Browsing by Author "Mahmoudi M."

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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
    (Public Library of Science, 2019) Li Z.; Akar S.; Yarkan H.; Lee S.K.; Çetin P.; Can G.; Kenar G.; Çapa F.; Pamuk O.N.; Pehlivan Y.; Cremin K.; de Guzman E.; Harris J.; Wheeler L.; Jamshidi A.; Vojdanian M.; Farhadi E.; Ahmadzadeh N.; Yüce Z.; Dalkılıç E.; Solmaz D.; Akın B.; Dönmez S.; Sarı İ.; Leo P.J.; Kenna T.J.; Önen F.; Mahmoudi M.; Brown M.A.; Akkoc N.
    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. © 2019 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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    Polygenic Risk Scores have high diagnostic capacity in ankylosing spondylitis
    (BMJ Publishing Group, 2021) Li Z.; Wu X.; Leo P.J.; De Guzman E.; Akkoc N.; Breban M.; MacFarlane G.J.; Mahmoudi M.; Marzo-Ortega H.; Anderson L.K.; Wheeler L.; Chou C.-T.; Harrison A.A.; Stebbings S.; Jones G.T.; Bang S.-Y.; Wang G.; Jamshidi A.; Farhadi E.; Song J.; Lin L.; Li M.; Wei J.C.-C.; Martin N.G.; Wright M.J.; Lee M.; Wang Y.; Zhan J.; Zhang J.-S.; Wang X.; Jin Z.-B.; Weisman M.H.; Gensler L.S.; Ward M.M.; Rahbar M.H.; Diekman L.; Kim T.-H.; Reveille J.D.; Wordsworth B.P.; Xu H.; Brown M.A.
    Objective We sought to test the hypothesis that Polygenic Risk Scores (PRSs) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain. Methods PRSs were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15 585 AS cases and 20 452 controls. The discriminatory values of PRSs in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), HLA-B27 and sacroiliac MRI. Results In people of European descent, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for HLA-B27 testing alone (AUC=0.869), MRI (AUC=0.885) or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain under 45 years of age, compared with HLA-B27 testing alone, PRS provides higher positive values for 35% of patients and negative predictive values for 67.5% of patients. For PRS, in people of European descent, the maximum positive predictive value was 78.2% and negative predictive value was 100%, whereas for HLA-B27, these values were 51.9% and 97.9%, respectively. Conclusions PRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI or HLA-B27 status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.