Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility

Abstract

BackgroundJuvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children, the etiology of which involves a strong genetic component, but much of the underlying genetic determinants still remain unknown. Our aim was to identify novel genetic variants that predispose to JIA.MethodsWe performed a genome-wide association study (GWAS) and replication in a total of 1166 JIA cases and 9500 unrelated controls of European ancestry. Correlation of SNP genotype and gene expression was investigated. Then we conducted targeted resequencing of a candidate locus, among a subset of 480 cases and 480 controls. SUM test was performed to evaluate the association of the identified rare functional variants.ResultsThe CXCR4 locus on 2q22.1 was found to be significantly associated with JIA, peaking at SNP rs953387. However, this result is subjected to subpopulation stratification within the subjects of European ancestry. After adjusting for principal components, nominal significant association remained (p < 10−4). Because of its interesting known function in immune regulation, we carried out further analyses to assess its relationship with JIA. Expression of CXCR4 was correlated with CXCR4 rs953387 genotypes in lymphoblastoid cell lines (p = 0.014) and T-cells (p = 0.0054). In addition, rare non-synonymous and stop-gain sequence variants in CXCR4, putatively damaging for CXCR4 function, were significantly enriched in JIA cases (p = 0.015).ConclusionOur results suggest the association of CXCR4 variants with JIA, implicating that this gene may be involved in the pathogenesis of autoimmune disease. However, because this locus is subjected to population stratification within the subjects of European ancestry, additional replication is still necessary for this locus to be considered a true risk locus for JIA. This cell-surface chemokine receptor has already been targeted in other diseases and may serve as a tractable therapeutic target for a specific subset of pediatric arthritis patients with additional replication and functional validation of the locus.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-016-0285-3) contains supplementary material, which is available to authorized users.

Genomic risk scores for juvenile idiopathic arthritis and its subtypes

“…For the CHOP cohort 18,39 , the clinical data of JIA cases were collected from the electronic health records (EHR) completed by the pediatric rheumatology specialist within the Division of Rheumatology at CHOP and abstracted into a JIA Registry maintained within the Center for Applied Genomics (CAG) at CHOP. Control subjects were unrelated and disease-free children recruited by the CAG recruitment team within the CHOP Healthcare Network.…”

Peer Review #2 of "Genetic architecture study of rheumatoid arthritis and juvenile idiopathic arthritis (v0.2)"

“…JIA genetic loci information came from two resources. First, summary statistics of our previous GWAS on JIA (Finkel et al 2016) was included in the current study. Our JIA GWAS is composed of discovery and replication cohorts with 1166 JIA cases and 9500 unrelated controls of European ancestry totally.…”

“…Summary statistics of meta-analysis on the discovery and replication cohorts were used in our current study. Second, JIA variants revealed in published GWASs (Behrens et al 2008;Cobb et al 2014;Finkel et al 2016;Hinks et al 2009;Hinks et al 2013;Li et al 2015a;Ombrello et al 2017;Thompson et al 2012) were extracted from GWAS catalog (Buniello et al 2019).…”

Genetic aspects of idiopathic paediatric uveitis and juvenile idiopathic arthritis associated uveitis in Chinese Han

“…The r 2 value for linkage disequilibrium had to be less than 0.8 between adjacent loci and the minor allele frequency had to be larger than 0.05 in the CHB. Based on the above criteria, we finally included 84 SNPs in or near 60 loci: ANTXR2, 18 CXCR4, 18 CD226, 19 TNFA, 19 MIF, 19 CD28, 19 KIAA1109, 19 PSMC6, 20 PSMA3, 20 STAT4, 21 24 IL20, 24 CDGAP/ARHGAP31, 25 C3orf1/ TIMMDC1, 25 IL15, 25 NRBF2-EGR2, 25 JMJD1C, 25 REEP3, 25 IGF1R-FAM169B, 25 CHD9-TOX3, 25 IRF5, 26 BLK, 27 C5orf30, 27 CD247, 27 ORMDL3, 27 PTPRC, 27 ERAP1, 28 LPP, 29 TRAF1/C5, 30 IL2RA, 31 Intergenic, 31 32 The selected SNPs were genotyped by MassARRAY platform (Sequenom, San Diego, California, USA) and iPLEX Gold Genotyping Assay, and analysed by TYPER software V.4.0. The PCR was performed with the GeneAmp PCR System 9700 thermocycler (ABI, Foster City, California, USA).…”