Genetics and pathophysiology of systemic juvenile idiopathic arthritis and other complex autoinflammatory diseases

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications & trials

Abstract

1. Investigation of systemic arthritis in populations To investigate the genetic susceptibility of sJIA on the population level, we established the International Childhood Arthritis Genetics (INCHARGE) Consortium. Working with this worldwide network of collaborators, we assembled a collection of DNA specimens from over 1000 children with sJIA from North America, South America and Europe. Using this collection, we generated a dataset of over 6.7 million common genetic markers or single nucleotide polymorphisms (SNPs) across the entire genome. When combined with genome-wide SNP data from a collection of 8010 geographically matched control subjects, this case-control collection became the basis for the first genome-wide association study (GWAS) and a series of related genomic investigations of sJIA. In our first study, we discovered that a class II human leukocyte antigen (HLA) region haplotype that encodes the HLA-DRB1*11 allele was the strongest genetic risk factor for sJIA (odds ratio 2.6). The class II HLA proteins encoded by this locus are essential elements of the adaptive immune system that initiate antigen-specific responses. We next identified a strong sJIA susceptibility locus within an intergenic region of chromosome 1, where a group of SNPs were associated with an increased risk of developing sJIA (odds ratio 2.4). Moving beyond singular genetic associations, we used the sJIA GWAS dataset to perform a formal comparison of the genetic architecture of sJIA with those of the other forms of JIA. In doing so, we unambiguously revealed the unique genetic architecture of sJIA, distinct from all the other JIA subtypes. Based on this observation, we strongly advocate for the removal of systemic arthritis from future classification schemes of childhood arthritis. We also used the INCHARGE dataset to examine sJIA candidate susceptibility loci that had been reported prior to the GWAS era. This identified a single association between sJIA and a group of regulatory SNPs in the promoter of the interleukin-1 receptor antagonist (IL1RN) gene. The sJIA risk SNPs were among the strongest predictors of IL1RN gene expression and serum levels of the interleukin-1 receptor antagonist protein (IL1Ra). We demonstrated that low IL1RN expression correlated with increased risk of sJIA. More importantly, we observed that homozygosity for the high expression IL1RN genotypes in sJIA patients was highly predictive of non-response to treatment with human recombinant IL1Ra (anakinra; sensitivity 0.92; specificity 0.71). Based on this finding, we suggest employing these SNPs as biomarkers to guide the personalized treatment of systemic arthritis, avoiding the use of anakinra in predictable non-responders. In the current reporting period, we continued to use the INCHARGE cohort for population-based genomic investigations of sJIA. By uniting INCHARGE and the Juvenile Arthritis Consortium for Immunochip (JACI), we have performed an Immunochip genetic association study of 889 sJIA cases and 16,114 healthy subjects. Using association testing by logistic regression, we identified a novel, highly significant sJIA susceptibility locus on chromosome 2. The sJIA risk factor is a 6-SNP haplotype of the gene that encodes C-X-C chemokine receptor type 4 (p = 4.3 times 10 to the negative 10; odds ratio = 1.7; 95% confidence interval 1.5 to 1.9). Analysis of paired whole genome sequencing data and lymphoblastoid cell (LCL) RNA sequencing data from 1000 Genomes Project subjects revealed positive correlation between the sJIA risk haplotype and CXCR4 expression in LCLs. Examination of the risk haplotype in public databases revealed chromatin looping, protein binding and high gene regulatory activity. To facilitate mechanistic investigations of the sJIA risk haplotype, we have screened and identified 40 subjects from the NHGRI Genomic Ascertainment Cohort carrying haplotype configurations of interest. We are actively recruiting these subjects to the NIH Clinical Center for immunophenotyping. This work was selected as a plenary presentation at the 2020 Pediatric Rheumatology Symposium of the American College of Rheumatology, where it was the recipient of the Best Genetics and Pathogenesis Abstract Award. It was also selected for a 2021 NIH Fellows Award for Research Excellence. A manuscript describing these findings is in preparation. In addition to the Immunochip study, we have also leveraged the INCHARGE GWAS dataset in an investigation of HLA alleles in children with sJIA, lung disease and hypersensitivity (see section 2 below). 2. Investigation of systemic arthritis in individuals To investigate whether high-impact genetic variation influences sJIA susceptibility on an individual level, we apply sequencing-based approaches to identify rare genetic variation in subjects with sJIA. We are actively recruiting individuals and families with systemic arthritis to participate in our NIH Intramural Research Program research protocol entitled Investigation of the Natural History, Genetics, and Pathophysiology of Systemic Juvenile Idiopathic Arthritis, Adult-Onset Stills Disease and Related Inflammatory Conditions (18-AR-0081). This protocol is designed to facilitate broad recruitment of children, adults and families with systemic arthritis to the NIH Clinical Center for family-based genomic sequencing, coupled with systematic, longitudinal characterization of clinical and immunological phenotypes. To date, we have enrolled nearly 150 subjects in this research protocol, including many subjects with severe manifestations of sJIA. During the current reporting period, we worked in collaboration with colleagues from across the world to study the etiology of the severe form of lung disease with features of hypersensitivity that has been identified in a subset of children with sJIA following treatment with anakinra, canakinumab or tocilizumab (ACT). Using a validated classification system for hypersensitivity reactions, we found that all subjects in our sJIA-lung disease cohort also fulfilled criteria for DRESS (drug reaction with eosinophilia and systemic symptoms). We determined class I and II HLA alleles in subjects with sJIA-DRESS and compared the allele frequencies to those of the INCHARGE sJIA cases. This revealed strong enrichment of HLA-DRB1*15:01 alleles among sJIA-DRESS, when compared to typical sJIA (p = 2.3 times 10 to the negative 13; odds ratio 10.8; 95% confidence interval 5.4 to 21.8). These findings indicate that subjects with sJIA and HLA-DRB1*15:01 alleles are at very high risk for developing DRESS if treated with ACT. Based on this observation, pre-treatment HLA typing in sJIA should be considered to reduce the risk of DRESS. A draft manuscript describing this work is archived at MedRxiv. A revised manuscript describing this work is under review. 3. Development of guidelines for childhood arthritis Over the past 4 years, we have partnered with the American College of Rheumatology and other experts in childhood arthritis to develop evidence-based guidelines for the management of juvenile idiopathic arthritis. Using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology, we developed and published two sets of guidelines in 2019. In the current reporting period, we have developed two additional sets of guidelines: 1) Therapeutic Approaches for Oligoarthritis, Temporomandibular Joint (TMJ) Arthritis and Systemic Juvenile Idiopathic Arthritis, and 2) Recommendations for Non-Pharmacologic Therapies, Medication Monitoring, Immunizations, and Imaging in Juvenile Idiopathic Arthritis. In both cases, most recommendations relied heavily on expert consensus because there was a lack of literature with good quality evidence. These recommendations will be published in Arthritis and Rheumatology.