Genetic Association of a Gain-of-Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet's Disease
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Genetic Association of a Gain-of-Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet's Disease. / Ortiz Fernández, Lourdes; Coit, Patrick; Yilmaz, Vuslat; Yentür, Sibel P; Alibaz-Oner, Fatma; Aksu, Kenan; Erken, Eren; Düzgün, Nursen; Keser, Gokhan; Cefle, Ayse; Yazici, Ayten; Ergen, Andac; Alpsoy, Erkan; Salvarani, Carlo; Casali, Bruno; Kısacık, Bünyamin; Kötter, Ina; Henes, Jörg; Çınar, Muhammet; Schaefer, Arne; Nohutcu, Rahime M; Zhernakova, Alexandra; Wijmenga, Cisca; Takeuchi, Fujio; Harihara, Shinji; Kaburaki, Toshikatsu; Messedi, Meriam; Song, Yeong-Wook; Kaşifoğlu, Timuçin; Carmona, F David; Guthridge, Joel M; James, Judith A; Martin, Javier; González Escribano, María Francisca; Saruhan-Direskeneli, Güher; Direskeneli, Haner; Sawalha, Amr H.
In: ARTHRITIS RHEUMATOL, Vol. 73, No. 7, 07.2021, p. 1244-1252.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Genetic Association of a Gain-of-Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet's Disease
AU - Ortiz Fernández, Lourdes
AU - Coit, Patrick
AU - Yilmaz, Vuslat
AU - Yentür, Sibel P
AU - Alibaz-Oner, Fatma
AU - Aksu, Kenan
AU - Erken, Eren
AU - Düzgün, Nursen
AU - Keser, Gokhan
AU - Cefle, Ayse
AU - Yazici, Ayten
AU - Ergen, Andac
AU - Alpsoy, Erkan
AU - Salvarani, Carlo
AU - Casali, Bruno
AU - Kısacık, Bünyamin
AU - Kötter, Ina
AU - Henes, Jörg
AU - Çınar, Muhammet
AU - Schaefer, Arne
AU - Nohutcu, Rahime M
AU - Zhernakova, Alexandra
AU - Wijmenga, Cisca
AU - Takeuchi, Fujio
AU - Harihara, Shinji
AU - Kaburaki, Toshikatsu
AU - Messedi, Meriam
AU - Song, Yeong-Wook
AU - Kaşifoğlu, Timuçin
AU - Carmona, F David
AU - Guthridge, Joel M
AU - James, Judith A
AU - Martin, Javier
AU - González Escribano, María Francisca
AU - Saruhan-Direskeneli, Güher
AU - Direskeneli, Haner
AU - Sawalha, Amr H
N1 - This article is protected by copyright. All rights reserved.
PY - 2021/7
Y1 - 2021/7
N2 - OBJECTIVE: 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.METHODS: 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.RESULTS: We identified 2 novel genetic susceptibility loci for Behçet's disease, including a risk locus in IFNGR1 (rs4896243) (odds ratio [OR] 1.25; P = 2.42 × 10 -9 ) and within the intergenic region LNCAROD/DKK1 (rs1660760) (OR 0.78; P = 2.75 × 10 -8 ). The risk variants in IFNGR1 significantly increased IFNGR1 messenger RNA expression in lipopolysaccharide-stimulated monocytes. In addition, our results replicated the association (P < 5 × 10 -8 ) of 6 previously identified susceptibility loci in Behçet's disease: IL10, IL23R, IL12A-AS1, CCR3, ADO, and LACC1, 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 (P < 5 × 10 -5 ), 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. CONCLUSION: 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.
AB - OBJECTIVE: 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.METHODS: 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.RESULTS: We identified 2 novel genetic susceptibility loci for Behçet's disease, including a risk locus in IFNGR1 (rs4896243) (odds ratio [OR] 1.25; P = 2.42 × 10 -9 ) and within the intergenic region LNCAROD/DKK1 (rs1660760) (OR 0.78; P = 2.75 × 10 -8 ). The risk variants in IFNGR1 significantly increased IFNGR1 messenger RNA expression in lipopolysaccharide-stimulated monocytes. In addition, our results replicated the association (P < 5 × 10 -8 ) of 6 previously identified susceptibility loci in Behçet's disease: IL10, IL23R, IL12A-AS1, CCR3, ADO, and LACC1, 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 (P < 5 × 10 -5 ), 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. CONCLUSION: 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.
KW - Behcet Syndrome/genetics
KW - Case-Control Studies
KW - Chromosomes, Human, Pair 10/genetics
KW - DNA, Intergenic/genetics
KW - Epigenesis, Genetic
KW - Female
KW - Gain of Function Mutation
KW - Gene Expression Regulation
KW - Genetic Predisposition to Disease
KW - Humans
KW - Intercellular Signaling Peptides and Proteins/genetics
KW - Lipopolysaccharides
KW - Male
KW - Monocytes/immunology
KW - Polymorphism, Single Nucleotide
KW - RNA, Long Noncoding/genetics
KW - RNA, Messenger/metabolism
KW - Receptors, Interferon/genetics
U2 - 10.1002/art.41637
DO - 10.1002/art.41637
M3 - SCORING: Journal article
C2 - 33393726
VL - 73
SP - 1244
EP - 1252
JO - ARTHRITIS RHEUMATOL
JF - ARTHRITIS RHEUMATOL
SN - 2326-5191
IS - 7
ER -