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


Ince B., Kamali S., Bektas M., Ogret Y., Savran F., Yalcinkaya Y., ...More

RHEUMATOLOGY INTERNATIONAL, vol.41, no.9, pp.1667-1672, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 41 Issue: 9
  • Publication Date: 2021
  • Doi Number: 10.1007/s00296-021-04789-4
  • Journal Name: RHEUMATOLOGY INTERNATIONAL
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, EMBASE, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.1667-1672
  • Keywords: ANCA-associated vasculitis, Granulomatosis with polyangiitis, Anti-PR3, HLA-DPB1
  • Istanbul University Affiliated: Yes

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 alpha and beta 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.