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An immunogenomic exome landscape of triple positive primary antiphospholipid patients

Genes & Immunity volume 25, pages 108–116 (2024)Cite this article

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A Correction to this article was published on 19 March 2024

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Abstract

Primary antiphospholipid syndrome is characterized by thrombosis and autoantibodies directed against phospholipids or associated proteins. The genetic etiology of PAPS remains unknown. We enrolled 21 patients with thromboembolic events associated to lupus anticoagulant, anticardiolipin and anti β2 glycoprotein1 autoantibodies. We performed whole exome sequencing and a systematic variant-based analysis in genes associated with thrombosis, in candidate genes previously associated with APS or inborn errors of immunity. Data were compared to public databases and to a control cohort of 873 non-autoimmune patients. Variants were identified following a state-of-the-art pipeline. Enrichment analysis was performed by comparing with the control cohort. We found an absence of significant HLA bias and genetic heterogeneity in these patients, including when testing combinations of rare variants in genes encoding for proteins involved in thrombosis and of variants in genes linked with inborn errors of immunity. These results provide evidence of genetic heterogeneity in PAPS, even in a homogenous series of triple positive patients. At the individual scale, a combination of variants may participate to the breakdown of B cell tolerance and to the vessel damage.

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Fig. 1: Study flowchart.
Fig. 2: Design of the WES analysis strategy.
Fig. 3: HLA analysis.

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Original data are available in Supplemental material.

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Acknowledgements

The authors sincerely thank the patients for participating in this study. We thank Pr. Laurent Abel (HLA analysis) and Dr Isabelle Andre (Moesin variation) for fruitful discussions. We thank the patients and their families for participating in our study.

Funding

This work was supported by Strasbourg Hospital and University, by the France’s National Research Agency (Agence Nationale de Recherche; ANR), the Investment for the Future Program (Programme des Investissements d’Avenir; PIA) through a “Laboratoire d’Excellence” (LabEx) TRANSPLANTEX [ANR-11-LABX-0070_TRANSPLANTEX] as well as by Strasbourg’s Interdisciplinary Thematic Institute (ITI) for Precision Medicine, TRANSPLANTEX NG, as part of the ITI 2021-2028 program of the University of Strasbourg, CNRS and INSERM, funded by IdEx Unistra [ANR-10-IDEX-0002] and SFRI-STRAT’US [ANR-20-SFRI-0012]. Additional funding was provided by INSERM (UMR_S 1109), the Fédération Hospitalo-Universitaire (FHU) OMICARE, MSD Avenir “Autogen”, and finally the European regional development fund (European Union) INTERREG IV (project RARENET) and V programs (project PERSONALIS).

Author information

Author notes

  1. These authors contributed equally: A. Cobat, B. Boisson, R. Carapito, A. S. Korganow.

Authors and Affiliations

  1. Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, F-67000, Strasbourg, France

    A. Guffroy, L. Jacquel, V. Poindron, V. Delannoy, P. Soulas-Sprauel, T. Martin, V. Gies & A. S. Korganow

  2. University Strasbourg, INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), F-67000, Strasbourg, France

    A. Guffroy, N. Paul, A. Molitor, P. Soulas-Sprauel, T. Martin, S. Bahram, V. Gies, R. Carapito & A. S. Korganow

  3. University de Strasbourg, Faculty of Medicine, F-67000, Strasbourg, France

    A. Guffroy, L. Jacquel, T. Martin, R. Carapito & A. S. Korganow

  4. University Paris-Cité, Imagine Institute, F-75015, Paris, France

    Y. Seeleuthner, J. L. Casanova, A. Cobat & B. Boisson

  5. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France

    Y. Seeleuthner, J. L. Casanova, A. Cobat & B. Boisson

  6. Department of Internal Medicine, Belle-Isle Hospital, Metz, France

    F. Maurier

  7. Laboratoire de Biochimie et de Biologie Moléculaire, Hôpital Universitaire, Strasbourg, France

    A. C. Voegeli

  8. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA

    P. Zhang, J. L. Casanova & B. Boisson

  9. Laboratoire d’Immunologie, Plateau technique de Biologie, Hôpital Universitaire, Strasbourg, France

    B. Nespola

  10. Laboratoire d’exploration du HLA, Centre de Transfusion sanguine, Strasbourg, France

    M. J. Apithy

  11. University Strasbourg, Faculty of Pharmacy, F-67400, Illkirch, France

    P. Soulas-Sprauel

  12. Department of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    R. E. Voll

Authors
  1. A. Guffroy
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  2. L. Jacquel
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Contributions

Conceptualization AG, ASK, VG, RC, BB, AC, JLC Methodology AG, ASK, RC, BB, AC, JLC Investigation AG, LJ, YS, NP, VP, FM, VD, ACV, PZ, BN, AM, MJA, ASK, RC, AC, BB Data Curation ASK, AG, AC, BB, LJ, VD Writing, Review & Editing all authors, Funding Acquisition ASK,TM, RV, PSP, RC, SB, JLC, AC.

Corresponding authors

Correspondence to A. Guffroy or A. S. Korganow.

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The authors declare no competing interests.

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The study was approved by the Commission Nationale Informatique et Liberté (CNIL) and the Institutional Board (CPP13/48). All the enrolled subjects provided written informed consent and the study was performed according to the principles of the Helsinski declaration.

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Guffroy, A., Jacquel, L., Seeleuthner, Y. et al. An immunogenomic exome landscape of triple positive primary antiphospholipid patients. Genes Immun 25, 108–116 (2024). https://doi.org/10.1038/s41435-024-00255-w

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