JIA Susceptibility: 14 New Genes Found

Janis C. Kelly

April 30, 2013

A landmark international study has identified 14 new genetic loci associated with juvenile idiopathic arthritis (JIA). The discovery is expected to open up major new avenues of research, including the possible use of treatments already proven effective in other autoimmune disorders.

The study, by Anne Hinks, PhD, from the Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, University of Manchester, and the National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Science Centre, United Kingdom, and colleagues in the United Kingdom, the United States, and Germany, was published online April 21 in Nature Genetics.

"The broad long-term objective of our work is to understand genetic variation at the level of the individual patient in order to develop strategies for personalized treatment, as well as to understand the difference in genetic risk factors of patients who have inadequate responses to available treatments. To do this, we must first determine the causal variant and biological mechanisms involved in each locus," senior author Susan D. Thompson, PhD, told Medscape Medical News. Dr. Thompson is professor of rheumatology at Cincinnati Children's Hospital Medical Center and professor of pediatrics at the University of Cincinnati College of Medicine in Ohio. "Since investigators studying other autoimmune disease are pursuing causal variants based on their own Immunochip findings, we will all benefit by testing each other's causal variants and genetic models in our respective disease cohorts. It is potentially interesting to know which autoimmune diseases are most similar genetically and whether there might be common therapeutic options."

Custom Immunochip Used

The researchers genotyped 2816 participants with JIA and 13,056 control participants. The analysis confirmed the association of 3 previously identified loci (the human leukocyte antigen [HLA] region, PTPN22, and PTPN2) with JIA. The analysis also revealed 14 novel loci associated with JIA.

Genotyping was done with a custom array designed by the Immunochip Consortium around confirmed risk loci for 12 autoimmune diseases (not including JIA) and dense coverage of the extended HLA region and 186 non-HLA loci.

The researchers restricted the study to the 2 most common subtypes of JIA, oligoarticular arthritis and polyarthritis, which differ by number of joints involved at 6 months' disease duration and by age at onset. The 2 subtypes account for approximately 70% of all JIA cases, according to the authors.

"When we did subtype-specific association testing, and not including the HLA region, we found only 1 gene that differed between oligo and poly. This was IRF1 (strongly associated in oligo JIA). IRF1 is a transcription factor that binds to a number of genes that contain an interferon-stimulated response element, and therefore is an important regulator of the immune response. To my knowledge, associations with IRF1 are not reported for adult arthritis, making it particularly attractive to work on," Dr. Thompson said.

"This is a nice piece of work that reflects a massive international effort to define the genetics of 2 of the major subtypes of JIA," Peter K. Gregersen, MD, told Medscape Medical News. "This has been very challenging because, unlike adult [rheumatoid arthritis], the juvenile forms are more clinically diverse and much less common than adult [rheumatoid arthritis]. The results offer no surprises, with lots of genes that have been implicated in other autoimmune diseases. This is expected because the genotyping platform they used, the Immunochip, was designed to interrogate genetic loci that have been implicated in immune disorders."

Dr. Gregersen, a noted expert on the genetics of adult rheumatoid arthritis, is from the Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York. He provided US control genotyping from the Genotype and Phenotype Registry, supported by the National Institutes of Health, but was not otherwise involved in the study.

Links to Other Autoimmune Diseases

Dr. Thompson added, "The most exciting aspect of this research may be the integration of JIA genetic risk factors with those of other autoimmune diseases. The loci we identified have been reported for one or more other autoimmune diseases such as adult arthritis, lupus, or type 1 diabetes. All are interesting relative to the concept of shared risk factors among autoimmune diseases. Notably, our findings include several loci involved in the interleukin 2 [IL-2] pathway, which is important for T-cell activation, T-cell development, and overall regulation of the immune system. Regions which reached genome-wide significance within this pathway included the genes IL-2 to IL-21, IL-2RA, and IL-2RB regions. The findings also include SH2B3, which is involved in T-cell activation, as it mediates the interaction between the T-cell receptor and intracellular signaling pathways, and STAT4 is involved in T cell differentiation."

"Probably we are coming shortly to the point where [more comprehensive assessment of the genome] should be done with whole-genome sequencing of the entire cohort. This is just a matter of waiting until the price of whole-genome sequencing comes down. In my view, the most urgent need is to start understanding the actual functional significance of all these new risk genes," Dr. Gregersen said.

The authors and Dr. Gregersen have disclosed no relevant financial relationships.

Nat Genet. Published online April 21, 2013. Abstract