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

被引:42
作者
Li, Zhixiu [1 ]
Akar, Servet [2 ]
Yarkan, Handan [3 ]
Lee, Sau Kuen [1 ]
Cetin, Pinar [3 ]
Can, Gercek [3 ]
Kenar, Gokce [3 ]
Capa, Femur [4 ]
Pamuk, Omer Nuri [5 ]
Pehlivan, Yavuz [6 ]
Cremin, Katie [7 ]
De Guzman, Erika [1 ]
Harris, Jessica [1 ]
Wheeler, Lawrie [1 ]
Jamshidi, Ahmadreza [8 ]
Vojdanian, Mahdi [8 ]
Farhadi, Elham [8 ]
Ahmadzadeh, Nooshin [8 ]
Yuce, Zeynep [4 ]
Dalkilic, Ediz [6 ]
Solmaz, Dilek [2 ]
Akin, Berrin [3 ]
Donmez, Salim [5 ]
Sari, Ismail [3 ]
Leo, Paul J. [1 ]
Kenna, Tony J. [1 ]
Onen, Fatos [3 ]
Mahmoudi, Mahdi [8 ]
Brown, Matthew A. [1 ]
Akkoc, Nurullah [9 ]
机构
[1] Queensland Univ Technol, Translat Res Inst, Princess Alexandra Hosp, Translat Genom Grp,Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia
[2] Izmir Katip Celebi Univ, Dept Internal Med, Div Rheumatol, Sch Med, Izmir, Turkey
[3] Dokuz Eylul Univ, Fac Med, Div Rheumatol, Dept Internal Med, Izmir, Turkey
[4] Dokuz Eylul Univ, Dept Mol Med, Hlth Sci Inst, Izmir, Turkey
[5] Trakya Univ, Dept Internal Med, Div Rheumatol, Med Fac, Edirne, Turkey
[6] Uludag Univ, Sch Med, Dept Rheumatol, Bursa, Turkey
[7] Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia
[8] Univ Tehran Med Sci, Rheumatol Res Ctr, Tehran, Iran
[9] Celal Bayar Univ, Dept Internal Med, Div Rheumatol, Manisa, Turkey
基金
英国医学研究理事会;
关键词
INFLAMMATORY-BOWEL-DISEASE; SERONEGATIVE SPONDYLOARTHROPATHY; TNF-ALPHA; IL-1-BETA; MUTATIONS; AUTOPHAGY; ANAKINRA; PROTEIN; PYRIN; INTERLEUKIN-1-BETA;
D O I
10.1371/journal.pgen.1008038
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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-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.
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页数:18
相关论文
共 54 条
[1]   High prevalence of spondyloarthritis and ankylosing spondylitis among familial Mediterranean fever patients and their first-degree relatives: further evidence for the connection [J].
Akar, Servet ;
Soysal, Ozgul ;
Balci, Ali ;
Solmaz, Dilek ;
Gerdan, Vedat ;
Onen, Fatos ;
Tunca, Mehmet ;
Akkoc, Nurullah .
ARTHRITIS RESEARCH & THERAPY, 2013, 15 (01)
[2]   Familial Mediterranean Fever and Seronegative Arthritis [J].
Akkoc, Nurullah ;
Gul, Ahmet .
CURRENT RHEUMATOLOGY REPORTS, 2011, 13 (05) :388-394
[3]   Increased Prevalence of M694V in Patients With Ankylosing Spondylitis Additional Evidence for a Link With Familial Mediterranean Fever [J].
Akkoc, Nurullah ;
Sari, Ismail ;
Akar, Servet ;
Binicier, Omer ;
Thomas, Mark G. ;
Weale, Michael E. ;
Birlik, Merih ;
Savran, Yusuf ;
Onen, Fatos ;
Bradman, Neil ;
Plaster, Christopher A. .
ARTHRITIS AND RHEUMATISM, 2010, 62 (10) :3059-3063
[4]   Comment on the article by Durmus et al. "Clinical significance of MEFV mutations in ankylosing spondylitis" [J].
Akkoc, Nurullah ;
Gul, Ahmet .
JOINT BONE SPINE, 2010, 77 (03) :281-281
[5]   Association of the MEFV Gene Variations With Inflammatory Bowel Disease in Turkey [J].
Akyuz, Filiz ;
Besisik, Fatih ;
Ustek, Duran ;
Ekmekci, Cumhur ;
Uyar, Aytul ;
Pinarbasi, Binnur ;
Demir, Kadir ;
Ozdil, Sadakat ;
Kaymakoglu, Sabahattin ;
Boztas, Gungor ;
Mungan, Zeynel ;
Gul, Ahmet .
JOURNAL OF CLINICAL GASTROENTEROLOGY, 2013, 47 (03) :E23-E27
[6]   Pathogenesis of spondyloarthritis: autoimmune or autoinflammatory? [J].
Ambarus, Carmen ;
Yeremenko, Nataliya ;
Tak, Paul P. ;
Baeten, Dominique .
CURRENT OPINION IN RHEUMATOLOGY, 2012, 24 (04) :351-358
[7]  
[Anonymous], 2003, CLIN EXP RHEUMATOL, V21, pS49
[8]   Comparison of serum IL-1β, sIL-2R, IL-6, and TNF-α levels with disease activity parameters in ankylosing spondylitis [J].
Bal, A. ;
Unlu, E. ;
Bahar, G. ;
Aydog, E. ;
Eksioglu, E. ;
Yorgancioglu, R. .
CLINICAL RHEUMATOLOGY, 2007, 26 (02) :211-215
[9]   Sacroiliitis in familial Mediterranean fever and seronegative spondyloarthropathy: importance of differential diagnosis [J].
Balaban, B ;
Yasar, E ;
Ozgul, A ;
Dincer, K ;
Kalyon, TA .
RHEUMATOLOGY INTERNATIONAL, 2005, 25 (08) :641-644
[10]   HLA class I associations of ankylosing spondylitis in the white population in the united Kingdom [J].
Brown, MA ;
Pile, KD ;
Kennedy, LG ;
Calin, A ;
Darke, C ;
Bell, J ;
Wordsworth, BP ;
Cornelis, F .
ANNALS OF THE RHEUMATIC DISEASES, 1996, 55 (04) :268-270