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A shared motif of hla-dpb1 affecting the susceptibility to pr3-anca positive granulomatosis with polyangiitis: comparative analysis of a Turkish cohort with matched healthy controls

  • Genes and Disease
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Abstract

We aimed to analyse the distribution of HLA Class 2 genotypes which were reported among the genetic risk factors for ANCA-associated vasculitis (AAV) among Turkish patients in comparison with healthy subjects and previously reported data of AAV cohorts. Ninety-eight patients (F/M: 47/51 and mean age: 49 ± 1.14) were enrolled in the study and records of gender and birthplace-matched 196 healthy kidney donors were used as the control group. Patients were classified according to the clinical subgroups and ANCA serotypes (MPO-AAV, PR3-AAV). DNA was isolated from venous blood from all patients, and high-resolution HLA Class 2 genotyping was carried out by using NGS-Omixon Holotype HLA Kit. The frequencies of HLA-DQB1*03:03, - *06:04, and -DPB1*13:01, -*16:01 and -*66:01:00 alleles were significantly higher, and the frequencies of HLA-DQB1*02:02, -DPB1*02:01 and -*04:01 alleles were lower in the PR3-AAV subgroup (n = 53) compared to the controls. Comparison of amino acid sequences of the associated HLA-DPB1 alleles revealed the sequence of D-E-A-V in risk alleles replaced with the G-G-P-M sequence in protective alleles between 84 and 87th positions. Structural analysis of the HLA-DPB1*02:01 showed that this shared position is in the contact area between HLA-DP α and β chains and within pocket 1 of the antigen-binding groove. First HLA genotyping analysis in Turkish AAV patients revealed a negative correlation between PR3-ANCA positivity and certain HLA-DPB1 alleles contradictory to the results reported from European cohorts. Known functional effects of D-E-A-V sequence on HLA-DPB1 support the importance of our finding, but further studies are needed to reveal its pathogenic mechanisms.

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Data availability

Datasets of the study are available from the corresponding author on reasonable request.

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Funding

This study was funded by Istanbul University Research Fund and Turkish Society for Rheumatology.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Topkapı, Turgut Özal Millet Cd, Fatih, 34093, Istanbul, Turkey

    Burak Ince, Murat Bektaş, Yasemin Yalçinkaya, Bahar Artim-Esen, Murat Inanç, Lale Öcal & Ahmet Gül

  2. Gaziosmanpaşa Hospital, Istanbul Yeni Yüzyıl University, Istanbul, Turkey

    Sevil Kamali

  3. Department of Biology, Istanbul Faculty of Medicine, Istanbul University, Topkapı, Turgut Özal Millet Cd, Fatih, 34093, Istanbul, Turkey

    Yeliz Duvarci Ögret & Fatma Oğuz Savran

Authors
  1. Burak Ince
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  2. Sevil Kamali
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  3. Murat Bektaş
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  4. Yeliz Duvarci Ögret
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  5. Fatma Oğuz Savran
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  6. Yasemin Yalçinkaya
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  7. Bahar Artim-Esen
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  8. Murat Inanç
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  9. Lale Öcal
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  10. Ahmet Gül
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Contributions

BI, SK, MI, LO and AG designed and planned the study, BI and MB collected the samples from patients, BI, YY and BAE carried out the data evaluation and basic analysis. YDO and FOS performed the HLA Class 2 genotyping analysis. All authors contributed to the follow-up of the patients and interpretation of results. BI wrote the first draft with AG; YDO and FOS contributed to the methods section. All authors provided critical feedback for the last version.

Corresponding author

Correspondence to Ahmet Gül.

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Conflict of interest

All authors declare no conflicts of interest.

Ethical approval

The Istanbul Faculty of Medicine Ethics Committee approved the study protocol (2014/613), and all patients provided written informed consent prior to the study participation.

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Ince, B., Kamali, S., Bektaş, M. et al. A shared motif of hla-dpb1 affecting the susceptibility to pr3-anca positive granulomatosis with polyangiitis: comparative analysis of a Turkish cohort with matched healthy controls. Rheumatol Int 41, 1667–1672 (2021). https://doi.org/10.1007/s00296-021-04789-4

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  • DOI: https://doi.org/10.1007/s00296-021-04789-4

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