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

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.Author summary: Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthritis. To identify new genetic associations with AS, we performed genome-wide association studies in Turkish and Iranian AS patients and controls. We identified a novel rare coding MEFV variant associated with AS. Rare polymorphisms of MEFV, which encodes the protein pyrin, are known to cause Familial Mediterranean Fever (FMF), a monogenic, autosomal recessive, autoinflammatory disease which can be complicated by arthritis. 99.6% of Turkish AS cases, and 96% of those carrying the MEFV variant, did not have FMF, and the association with AS remains excluding cases with FMF. In Turkish subjects, the MEFV variant association was particularly strong in HLA-B27-negative cases, but also positive in HLA-B27-positive cases. This represents the first rare variant association with AS, and has the highest odds ratio for AS of any non-MHC reported hitherto, indicating a major effect on disease pathogenesis. We assessed serum cytokine levels in the cohort, and found that IL-1β, IL-17 and IL-23 levels were higher in AS cases. Furthermore, among AS cases, IL-1β and IL-23 levels were increased in MEFV variant carriers compared with non-carriers. This study has therapeutic implications; as IL-1 inhibition is effective in FMF, AS cases carrying FMF-associated MEFV variants may benefit from such therapy.