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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.

Author information

1
Translational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
2
Department of Internal Medicine, Division of Rheumatology, Izmir Katip Çelebi University School of Medicine, İzmir, Turkey.
3
Department of Internal Medicine, Division of Rheumatology, Dokuz Eylul University, Faculty of Medicine, İzmir, Turkey.
4
Department of Molecular Medicine, Dokuz Eylul University Health Sciences Institute, İzmir, Turkey.
5
Department of Internal Medicine, Division of Rheumatology, Trakya University Medical Faculty, Edirne, Turkey.
6
Department of Rheumatology, School of Medicine, Uludağ University, Bursa, Turkey.
7
The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
8
Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
9
Department of Internal Medicine, Division of Rheumatology, Celal Bayar University, Manisa, Turkey.

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.

PMID:
30946743
PMCID:
PMC6467421
DOI:
10.1371/journal.pgen.1008038
[Indexed for MEDLINE]
Free PMC Article

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