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P76 Established risk alleles at HLA-A, -DPB1, -DQB1 and -DRB1 for systemic lupus erythematosus associate with distinct clinical manifestations
  1. Henrik Christian Bidstrup Leffers1,2,3,
  2. Ingileif Jonsdottir4,5,
  3. Saedis Saevarsdottir4,5,
  4. Ole Birger Pedersen6,7,
  5. DBDS genomic consortium,
  6. Anne Troldborg8,
  7. Anne Voss9,
  8. Salome Kristensen2,10,
  9. Jesper Lindhardsen1,
  10. Prabhat Kumar11,
  11. Asta Linauskas11,12,
  12. Lars Juul13,
  13. Niels Steen Krogh2,14,
  14. Bent Deleuran8,
  15. Lene Dreyer10,12,
  16. Michael Schwinn3,
  17. Lise Wegner Thørner15,
  18. Lotte Hindhede16,
  19. Christian Erikstrup7,16,
  20. Sisse Rye Ostrowski15,17,
  21. Søren Brunak18,
  22. Kari Stefansson4,5 and
  23. Søren Jacobsen1,17
  1. 1Copenhagen Lupus and Vasculitis Clinic, Centre for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
  2. 2The DANBIO Registry, Denmark
  3. 3The Danish Reuma Biobank, Denmark
  4. 4deCODE genetics/Amgen, Inc., Reykjavik, Iceland
  5. 5Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
  6. 6Dept. of Clinical Immunology, Zealand University Hospital, Denmark
  7. 7Dept. of Clinical Medicine, Aarhus University, Aarhus, Denmark
  8. 8Dept. of Biomedicine, Aarhus University; Dept. of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
  9. 9Dept. of Rheumatology, Odense University Hospital, Odense, Denmark
  10. 10Dept. of Rheumatology, Aalborg University Hospital, Aalborg, Denmark
  11. 11Dept. of Rheumatology, North Denmark Regional Hospital, Hjørring, Denmark
  12. 12Clinical Institute Aalborg University, Aalborg, Denmark
  13. 13Dept. of Rheumatology, Centre for Rheumatology and Spine Diseases, Gentofte Hospital, Copenhagen, Denmark
  14. 14Zitelab ApS, Copenhagen, Denmark
  15. 15Dept. of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark
  16. 16Dept. of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
  17. 17Dept. of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  18. 18The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark

Abstract

Objective We aimed to investigate associations between disease manifestations of SLE and HLA risk alleles relevant to Danish subjects of European ancestry.

Methods HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1 alleles were assigned from whole genome sequence data of 25,215 Scandinavian samples, called by Graphtyper, and imputed into 270,627 chiptyped Danes as described,1 including 427 SLE patients of Danish descent, previously characterized with respect to demographic, clinical and genotypic characteristics2 and controls available by collaboration with the Danish Blood Donor Study. Logistic regression was used for association testing of the imputed alleles with SLE. For SLE patients, associations between HLA risk alleles and SLE disease manifestations according to the ACR-1997 classification criteria were examined by multivariate logistic regression analyses adjusted for age and sex; one model for each disease manifestation.

Results We identified eight HLA alleles that associate significantly (p<10–4, threshold for 2- and 4-digit HLA alleles) with risk of SLE: HLA-A*01:01, HLA-B*08:01, HLA-C*07:01, HLA-DPB1*01:01, HLA-DQB1*02:01, HLA-DQB1*06:02, HLA-DRB1*03:01 and HLA-DRB1*15:01, and two with protection from SLE: HLA-DQB1*05:01 and HLA-DRB1*01:01.

Among the SLE patients, the most frequently observed disease manifestations were immunologic disorder (80%), non-erosive arthritis (80%), haematologic disorder (78%), malar rash (55%), photosensitivity (51%) and persistent proteinuria (37%). We further tested the association of the eight SLE associated HLA alleles, with specific disease manifestations (N=17). Nominally significant associations (OR (95%CI)) were found between HLA-A*01:01 and serositis 0.51 (0.29–0.91), pericarditis 0.40 (0.19–0.83) and leukopenia 0.46 (0.25–0.84), HLA-DPB1*01:01 and seizures 3.58 (1.12–11.47), HLA-DQB1*02:01 and pericarditis 3.78 (1.45–9.89) and between HLA-DRB1*03:01 and anti-phospholipid antibodies 0.50 (0.34–0.75), but these were not significant after multiple testing correction (p<3.7*10–4).

Conclusion This study confirms the association of known SLE susceptibility HLA-A, -DPB1, DQB1 and -DRB1 alleles with SLE in Danes of European ancestry.

References

  1. Eggertsson HP, Kristmundsdottir S, Beyter D, et al. GraphTyper2 enables population-scale genotyping of structural variation using pangenome graphs. Nat Commun. 2019;10(1):5402.

  2. Leffers HCB, Westergaard D, Saevarsdottir S, et al. Established risk loci for systemic lupus erythematosus at NCF2, STAT4, TNPO3, IRF5 and ITGAM associate with distinct clinical manifestations: a Danish genome-wide association study. Joint Bone Spine. 2022;89(4):105357.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/lupus-2024-el.130

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