for Structural Biology, Vanderbilt University, Nashville, TN, United StatesDepartment of Food Science and Technology, Faculty of Environmental Sciences, Ionian University, Argostoli GR26100, Cephalonia, GreeceLaboratory of Biophysics, Biochemistry, Biomaterials and Bioprocessing, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, Arta GR47100, GreeceDepartment of Clinical Sciences, Lund University, Skåne University Hospital, Lund, SwedenDepartment of Clinical Sciences, Lund University CRC, Skåne University Hospital, Jan Waldenströms gata 35, Skåne University Hospital SUS, Malmö SE-205 02, SwedenCrown Princess Victoria Children´s Hospital and Div of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenDepartment of Clinical Science and Education Karolinska Institutet and Institution of Medicine, Clinical Epidemiology, Karolinska Institutet, Stockholm, SwedenDepartment of Medicine, Clinical Epidemiological Unit, Karolinska Institutet, Stockholm, SwedenCrown Princess Victoria Children´s Hospital and Div of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United StatesClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United StatesClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United StatesClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United StatesCenter for Public Health Genomics, University of Virginia, PO Box 800717, MSB Room 3232, 1300 Jefferson Park Ave, Charlottesville, VA 22908, United StatesDepartment of Clinical Sciences, Lund University CRC, Skåne University Hospital, Jan Waldenströms gata 35, Skåne University Hospital SUS, Malmö SE-205 02, Sweden; Corresponding authors.Background: HLA-DR4, a common antigen of HLA-DRB1, has multiple subtypes that are strongly associated with risk of type 1 diabetes (T1D); however, some are risk neutral or resistant. The pathobiological mechanism of HLA-DR4 subtypes remains to be elucidated. Methods: We used a population-based case-control study of T1D (962 patients and 636 controls) to decipher genetic associations of HLA-DR4 subtypes and specific residues with susceptibility to T1D. Using a birth cohort of 7865 children with periodically measured islet autoantibodies (GADA, IAA or IA-2A), we proposed to validate discovered genetic associations with a totally different study design and time-to-seroconversions prior to clinical onset of T1D. A novel analytic strategy hierarchically organized the HLA-DRB1 alleles by sequence similarity and identified critical amino acid residues by minimizing local genomic architecture and higher-order interactions. Findings: Three amino acid residues of HLA-DRB1 (β71, β74, β86) were found to be predictive of T1D risk in the population-based study. The “KAG” motif, corresponding to HLA-DRB1×04:01, was most strongly associated with T1D risk ([O]dds [R]atio=3.64, p = 3.19 × 10−64). Three less frequent motifs (“EAV”, OR = 2.55, p = 0.025; “RAG”, OR = 1.93, p = 0.043; and “RAV”, OR = 1.56, p = 0.003) were associated with T1D risk, while two motifs (“REG” and “REV”) were equally protective (OR = 0.11, p = 4.23 × 10−4). In an independent birth cohort of HLA-DR3 and HLA-DR4 subjects, those having the “KAG” motif had increased risk for time-to-seroconversion (Hazard Ratio = 1.74, p = 6.51 × 10−14) after adjusting potential confounders. Interpretations: DNA sequence variation in HLA-DRB1 at positions β71, β74, and β86 are non-conservative (β74 A→E, β71 E vs K vs R and β86 G vs V). They result in substantial differences in peptide antigen anchor pocket preferences at p1, p4 and potentially neighboring regions such as pocket p7. Differential peptide antigen binding is likely to be affected. These sequence substitutions may account for most of the HLA-DR4 contribution to T1D risk as illustrated in two HLA-peptide model complexes of the T1D autoantigens preproinsulin and GAD65. Funding: National Institute of Diabetes and Digestive and Kidney Diseases and the Swedish Child Diabetes Foundation and the Swedish Research Council.http://www.sciencedirect.com/science/article/pii/S2352396421002243HLA-DRB1 subtypesMotif analysisSeroconversionStructural analysisType 1 diabetes |
| spellingShingle | Lue Ping Zhao George K Papadopoulos Terry P. Lybrand Antonis K. Moustakas George P. Bondinas Annelie Carlsson Helena Elding Larsson Johnny Ludvigsson Claude Marcus Martina Persson Ulf Samuelsson Ruihan Wang Chul-Woo Pyo Wyatt C. Nelson Daniel E. Geraghty Stephen S. Rich Åke Lernmark The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes EBioMedicine HLA-DRB1 subtypes Motif analysis Seroconversion Structural analysis Type 1 diabetes |
| title | The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes |
| title_full | The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes |
| title_fullStr | The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes |
| title_full_unstemmed | The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes |
| title_short | The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes |
| title_sort | kag motif of hla drb1 β71 β74 β86 predicts seroconversion and development of type 1 diabetes |
| topic | HLA-DRB1 subtypes Motif analysis Seroconversion Structural analysis Type 1 diabetes |
| url | http://www.sciencedirect.com/science/article/pii/S2352396421002243 |
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