The HLA region in ANCA-associated vasculitis: characterisation of genetic associations in a Scandinavian patient population

Christian Lundtoft; Ann Knight; Jennifer R S Meadows; Åsa Karlsson; Solbritt Rantapää-Dahlqvist; Ewa Berglin; Øyvind Palm; Hilde Haukeland; Iva Gunnarsson; Annette Bruchfeld; Mårten Segelmark; Sophie Ohlsson; Aladdin J Mohammad; Per Eriksson; Peter Söderkvist; Lars Ronnblom; Roald Omdal; Roland Jonsson; Kerstin Lindblad-Toh; Johanna Dahlqvist

doi:10.1136/rmdopen-2023-004039

The HLA region in ANCA-associated vasculitis: characterisation of genetic associations in a Scandinavian patient population

RMD Open. 2024 Apr 4;10(2):e004039. doi: 10.1136/rmdopen-2023-004039.

Authors

Christian Lundtoft¹, Ann Knight^{1

2}, Jennifer R S Meadows³, Åsa Karlsson³, Solbritt Rantapää-Dahlqvist⁴, Ewa Berglin⁴, Øyvind Palm⁵, Hilde Haukeland⁶, Iva Gunnarsson^{7

8}, Annette Bruchfeld^{9

10}, Mårten Segelmark¹¹, Sophie Ohlsson¹¹, Aladdin J Mohammad^{11

12}, Per Eriksson¹³, Peter Söderkvist¹³, Lars Ronnblom¹, Roald Omdal^{14

15}, Roland Jonsson¹⁶, Kerstin Lindblad-Toh^{3

17}, Johanna Dahlqvist^{18

2}

Affiliations

¹ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
² Uppsala University Hospital, Uppsala, Sweden.
³ Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
⁴ Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
⁵ Department of Rheumatology, Oslo University Hospital, Oslo, Norway.
⁶ Department of Rheumatology, Martina Hansens Hospital, Sandvika, Norway.
⁷ Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
⁸ Unit of Rheumatology, Karolinska University Hospital, Stockholm, Sweden.
⁹ Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
¹⁰ Department of Renal Medicine, Karolinska University Hospital and CLINTEC Karolinska Institutet, Stockholm, Sweden.
¹¹ Department of Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
¹² Department of Medicine, University of Cambridge, Cambridge, UK.
¹³ Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
¹⁴ Research Department, Stavanger University Hospital, Stavanger, Norway.
¹⁵ Department of Clinical Science, University of Bergen, Bergen, Norway.
¹⁶ Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Hordaland, Norway.
¹⁷ The Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.
¹⁸ Department of Medical Sciences, Uppsala University, Uppsala, Sweden johanna.dahlqvist@imbim.uu.se.

Abstract

Objective: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV.

Methods: Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively.

Results: PR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at the HLA-DPB1 locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLA-DRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse.

Conclusions: The association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to the HLD-DPB1 region mediate potentially different functional effects.

Keywords: Autoimmune Diseases; Granulomatosis with polyangiitis; Polymorphism, Genetic; Systemic vasculitis.

MeSH terms

Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis* / genetics
Antibodies, Antineutrophil Cytoplasmic* / genetics
Genotype
Humans
Myeloblastin / genetics
Recurrence

Substances

Antibodies, Antineutrophil Cytoplasmic
Myeloblastin