Genetic Association of a Gain‐of‐Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet’s Disease
- 18 May 2021
- journal article
- research article
- Published by Wiley in Arthritis & Rheumatology
- Vol. 73 (7), 1244-1252
- https://doi.org/10.1002/art.41637
Abstract
Objective Behçet’s disease is a complex systemic inflammatory vasculitis of incompletely understood etiology. We performed a large genetic study in Behçet’s disease in a diverse multi‐ethnic population. Methods A total of 9,444 patients and controls from seven different populations were included in this study. Genotyping was performed using the 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 two novel genetic susceptibility loci for Behçet’s disease, including a risk locus in IFNGR1 (rs4896243, p value= 2.42 X 10‐9; OR=1.25) and within the intergenic region LNCAROD/DKK1 (rs1660760, p value= 2.75 x 10‐8; OR= 0.78). The risk variants in IFNGR1 significantly increase IFNGR1 mRNA expression in lipopolysaccharide‐stimulated monocytes. In addition, our results replicated the association (p value< 5 x 10‐8) of six previously identified susceptibility loci in Behçet’s disease: IL10, IL23R, IL12A‐AS1, CCR3, ADO, and LACC1, reinforcing these loci as strong genetic factors in Behçet’s disease shared across ancestries. We also identified >30 genetic susceptibility loci with a suggestive level of association (p value< 5 x 10‐5), which will require replication. Finally, functional annotation of genetic susceptibility loci in Behçet’s disease uncovered 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 and revealed novel putative functional variants associated with the disease. We also replicate and extend the genetic associations in other loci across multiple ancestries.Keywords
Funding Information
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR070148)
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