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PLoS Genet. 2019 Apr 4;15(4):e1008038. doi: 10.1371/journal.pgen.1008038. eCollection 2019 Apr.

Genome-wide association study in Turkish and Iranian populations identify rare familial Mediterranean fever gene (MEFV) polymorphisms associated with ankylosing spondylitis.

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Translational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
Department of Internal Medicine, Division of Rheumatology, Izmir Katip Çelebi University School of Medicine, İzmir, Turkey.
Department of Internal Medicine, Division of Rheumatology, Dokuz Eylul University, Faculty of Medicine, İzmir, Turkey.
Department of Molecular Medicine, Dokuz Eylul University Health Sciences Institute, İzmir, Turkey.
Department of Internal Medicine, Division of Rheumatology, Trakya University Medical Faculty, Edirne, Turkey.
Department of Rheumatology, School of Medicine, Uludağ University, Bursa, Turkey.
The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Department of Internal Medicine, Division of Rheumatology, Celal Bayar University, Manisa, Turkey.


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.

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