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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. [ABSTRACT FROM AUTHOR]

Ankylosing Spondylitis (AS) is a chronic rheumatic disease which mainly involves the axial skeleton. It seems that non-HLA genes, as well as HLA-B27 gene, are linked to the etiology of the disease. Recently, it has been documented that KIRs and their HLA ligands are contributed to the Ankylosing Spondylitis. The aim of this study was to evaluate the KIR genes and their HLA ligands in Iranian AS patients and healthy individuals. The present study includes 200 AS patient samples and 200 healthy control samples. KIR genotyping was performed using the polymerase chain reaction sequence-specific primer (PCR-SSP) method to type the presence or absence of the 16 KIR genes, 6 known specific HLA class I ligands and also, two pseudogenes. Two KIR genes (KIR-2DL3 and KIR2DL5), and among the HLA ligands, two HLA ligands (HLA-C2Lys80 and HLA-B27) genes were significantly different between case and control groups. In addition, we found some interesting KIR/HLA compound genotypes, which were associated with AS susceptibility. Our results suggest that the AS patients present more activating and less inhibitory KIR genes with combination of their HLA ligands than healthy controls. Once the balance of signal transduction between activating and inhibitory receptors is disturbed, the ability of NK cells to identify and lyse the targets in immune responses will be compromised. Accordingly, imbalance of activating and inhibitory KIR genes by up-regulating the activation and losing the inhibition of KIRs signaling or combination of both might be one of the important factors which underlying the pathogenesis of AS. [ABSTRACT FROM AUTHOR]

Background: Ankylosing Spondylitis (AS) is a chronic autoinflammatory Spondyloarthropathy (SpA) which is characterized by sacroiliitis, which progresses to the axial skeleton. It seems that non-Human Leukocyte Antigen (HLA) and also HLA-B27 are associated with the susceptibility and pathogenesis of the disease. The recent Genome-Wide Association Studies (GWASs) have reported intergenic rs6759298 to be associated with AS etiology. The aim of this study was investigation of the rs6759298 polymorphism in Iranian AS patients. In addition, probable correlations with clinical indices and manifestations were considered. Methods: This study included 403 patients with AS. The control group consisted of 506 healthy individuals who were matched for sex, age, and ethnicity with AS group. Genotyping of rs6759298 was determined using the Amplification-Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR). Results: The GG genotype and G allele were found to be significantly more prevalent in the patient group in comparison to the control group [(p=2x10-6 and 7.44x10-9; OR (95% CI) =2.16 (1.56-2.98) and 1.73 (1.43-2.08)], respectively. Conclusion: No associations were found between patients with three genotypes and any disease manifestations or clinical indices. This investigation confirmed a highly significant association of rs6759298 with disease susceptibility, with no effect on disease progress or clinical presentations. Since rs6759298 belongs to the 2p15 gene desert, further studies would elucidate the exact role of this polymorphism in the pathogenesis of AS. [ABSTRACT FROM AUTHOR]