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

Basit Öğe Kaydı
dc.authoridKenar, Gokce/0000-0002-0485-1369
dc.authoridyarkan tuğsal, handan/0000-0003-0633-790X
dc.authoridAkkoc, Nurullah/0000-0002-3718-171X
dc.authoridBrown, Matthew A/0000-0003-0538-8211
dc.authoridOnen, Fatos/0000-0002-6341-2622
dc.authoridJamshidi, Ahmadreza/0000-0002-2554-0412
dc.authoridLi, Zhixiu/0000-0002-2924-9120
dc.authorwosidSolmaz, Dilek/B-1448-2016
dc.authorwosidLeo, Paul J/B-3470-2011
dc.authorwosidpehlivan, yavuz/AAG-8227-2021
dc.authorwosidLi, Zhixiu/AAK-4021-2021
dc.authorwosidKenar, Gokce/AAG-3961-2019
dc.authorwosidOnen, Fatos/AAA-8970-2021
dc.authorwosidYuce, Zeynep/JDW-8153-2023
dc.contributor.authorLi, Zhixiu
dc.contributor.authorAkar, Servet
dc.contributor.authorYarkan, Handan
dc.contributor.authorLee, Sau Kuen
dc.contributor.authorCetin, Pinar
dc.contributor.authorCan, Gercek
dc.contributor.authorKenar, Gokce
dc.date.accessioned2024-06-12T11:19:11Z
dc.date.available2024-06-12T11:19:11Z
dc.date.issued2019
dc.departmentTrakya Üniversitesien_US
dc.description.abstractAnkylosing 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-1, 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 = 7.63x10(-12)), Iranian cohort (OR = 2.9, P = 0.042), and combined dataset (OR = 5.1, P = 1.65x10(-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 = 8.93x10(-15)), but also positive in HLA-B27-positive cases (OR = 4.3, P = 7.69x10(-8)). Serum IL-1, IL-17 and IL-23 levels were higher in AS cases than controls. Among AS cases, serum IL-1 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-1 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-1, IL-17 and IL-23 levels were higher in AS cases. Furthermore, among AS cases, IL-1 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.en_US
dc.description.sponsorshipPfizer Inc.; National Health and Medical Research Council (Australia)en_US
dc.description.sponsorshipFunding was received for this study from Pfizer Inc. MAB was funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en_US
dc.identifier.doi10.1371/journal.pgen.1008038
dc.identifier.issn1553-7404
dc.identifier.issue4en_US
dc.identifier.pmid30946743en_US
dc.identifier.scopus2-s2.0-85064997427en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1371/journal.pgen.1008038
dc.identifier.urihttps://hdl.handle.net/20.500.14551/25095
dc.identifier.volume15en_US
dc.identifier.wosWOS:000466866000015en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherPublic Library Scienceen_US
dc.relation.ispartofPlos Geneticsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectInflammatory-Bowel-Diseaseen_US
dc.subjectSeronegative Spondyloarthropathyen_US
dc.subjectTnf-Alphaen_US
dc.subjectIl-1-Betaen_US
dc.subjectMutationsen_US
dc.subjectAutophagyen_US
dc.subjectAnakinraen_US
dc.subjectProteinen_US
dc.subjectPyrinen_US
dc.subjectInterleukin-1-Betaen_US
dc.titleGenome-wide association study in Turkish and Iranian populations identify rare familial Mediterranean fever gene (MEFV) polymorphisms associated with ankylosing spondylitisen_US
dc.typeArticleen_US

Dosyalar

Koleksiyon

WoS İndeksli Yayınlar Koleksiyonu
PubMed İndeksli Yayınlar Koleksiyonu
Scopus İndeksli Yayınlar Koleksiyonu