New discoveries in the genetics and genomics of systemic juvenile idiopathic arthritis

ABSTRACT

Introduction

Systemic juvenile idiopathic arthritis (sJIA) is a severe inflammatory condition with onset in childhood. It is sporadic, but elements of its stereotypical innate immune responses are likely genetically encoded by both common variants with small effect sizes and rare variants with larger effects.

Areas covered

Genomic investigations have defined the unique genetic architecture of sJIA. Identification of the class II HLA locus as the strongest sJIA risk factor for the first time brought attention to T lymphocytes and adaptive immune mechanisms in sJIA. The importance of the human leukocyte antigen (HLA) locus was reinforced by recognition that HLA-DRB1*15 alleles are strongly associated with development of drug reactions and sJIA-associated lung disease (sJIA-LD). At the IL1RN locus, genetic variation relates to both risk of sJIA and may also predict non-response to anakinra. Finally, rare genetic variants may have critical roles in disease complications, such as homozygous LACC1 mutations in families with an sJIA-like illness, and hemophagocytic lymphohistiocytosis (HLH) gene variants in some children with macrophage activation syndrome (MAS).

Expert opinion

Genetic and genomic analysis of sJIA holds great promise for both basic discovery of the course and complications of sJIA, and may help guide personalized medicine and therapeutic decision-making.

KEYWORDS:

• Macrophage activation syndrome
• still’s disease
• genetics
• genomics
• lung disease

Article highlights

• Despite the fact that sJIA does not generally cluster in families, population-based studies have demonstrated that there are genetic factors that influence its development. Therefore further genetic investigations of sJIA are warranted.

• The HLA locus is the strongest sJIA susceptibility locus, where disease-associated variants tag HLA-DRB1*11 alleles. This provided firm evidence implicating T cells in the pathophysiology of sJIA.

• The genetic architecture of sJIA is unique among JIA subtypes, which indicates that the pathophysiology of sJIA is distinct form the other forms of JIA.

• Genetically encoded factors may correlate with therapeutic response in a way that enables molecularly guided therapy of sJIA. This has been suggested for variants of IL1RN

• Genetic factors may also correlate with prognosis, disease course or development of an adverse event. HLA-DRB1*15 has been identified as a risk factor for lung disease and drug reactions reactions.

Declaration of interest

G Schulert has received research support from IpiNovyx, and consulting fees from Boehringer Ingelheim and SOBI. M Correia Marques was supported by the Intramural Reseach Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. M Ombrello was supported by Z01-AR041198 from the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. G Schulert was supported by R01-AR079524 from the National Institute of Arthriits and Musculoskeletal and Skin Diseases, National Institutes of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.