Genetic Association of a Gain‐of‐Function <i>IFNGR1</i> Polymorphism and the Intergenic Region <i>LNCAROD/DKK1</i> With Behçet’s Disease
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- Lourdes Ortiz Fernández
- University of Pittsburgh Pittsburgh Pennsylvania
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- Patrick Coit
- University of Pittsburgh Pittsburgh Pennsylvania
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- Vuslat Yilmaz
- Istanbul University Istanbul Turkey
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- Sibel P. Yentür
- Istanbul University Istanbul Turkey
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- Fatma Alibaz‐Oner
- Marmara University School of Medicine Istanbul Turkey
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- Kenan Aksu
- Ege University School of Medicine Izmir Turkey
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- Eren Erken
- Cukurova University School of Medicine Adana Turkey
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- Nursen Düzgün
- Ankara University School of Medicine Ankara Turkey
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- Gokhan Keser
- Ege University School of Medicine Izmir Turkey
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- Ayse Cefle
- Kocaeli University School of Medicine Kocaeli Turkey
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- Ayten Yazici
- Kocaeli University School of Medicine Kocaeli Turkey
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- Andac Ergen
- Okmeydanı Research and Education Hospital Istanbul Turkey
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- Erkan Alpsoy
- Akdeniz University School of Medicine Antalya Turkey
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- Carlo Salvarani
- Azienda USL‐IRCCS di Reggio Emilia and Università di Modena e Reggio Emilia Modena Italy
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- Bruno Casali
- Azienda Ospedaliera Arcispedale Santa Maria Nuova‐IRCCS di Reggio Emilia Reggio Emilia Italy
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- Bünyamin Kısacık
- Gaziantep University Gaziantep Turkey
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- Ina Kötter
- University Medical Center Hamburg‐Eppendorf Hamburg Germany
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- Jörg Henes
- University Hospital Tuebingen Tuebingen Germany
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- Muhammet Çınar
- University of Health Sciences Turkey Ankara Turkey
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- Arne Schaefer
- Charité University Medicine Berlin Germany
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- Rahime M. Nohutcu
- Hacettepe University Sihhiye Ankara Turkey
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- Alexandra Zhernakova
- University of Groningen and University Medical Center Groningen Groningen The Netherlands
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- Cisca Wijmenga
- University of Groningen and University Medical Center Groningen Groningen The Netherlands
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- Fujio Takeuchi
- Tokyo Seiei University Tokyo Japan
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- Shinji Harihara
- University of Tokyo Graduate School of Science Tokyo Japan
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- Toshikatsu Kaburaki
- Jichi Medical University Saitama Medical Center Saitama Japan
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- Meriam Messedi
- Research Laboratory of Molecular Bases of Human Diseases 12ES17 and University of Sfax Sfax Tunisia
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- Yeong‐Wook Song
- Seoul National University College of Medicine Seoul Republic of Korea
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- Timuçin Kaşifoğlu
- Eskisehir Osmangazi University School of Medicine Eskisehir Turkey
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- F. David Carmona
- Universidad de Granada and ibs.GRANADA Instituto de Investigación Biosanitaria Granada Spain
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- Joel M. Guthridge
- Oklahoma Medical Research Foundation Oklahoma City
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- Judith A. James
- Oklahoma Medical Research Foundation Oklahoma City
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- Javier Martin
- Instituto de Parasitología y Biomedicina ‘López‐Neyra’ Granada Spain
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- María Francisca González Escribano
- Instituto de Biomedicine de Sevilla Hospital Universitario Virgen del Rocío CSIC Universidad de Sevilla Seville Spain
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- Güher Saruhan‐Direskeneli
- Istanbul University Istanbul Turkey
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- Haner Direskeneli
- Marmara University School of Medicine Istanbul Turkey
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- Amr H. Sawalha
- University of Pittsburgh Pittsburgh Pennsylvania
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説明
<jats:sec><jats:title>Objective</jats:title><jats:p>Behçet’s disease is a complex systemic inflammatory vasculitis of incompletely understood etiology. This study was undertaken to investigate genetic associations with Behçet’s disease in a diverse multiethnic population.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A total of 9,444 patients and controls from 7 different populations were included in this study. Genotyping was performed using an Infinium ImmunoArray‐24 v.1.0 or v.2.0 BeadChip. Analysis of expression data from stimulated monocytes, and epigenetic and chromatin interaction analyses were performed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We identified 2 novel genetic susceptibility loci for Behçet’s disease, including a risk locus in <jats:italic>IFNGR1</jats:italic> (rs4896243) (odds ratio [OR] 1.25; <jats:italic>P</jats:italic> = 2.42 × 10<jats:sup>−9</jats:sup>) and within the intergenic region <jats:italic>LNCAROD/DKK1</jats:italic> (rs1660760) (OR 0.78; <jats:italic>P</jats:italic> = 2.75 × 10<jats:sup>−8</jats:sup>). The risk variants in <jats:italic>IFNGR1</jats:italic> significantly increased <jats:italic>IFNGR1</jats:italic> messenger RNA expression in lipopolysaccharide‐stimulated monocytes. In addition, our results replicated the association (<jats:italic>P</jats:italic> < 5 × 10<jats:sup>−8</jats:sup>) of 6 previously identified susceptibility loci in Behçet’s disease: <jats:italic>IL10</jats:italic>, <jats:italic>IL23R</jats:italic>, <jats:italic>IL12A‐AS1</jats:italic>, <jats:italic>CCR3</jats:italic>, <jats:italic>ADO</jats:italic>, and <jats:italic>LACC1</jats:italic>, reinforcing the notion that these loci are strong genetic factors in Behçet’s disease shared across ancestries. We also identified >30 genetic susceptibility loci with a suggestive level of association (<jats:italic>P</jats:italic> < 5 × 10<jats:sup>−5</jats:sup>), which will require replication. Finally, functional annotation of genetic susceptibility loci in Behçet’s disease revealed their possible regulatory roles and suggested potential causal genes and molecular mechanisms that could be further investigated.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>We performed the largest genetic association study in Behçet’s disease to date. Our findings reveal novel putative functional variants associated with the disease and replicate and extend the genetic associations in other loci across multiple ancestries.</jats:p></jats:sec>
収録刊行物
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- Arthritis & Rheumatology
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Arthritis & Rheumatology 73 (7), 1244-1252, 2021-05-18
Wiley
- Tweet
キーワード
- Lipopolysaccharides
- Male
- Identification
- SUSCEPTIBILITY LOCI
- 610
- VARIANTS
- Polymorphism, Single Nucleotide
- Monocytes
- Epigenesis, Genetic
- Genome-Wide Association
- Susceptibility Loci
- BINDING
- Humans
- Genetic Predisposition to Disease
- RNA, Messenger
- GENOME-WIDE ASSOCIATION
- Components
- Mhc Class-I
- Receptors, Interferon
- Interferon gamma Receptor
- INTERFERON-GAMMA
- IDENTIFICATION
- Chromosomes, Human, Pair 10
- Behcet Syndrome
- COMPONENTS
- Variants
- Promoter
- Binding
- MHC CLASS-I
- IL23R-IL12RB2
- Il23r-Il12rb2
- STATES
- Gene Expression Regulation
- Case-Control Studies
- Gain of Function Mutation
- Intercellular Signaling Peptides and Proteins
- DNA, Intergenic
- Female
- RNA, Long Noncoding
- Interferon-Gamma
詳細情報 詳細情報について
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- CRID
- 1360013168881342336
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- ISSN
- 23265205
- 23265191
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- PubMed
- 33393726
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- 資料種別
- journal article
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- データソース種別
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- Crossref
- KAKEN
- OpenAIRE