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PR3-ANCA-associated vasculitis is associated with a specific motif in the peptide-binding cleft of HLA-DP molecules
- Source :
- Gregersen, J W, Erikstrup, C, Ivarsen, P, Glerup, R, Krarup, E, Keller, K K, Hansen, I T & Møller, B K 2019, ' PR3-ANCA-associated vasculitis is associated with a specific motif in the peptide-binding cleft of HLA-DP molecules ', Rheumatology, vol. 58, no. 11, pp. 1942-1949 . https://doi.org/10.1093/rheumatology/kez111, Waarst Gregersen, J, Erikstrup, C, Ivarsen, P, Glerup, R, Krarup, E, Keller, K K, Hansen, I T & Møller, B K 2019, ' PR3-ANCA-associated vasculitis is associated with a specific motif in the peptide-binding cleft of HLA-DP molecules ', Rheumatology, vol. 58, no. 11, pp. 1942-1949 . https://doi.org/10.1093/rheumatology/kez111
- Publication Year :
- 2019
-
Abstract
- Objectives This study aimed to characterize the association between HLA alleles and ANCA-associated vasculitis (AAV) in a genetically homogeneous population, and to analyse the contribution of specific HLA molecule amino acid sequences to the risk of AAV. Methods We included 187 Danish patients with AAV and 1070 healthy controls. All were HLA typed at two-field resolution. The association of HLA alleles to PR3- or MPO-AAV was analysed. The contribution of the dominant molecular motifs of the HLA-DPB1 molecule to the risk of AAV was investigated by association studies that included specific amino acid sequences of the hypervariable regions in exon 2. Results Ninety-four percent of patients with PR3-AAV were carriers of HLA-DPB1*04:01 while all patients with PR3-AAV were carriers of an HLA-DPB1*04 allele, and 85% were homozygous. This was significantly more than in the control group (P < 0.0001). The association was even stronger when HLA-DPB1*04:02 and -DPB1*23:01 were included. HLA-DPB1*04:01, -DPB1*04:02 and -DPB1*23:01 share amino acids in positions 8–9, 69, 76 and 84–87 within the hypervariable regions, but only positions 69 and 84–87 contributed significantly to the disease risk. HLA-DRB1*15 was associated with an increased risk of developing PR3-AAV, while HLA-DRB1*04, -DRB1*07 and -DQB1*03 were associated with a reduced risk of kidney involvement in PR3-AAV. MPO-AAV was only weakly associated with HLA class I alleles. Conclusion PR3-AAV is strongly associated with the HLA-DPB1 alleles HLA-DPB1*04:01, -DPB1*04:02 and -DPB1*23:01, which share amino acid sequences crucial for the peptide-binding groove.
- Subjects :
- Adult
Male
HLA-DP Antigens
Genotype
Denmark
Myeloblastin
Population
Amino Acid Motifs
HLA-DP
Peptide binding
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Human leukocyte antigen
White People
03 medical and health sciences
Exon
0302 clinical medicine
Rheumatology
Risk Factors
Medicine
Humans
Pharmacology (medical)
Genetic Predisposition to Disease
peptide-binding cleft
Registries
Allele
education
Alleles
Genetic association
Aged
Peroxidase
Retrospective Studies
030203 arthritis & rheumatology
Genetics
education.field_of_study
business.industry
Homozygote
autoimmunity
Exons
Middle Aged
Hypervariable region
HLA
Case-Control Studies
Female
business
ANCA-associated vasculitis
030215 immunology
HLA-DRB1 Chains
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Gregersen, J W, Erikstrup, C, Ivarsen, P, Glerup, R, Krarup, E, Keller, K K, Hansen, I T & Møller, B K 2019, ' PR3-ANCA-associated vasculitis is associated with a specific motif in the peptide-binding cleft of HLA-DP molecules ', Rheumatology, vol. 58, no. 11, pp. 1942-1949 . https://doi.org/10.1093/rheumatology/kez111, Waarst Gregersen, J, Erikstrup, C, Ivarsen, P, Glerup, R, Krarup, E, Keller, K K, Hansen, I T & Møller, B K 2019, ' PR3-ANCA-associated vasculitis is associated with a specific motif in the peptide-binding cleft of HLA-DP molecules ', Rheumatology, vol. 58, no. 11, pp. 1942-1949 . https://doi.org/10.1093/rheumatology/kez111
- Accession number :
- edsair.doi.dedup.....f6195d24e98400e6aa7f79e7f4608e29