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

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.

Genetics and the axial spondyloarthritis spectrum

“…A recent GWAS of Turkish–Iranian AS has confirmed that the FMF gene MEFV M694V coding polymorphism is associated with a substantially increased risk of AS in these populations, consistent with previous candidate gene studies and reports of sacroiliitis complicating FMF [ 4 ]. The association was found in both HLA-B27-positive and negative cases, but was particularly strong in HLA-B27-negative cases (odds ratio 7.8 in HLA-B27-negative cases), making it the strongest non-MHC association reported to date with AS.…”

Assessment of effectiveness of anakinra and canakinumab in patients with colchicine-resistant/unresponsive familial Mediterranean fever

“…In the same study, the serum level of IL-1 was higher in AS patients. Therefore, the researchers emphasized that anti-IL-1 treatments would be an appropriate therapy in these patients [17]. However, in our study, ten patients had axialspondyloarthritis (AxSpA), and only half of these subjects had proper anti-IL-1 treatment.…”

The Influence of Vitamin D Receptor Gene Polymorphisms in Spondyloarthritis

“…However, it does not completely explain the pathogenesis of the disease, when we consider that other genetic factors of susceptibility outside of the MHC have been uncovered. Most of them are defined through genome-wide association studies (GWAS) [ 8 – 11 ] and mainly include ERAP1, IL23R , and RUNX3 [ 11 ].…”