Genetic Association of a Gain-of-Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet's Disease

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 -