WOOLLOONGABBA, Australia—Experts have known for years that more than 90% of the risk of developing ankylosing spondylitis (AS) is genetically determined, but apart from HLA-B27, the genetic villains have remained largely unapprehended. This is changing thanks to new genetic analysis methods such as high-density association studies.

In a major review of AS genetics published early online in Rheumatology, Matthew A. Brown, MD, describes two newly identified AS genes, which together contribute roughly one third of the population's attributable risk of AS, pointing to a completely new approach to treatment.¹

The two most important new discoveries are the association of AS with IL23R and with ARTS1. "The strong association with susceptibility to disease suggests that IL23/IL23R targeted therapies may even be capable of disease prevention, a particularly exciting potential," writes Dr. Brown, professor of immunogenetics at Diamantina Institute of Cancer, Immunology, and Metabolic Medicine at Princess Alexandra Hospital in Wooloongabba, Queensland, Australia. Dr. Brown is also associated with the Oxford University Institute of Musculoskeletal Sciences in England.

IL23R influences AS susceptibility, severity, age of onset

The IL23R gene encodes a cytokine receptor on TH17 cells, a subset that expresses high levels of pro-inflammatory interleukin (IL) -17 in response to stimulation. Variations in this gene also influence susceptibility to Crohn's disease and psoriasis, but it does not appear to be associated with rheumatoid arthritis. "This is, thus, not only a major gene for AS but also at least partially explains the clinical association of AS with Crohn's disease and psoriasis," said Dr. Brown, pointing out that this is the first seronegative pleiotropic gene (affecting more than one disease). Dr. Brown's group also has unpublished data suggesting that IL23R genetic variants influence both the severity and the age of onset of AS.

ARTS1 alters peptides, may explain link between B27 and AS

The other important new finding is the association between the gene ARTS1 and AS. This gene mediates peptide trimming within the endoplasmic reticulum to the best length for major histocompatibility complex Class I presentation. It also cleaves cell surface receptors for IL-1, IL-6, and TNF.

Changes in the first function of ARTS1 would be expected to alter HLA-Class I peptide presentation, and AS is primarily an HLA-Class I mediated autoimmune disease. More than 90% of AS patients have the HLA-B27 allele. Loss-of-function changes in the second function of ARTS1 would be expected to increase the inflammatory effects of the proinflammatory cytokines and of TNF.

Bigger studies, more patients needed

"Patients themselves, many of whom experienced substantial disillusionment with traditional medicine even in establishing a correct diagnosis for their symptoms, gave up seeking conventional treatment, which had little to offer them. This led to a vicious circle—AS was underresearched because it was not perceived to be a major public health problem and patients often withdrew from traditional medical attention because all that was offered was physiotherapy and anti-inflammatories," Dr. Brown said. He attributes the recent breakthroughs largely to "enthusiastic support of AS patient organizations for genetics research."

More of this support will be needed to move the field forward, however. Dr. Brown warns that genetic studies with only a few hundred cases and controls are underpowered and produce conclusions too weak to be useful, even if they report positive findings. "The successful identification of ARTS1 and IL23R should give those involved in AS genetics research great encouragement of the potential of this research. The main requirements now will be the support of AS patients, the rheumatology community, and funding agencies, to complete the task," he concluded.

Reference

1. Brown MA. Breakthroughs in genetic studies of ankylosing spondylitis. Rheumatology. 2007; [epub ahead of print] doi:10.1093/rheumatology/kem269.