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Genetic Association of a Gain‐of‐Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet’s Disease
Author(s) -
Ortiz Fernández Lourdes,
Coit Patrick,
Yilmaz Vuslat,
Yentür Sibel P.,
AlibazOner 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 YeongWook,
Kaşifoğlu Timuçin,
Carmona F. David,
Guthridge Joel M.,
James Judith A.,
Martin Javier,
González Escribano María Francisca,
SaruhanDireskeneli Güher,
Direskeneli Haner,
Sawalha Amr H.
Publication year - 2021
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41637
Subject(s) - genetics , biology , genome wide association study , behcet's disease , single nucleotide polymorphism , genetic association , genetic predisposition , genotype , disease , gene , medicine , pathology
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.