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Genome-Wide Association Study in Turkish and Iranian Populations Identify Rare Familial Mediterranean Fever Gene (Mefv) Polymorphisms Associated With Ankylosing Spondylitis Publisher Pubmed



Li Z1 ; Akar S2 ; Yarkan H3 ; Lee SK1 ; Cetin P3 ; Can G3 ; Kenar G3 ; Capa F4 ; Pamuk ON5 ; Pehlivan Y6 ; Cremin K7 ; De Guzman E1 ; Harris J1 ; Wheeler L1 Show All Authors
Authors
  1. Li Z1
  2. Akar S2
  3. Yarkan H3
  4. Lee SK1
  5. Cetin P3
  6. Can G3
  7. Kenar G3
  8. Capa F4
  9. Pamuk ON5
  10. Pehlivan Y6
  11. Cremin K7
  12. De Guzman E1
  13. Harris J1
  14. Wheeler L1
  15. Jamshidi A8
  16. Vojdanian M8
  17. Farhadi E8
  18. Ahmadzadeh N8
  19. Yuce Z4
  20. Dalkilic E6
  21. Solmaz D2
  22. Akin B3
  23. Donmez S5
  24. Sari I3
  25. Leo PJ1
  26. Kenna TJ1
  27. Onen F3
  28. Mahmoudi M8
  29. Brown MA1
  30. Akkoc N9
Show Affiliations
Authors Affiliations
  1. 1. Translational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia
  2. 2. Department of Internal Medicine, Division of Rheumatology, Izmir Katip Celebi University School of Medicine, Izmir, Turkey
  3. 3. Department of Internal Medicine, Division of Rheumatology, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey
  4. 4. Department of Molecular Medicine, Dokuz Eylul University Health Sciences Institute, Izmir, Turkey
  5. 5. Department of Internal Medicine, Division of Rheumatology, Trakya University Medical Faculty, Edirne, Turkey
  6. 6. Department of Rheumatology, School of Medicine, Uludag University, Bursa, Turkey
  7. 7. University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia
  8. 8. Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
  9. 9. Department of Internal Medicine, Division of Rheumatology, Celal Bayar University, Manisa, Turkey

Source: PLoS Genetics Published:2019


Abstract

Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthritis common in Turkish and Iranian populations. Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease most common in people of Mediterranean origin. MEFV, an FMF-associated gene, is also a candidate gene for AS. We aimed to identify AS susceptibility loci and also examine the association between MEFV and AS in Turkish and Iranian cohorts. We performed genome-wide association studies in 1001 Turkish AS patients and 1011 Turkish controls, and 479 Iranian AS patients and 830 Iranian controls. Serum IL-1β, IL-17 and IL-23 cytokine levels were quantified in Turkish samples. An association of major effect was observed with a novel rare coding variant in MEFV in the Turkish cohort (rs61752717, M694V, OR = 5.3, P = 7.63×10−12), Iranian cohort (OR = 2.9, P = 0.042), and combined dataset (OR = 5.1, P = 1.65×10−13). 99.6% of Turkish AS cases, and 96% of those carrying MEFV rs61752717 variants, did not have FMF. In Turkish subjects, the association of rs61752717 was particularly strong in HLA-B27-negative cases (OR = 7.8, P = 8.93×10−15), but also positive in HLA-B27-positive cases (OR = 4.3, P = 7.69×10−8). Serum IL-1β, IL-17 and IL-23 levels were higher in AS cases than controls. Among AS cases, serum IL-1β and IL-23 levels were increased in MEFV 694V carriers compared with non-carriers. Our data suggest that FMF and AS have overlapping aetiopathogenic mechanisms. Functionally important MEFV mutations, such as M694V, lead to dysregulated inflammasome function and excessive IL-1β function. As IL-1 inhibition is effective in FMF, AS cases carrying FMF-associated MEFV variants may benefit from such therapy. © 2019 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.