Article
Association of HLA-DPB1 polymorphism with ANCA-associated vasculitis
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Authors
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Alexandr Kuranov
- Klinik für Nephrologie und Rheumatologie, Universitätsmedizin Göttingen, Göttingen
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Johanna Charlotte Hoffmann
- Klinik für Nephrologie und Rheumatologie, Universitätsmedizin Göttingen, Göttingen
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Susann Patschan
- Medizinische Hochschule Brandenburg, Innere Medizin I, Brandenburg
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Gerhard A. Müller
- Klinik für Nephrologie und Rheumatologie, Universitätsmedizin Göttingen, Göttingen
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Claudia Müller
- Klinik für Nephrologie und Rheumatologie, Universitätsmedizin Göttingen, Göttingen
| Published: | February 5, 2019 |
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Outline
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Background: GWAS studies of European and American patient cohorts have shown that GPA/MPA patient subsets defined by presence of PR3 versus MPO antibodies differ in significant associations with HLA class II variants particularly of the HLA-DP and –DQ loci. The aim of this study was to replicate and extend these findings by direct NGS typing of HLA haplotypes of a German ANCA patient cohort.
Methods: 38 PR3-ANCA positive German patients were analyzed in comparison to 29 healthy controls. HLA typing by next-generation sequencing was performed using the GenDx HLA GeneSuite kit. HLA allele associations were compared to previously defined ANCA associated single nucleotide polymorphism. All statistical calculations were computed using the Epi Info™ v. 7.2.1.0 Bonferroni correction was applied to P-values. Allele and haplotype frequencies were analyzed using the Arlequin 3.1.
Results: As in previous GWAS studies HLA-DPB1*04:01 was found to be significantly associated with the GPA/PR3 positive patient cohort [pc = 0.024] in comparison to the respective controls. SNP analysis showed HLA-DPB1: rs9277535 (Position 10931), rs1042169 (Position 338), rs141530233 (Position 341) and rs386699872 (Position 346) that patients who were homozygous for the haplotype DPB1-338G-DPB1-341noA-DPB1-346CA-DPB1-10931A had a significantly increased ANCA risk compared to the cases heterozygous for this haplotype [pc = 0.0003, OR = 10.8, 95%CI 3.2-35.9]. Significant association of HLA-DPB1 with glycine at amino-acid position 84 (HLA-DPB1-84Gly-Gly) was found in the patients [pc = 0.0005, OR = 10.8, 95%CI 3.2-35.9] in comparison to the respective controls. HLA-DPB1-84Asp-Gly was increased in healthy cohort [pc = 0.001, OR = 0.11, 95%CI 0.3-0.35]. Homozygosity for rs9277535 gene polymorphism A-A of the HLA-DPB1 locus conferred a significantly increased risk of ANCA [pc=0.00025, OR=12.04, 95%CI=3.4-42.1].Rs9277535 G-A heterozygosity was negatively associated in the ANCA patients in comparison to the healthy cohort [pc=0.0007, OR=0.1, 95%CI=0.03- 0.34].
Conclusion: The study confirms HLA-DPB1*04:01 to be significantly associated in a German PR-3 positive /GPA ANCA vasculitis. SNP rs9277535-A/A homozygosity appeared to confer the highest risk for PR-3 ANCA in the patients independent of HLA-DPB1*04:01. So far, the pathogenetic role of rs9277535 which has been reported to also influence other autoimmune diseases such as rheumatoid arthritis and acute GvHD remains to be defined.
