Association analysis of juvenile idiopathic arthritis genetic susceptibility factors in Estonian patients

Abstract

Background Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition of childhood. Genetic association studies have revealed several JIA susceptibility loci with the strongest effect size observed in the human leukocyte antigen (HLA) region. Genome-wide association studies have augmented the number of JIA-associated loci, particularly for non-HLA genes. The aim of this study was to identify new associations at non-HLA loci predisposing to the risk of JIA development in Estonian patients. Methods We performed genome-wide association analyses in an entire JIA case–control sample (All-JIA) and in a case–control sample for oligoarticular JIA, the most prevalent JIA subtype. The entire cohort was genotyped using the Illumina HumanOmniExpress BeadChip arrays. After imputation, 16,583,468 variants were analyzed in 263 cases and 6956 controls. Results We demonstrated nominal evidence of association for 12 novel non-HLA loci not previously implicated in JIA predisposition. We replicated known JIA associations in CLEC16A and VCTN1 regions in the oligoarticular JIA sample. The strongest associations in the All-JIA analysis were identified at PRKG1 (P = 2,54 × 10−6), LTBP1 (P = 9,45 × 10−6), and ELMO1 (P = 1,05 × 10−5). In the oligoarticular JIA analysis, the strongest associations were identified at NFIA (P = 5,05 × 10−6), LTBP1 (P = 9,95 × 10−6), MX1 (P = 1,65 × 10−5), and CD200R1 (P = 2,59 × 10−5). Conclusion This study increases the number of known JIA risk loci and provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis. The reported loci are involved in molecular pathways of immunological relevance and likely represent genomic regions that confer susceptibility to JIA in Estonian patients. Key Points• Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease with heterogeneous presentation and genetic predisposition.• Present genome-wide association study for Estonian JIA patients is first of its kind in Northern and Northeastern Europe.• The results of the present study increase the knowledge about JIA risk loci replicating some previously described associations, so adding weight to their relevance and describing novel loci.• The study provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis.

Gene Signature of Regulatory T Cells Isolated from Children with Selective IgA Deficiency and Common Variable Immunodeficiency

“…dermatomyositis [47], systemic lupus erythematosus [48], Sjögren syndrome [49], juvenile idiopathic arthritis [50], type 1 diabetes [51], mixed connective tissue disease [52],…”

Genetic Background and Molecular Mechanisms of Juvenile Idiopathic Arthritis

“…Although a huge number of non-HLA candidate genes had been investigated in the past for associations with JIA, only a restricted number of associations were identified. Recently, GWASs have led to a better understanding of many novel non-HLA loci associated with JIA [81][82][83][84]. Moreover, many environmental factors have been widely studied, with unclear conclusions.…”

“…These data have been assessed by using a large variety of different genetic techniques, including the unbiased approach of GWAS and candidate gene approaches. The most important non-HLA genes that have been associated with JIA susceptibility are listed in Table S1 [81][82][83][84]87,90,102,104,105]. Many of these genes are widely expressed in haematopoietic tissues, including neutrophils and monocytes, and generally involved in T cell regulation and modulation, underlying once again the central role of both innate immune responses and adaptive immunity, through the modulation of many proinflammatory cytokines, including TNFα, highlighting interactions with each other in JIA pathophysiology [90].…”

Identification of candidate genes and pathways associated with juvenile idiopathic arthritis by integrative transcriptome-wide association studies and mRNA expression profiles

“…Juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by chronic inflammation of the joints, encompassing all forms of chronic inflammatory arthritis of unknown causes and having an onset before the age of 16 years [ 1 ]. The reported prevalence varies between 16 and 150 per 100,000 individuals [ 2 ].…”