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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

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 candidat...

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Autores principales: Li, Zhixiu, Akar, Servet, Yarkan, Handan, Lee, Sau Kuen, Çetin, Pınar, Can, Gerçek, Kenar, Gökce, Çapa, Fernur, Pamuk, Omer Nuri, Pehlivan, Yavuz, Cremin, Katie, De Guzman, Erika, Harris, Jessica, Wheeler, Lawrie, Jamshidi, Ahmadreza, Vojdanian, Mahdi, Farhadi, Elham, Ahmadzadeh, Nooshin, Yüce, Zeynep, Dalkılıç, Ediz, Solmaz, Dilek, Akın, Berrin, Dönmez, Salim, Sarı, İsmail, Leo, Paul J., Kenna, Tony J., Önen, Fatos, Mahmoudi, Mahdi, Brown, Matthew A., Akkoc, Nurullah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467421/
https://www.ncbi.nlm.nih.gov/pubmed/30946743
http://dx.doi.org/10.1371/journal.pgen.1008038
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author Li, Zhixiu
Akar, Servet
Yarkan, Handan
Lee, Sau Kuen
Çetin, Pınar
Can, Gerçek
Kenar, Gökce
Çapa, Fernur
Pamuk, Omer Nuri
Pehlivan, Yavuz
Cremin, Katie
De Guzman, Erika
Harris, Jessica
Wheeler, Lawrie
Jamshidi, Ahmadreza
Vojdanian, Mahdi
Farhadi, Elham
Ahmadzadeh, Nooshin
Yüce, Zeynep
Dalkılıç, Ediz
Solmaz, Dilek
Akın, Berrin
Dönmez, Salim
Sarı, İsmail
Leo, Paul J.
Kenna, Tony J.
Önen, Fatos
Mahmoudi, Mahdi
Brown, Matthew A.
Akkoc, Nurullah
author_facet Li, Zhixiu
Akar, Servet
Yarkan, Handan
Lee, Sau Kuen
Çetin, Pınar
Can, Gerçek
Kenar, Gökce
Çapa, Fernur
Pamuk, Omer Nuri
Pehlivan, Yavuz
Cremin, Katie
De Guzman, Erika
Harris, Jessica
Wheeler, Lawrie
Jamshidi, Ahmadreza
Vojdanian, Mahdi
Farhadi, Elham
Ahmadzadeh, Nooshin
Yüce, Zeynep
Dalkılıç, Ediz
Solmaz, Dilek
Akın, Berrin
Dönmez, Salim
Sarı, İsmail
Leo, Paul J.
Kenna, Tony J.
Önen, Fatos
Mahmoudi, Mahdi
Brown, Matthew A.
Akkoc, Nurullah
author_sort Li, Zhixiu
collection PubMed
description 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.
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spelling pubmed-64674212019-05-03 Genome-wide association study in Turkish and Iranian populations identify rare familial Mediterranean fever gene (MEFV) polymorphisms associated with ankylosing spondylitis Li, Zhixiu Akar, Servet Yarkan, Handan Lee, Sau Kuen Çetin, Pınar Can, Gerçek Kenar, Gökce Çapa, Fernur Pamuk, Omer Nuri Pehlivan, Yavuz Cremin, Katie De Guzman, Erika Harris, Jessica Wheeler, Lawrie Jamshidi, Ahmadreza Vojdanian, Mahdi Farhadi, Elham Ahmadzadeh, Nooshin Yüce, Zeynep Dalkılıç, Ediz Solmaz, Dilek Akın, Berrin Dönmez, Salim Sarı, İsmail Leo, Paul J. Kenna, Tony J. Önen, Fatos Mahmoudi, Mahdi Brown, Matthew A. Akkoc, Nurullah PLoS Genet Research Article 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. Public Library of Science 2019-04-04 /pmc/articles/PMC6467421/ /pubmed/30946743 http://dx.doi.org/10.1371/journal.pgen.1008038 Text en © 2019 Li et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Li, Zhixiu
Akar, Servet
Yarkan, Handan
Lee, Sau Kuen
Çetin, Pınar
Can, Gerçek
Kenar, Gökce
Çapa, Fernur
Pamuk, Omer Nuri
Pehlivan, Yavuz
Cremin, Katie
De Guzman, Erika
Harris, Jessica
Wheeler, Lawrie
Jamshidi, Ahmadreza
Vojdanian, Mahdi
Farhadi, Elham
Ahmadzadeh, Nooshin
Yüce, Zeynep
Dalkılıç, Ediz
Solmaz, Dilek
Akın, Berrin
Dönmez, Salim
Sarı, İsmail
Leo, Paul J.
Kenna, Tony J.
Önen, Fatos
Mahmoudi, Mahdi
Brown, Matthew A.
Akkoc, Nurullah
Genome-wide association study in Turkish and Iranian populations identify rare familial Mediterranean fever gene (MEFV) polymorphisms associated with ankylosing spondylitis
title Genome-wide association study in Turkish and Iranian populations identify rare familial Mediterranean fever gene (MEFV) polymorphisms associated with ankylosing spondylitis
title_full Genome-wide association study in Turkish and Iranian populations identify rare familial Mediterranean fever gene (MEFV) polymorphisms associated with ankylosing spondylitis
title_fullStr Genome-wide association study in Turkish and Iranian populations identify rare familial Mediterranean fever gene (MEFV) polymorphisms associated with ankylosing spondylitis
title_full_unstemmed Genome-wide association study in Turkish and Iranian populations identify rare familial Mediterranean fever gene (MEFV) polymorphisms associated with ankylosing spondylitis
title_short Genome-wide association study in Turkish and Iranian populations identify rare familial Mediterranean fever gene (MEFV) polymorphisms associated with ankylosing spondylitis
title_sort genome-wide association study in turkish and iranian populations identify rare familial mediterranean fever gene (mefv) polymorphisms associated with ankylosing spondylitis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467421/
https://www.ncbi.nlm.nih.gov/pubmed/30946743
http://dx.doi.org/10.1371/journal.pgen.1008038
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