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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

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Zhixiu Li, Servet Akar, Handan Yarkan, Sau Kuen Lee, Pınar Çetin, Gerçek Can, Gökce Kenar, Fernur Çapa, Omer Nuri Pamuk, Yavuz Pehlivan, Katie Cremin, Erika De Guzman, Jessica Harris, Lawrie Wheeler, Ahmadreza Jamshidi, Mahdi Vojdanian, Elham Farhadi, Nooshin Ahmadzadeh, Zeynep Yüce, Ediz Dalkılıç & 11 more Dilek Solmaz, Berrin Akın, Salim Dönmez, İsmail Sarı, Paul J. Leo, Tony J. Kenna, Fatos Önen, Mahdi Mahmoudi, Matthew A. Brown, Nurullah Akkoc, Seth Lucian Masters

Original languageEnglish
Article numbere1008038
JournalPLoS Genetics
Issue number4
Early online date4 Apr 2019
Publication statusPublished - 2019


King's Authors


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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