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Spondyloarthritis
Original article
Non-classical human leucocyte antigens in ankylosing spondylitis: possible association with HLA-E and HLA-F
  1. Margarida Rodrigues Santos1,
  2. Ana Rita Couto1,
  3. Iris Foroni1,
  4. Bruno Filipe Bettencourt1,
  5. Zhixiu Li2,
  6. Raquel Meneses1,
  7. Lawrie Wheeler2,
  8. Joaquim Pereira1,
  9. Fernando Pimentel-Santos3,
  10. João Eurico Fonseca4,
  11. Helena Alves5,
  12. António Martinho6,
  13. Manuela Lima7,
  14. Matthew A Brown2 and
  15. Jácome Bruges-Armas1,3
  1. 1 Serviço Especializado de Epidemiologia e Biologia Molecular, Hospital de Santo Espirito da Ilha Terceira, EPER, Angra do Heroismo, Portugal
  2. 2 Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Brisbane, Australia
  3. 3 CEDOC, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal
  4. 4 IMM, Universidade de Lisboa, Lisboa, Portugal
  5. 5 Centro de Histocompatibilidade do Norte, Instituto Português do Sangue e da Transplantação, Porto, Portugal
  6. 6 Centro de Sangue e Transplantação de Coimbra, Instituto Português do Sangue e da Transplantação, Coimbra, Portugal
  7. 7 Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal
  1. Correspondence to Margarida Rodrigues Santos; margarida.mp.santos{at}azores.gov.pt

Abstract

Objectives Ankylosing spondylitis (AS) is the most prevalent form of spondyloarthritis, with a known genetic association with the HLA-B27 molecule. The aim of this study was to assess the contribution of the HLA-G, HLA-E and HLA-F to AS susceptibility/protection in Portuguese patients with HLA-B27 AS and HLA-B27 unaffected controls.

Methods High-resolution typing of HLA-G, HLA - E and HLA - F was performed in 228 patients with HLA-B27 AS and 244 HLA-B27 unaffected controls. Allelic, genotypic and haplotypic frequencies were compared between cohorts. To replicate the results, single nucleotide polymorphisms (SNPs) in HLA-E and HLA-F genes were typed in Australian cohorts. For further confirmation, a group of European-descent patients with AS and unaffected controls were genotyped for Major Histocompatibility Complex SNPs using the Illumina microarray.

Results In the Portuguese population, no significant differences were found in HLA-G. For HLA-E, a significant difference was detected for the genotype HLA-E*01:01:01/01:03:01 (p=0.009; pc=0.009; OR=0.51), with a protection effect. For HLA-F, significant differences were detected in the allele HLA-F*01:01:02 (p=0.0049; pc=0.0098; OR=0.60) and corresponding SNP rs2075682 (p=0.0004; pc=0.0008; OR=0.53), suggesting protection and in the genotype HLA-F*01:01:01/01:03:01 (p=0.011; pc=0.043; OR=2.00), suggesting a susceptibility effect. Three G-E-F haplotypes with significant differences were detected but occur in a very small number of individuals. The only significant differences detected in the replication studies were for HLA-E rs1059510 in the Australians and for HLA-F rs1736924 in the European-descent cohorts.

Conclusion Our results reveal suggestive AS protective and susceptibility effects from both HLA-E and HLA - F loci, however with population differences. To our knowledge, this is the first study showing association of HLA-F with AS.

  • spondyloarthritis
  • ankylosing spondylitis
  • autoimmune diseases
  • inflammation
  • gene polymorphism
  • HLA.

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/rmdopen-2018-000677

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    Footnotes

    • Contributors MRS, MAB and JB-A conceived the study. FPS, JEF and JB-A provided clinical support to patient follow-up. MRS, IF, ZL, RM, LW and JP performed experiments. BFB, MRS, ZL, LW and IF performed statistical analysis. BFB, MRS, ZL, LW and MAB interpreted data. ARC, AM, HA, ML, MAB and JB-A gave critical revision of the manuscript for important intellectual content. All authors have read and accepted the submitted version of the manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Comissão de Ética do Hospital de Santo Espírito da Ilha Terceira.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data statement No additional data are available.