BioWorld International Correspondent

LONDON - Identification of genetic variants that are associated with the disease ankylosing spondylitis has provided important clues to the cause of this condition and may help direct the development of new therapies to treat it.

The finding is particularly exciting, David Evans, senior lecturer in biostatistical genetics at the University of Bristol, told BioWorld International, because one of the genes, called IL23R, has been implicated in other autoimmune diseases, including psoriasis and Crohn's disease.

A treatment for Crohn's disease that inhibits the activity of IL23R is already in clinical trials. The latest study suggested that the same treatment may work for ankylosing spondylitis, a common disease that causes back pain with progressive stiffness and disability.

Matthew Brown, professor of immunogenetics at the Diamantina Institute for Cancer, Immunology and Metabolic Medicine at the University of Queensland in Woolloongabba, Australia, told BioWorld International: "The findings are the first definite genes identified in ankylosing spondylitis for nearly 40 years, and represent a major breakthrough in research for this disease. There are no current treatments that induce remission in ankylosing spondylitis or that have been shown to retard its progression; these findings help us to understand what the basic causes of the disease are and are thus essential steps towards the development of new therapies."

Evans, Brown and other members of the Wellcome Trust Case Control Consortium and the Australo-Anglo-American Spondylitis Consortium carried out a genome-wide association scan with the aim of identifying new genetic variants associated with several common diseases.

A report on the study appears in Oct. 21, 2007, Nature Genetics, titled "Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants."

In the paper, the consortia describe work limited to so-called "non-synonymous SNPs" - those nsSNPs are SNPs that produce an amino acid change in a protein. Such nsSNPs are overrepresented in single-gene disorders where there is a clear relationship between genotype and phenotype. Perhaps, the researchers wondered, nsSNPs also might be overrepresented in the genetic causes of more complex genetic diseases.

To find out, the consortia compared the presence of nsSNPs in 1,500 healthy controls with that in four groups of about 1,000 individuals, each with a different disease: ankylosing spondylitis, autoimmune thyroid disease (all with Graves' disease), breast cancer and multiple sclerosis.

The variants found to be associated with ankylosing spondylitis are in the genes IL23R and ARTS1. The former provides instructions for making a receptor present on the surface of several types of cell in the immune system. It plays a role in triggering certain chemical signals inside the cell that promote inflammation and help to coordinate the response of the immune system to infection.

Brown said: "The association with the variant in IL23R strongly points to the involvement of a subset of inflammatory T-lymphocytes in the disease, which was previously unsuspected, and suggests that treatments targeting these lymphocytes or their products may be beneficial in the condition. One such treatment, an antibody to IL12, has already been trialed in Crohn's disease and was found to be beneficial in that condition. Other treatments are in development. Our studies suggest that these treatments might be effective in ankylosing spondylitis, too."

The involvement of a third gene associated with ankylosing spondylitis, called HLA-B27, has been known for 37 years, although no one has been able to work out how it plays a role. Brown believes that the gene ARTS1 may hold the answer, because the protein it encodes is involved in breaking up pathogens into small pieces that can be displayed by the HLA-B27 protein.

"This strongly suggests that in ankylosing spondylitis, there are problems with the information that the HLA-B27 protein receives, thereby causing the disease," Brown said.

The study also found an association between Graves' disease and genetic variants in the gene TSHR, which encodes the thyrotropin receptor, and a gene called FCRL3.

Evans said that the lack of statistically significant findings in the other diseases studied, including breast cancer and multiple sclerosis, might reflect the need for bigger sample sizes in order to identify smaller effects.

The researchers now hope to design functional studies that will reveal how variation in the genes they have identified translates into physiological processes that influence risk of disease. "For example, people will want to do gene expression studies that examine what effects these nsSNPs have on expression levels of messenger RNA, and there will probably be genetic knockout studies using animal models," Evans said.