The genomics and genetics of ankylosing spondylitis

Abstract

Abstract:The spondyloarthropathies are a group of arthritides which specifically target the spine and pelvis with ankylosing spondylitis (AS) being the most prevalent and debilitating of these conditions. Unique to AS is the progression to excessive uncontrolled bone formation following an initial inflammatory phase that can result in joint fusion and significant disability. Spondyloarthritis is estimated to affect 1%-2% of the population, twice as many as rheumatoid arthritis and thus constitutes a significant health problem. Currently AS pathogenesis is very poorly understood but recent large-scale genetics and gene expression profiling studies have identified some of the underlying mechanisms and pathways contributing to the disease. Genome-wide association studies have identified a number of candidate genes associated with AS sharing the same pathways which are now being targeted for therapeutic intervention. However, although such approaches can identify genes contributing to the disease process and are very informative as to disease aetiopathogenesis, they cannot profile the actual changes in gene/cell activity at any point in the disease process or possibly more importantly at specific sites. Such information is generated using expression profiling. A number of expression profiling studies have been undertaken in AS, looking at both circulating cells and tissues from affected joints. Although some common genes/pathways have been identified, overall the results to date have been somewhat disappointing due to differences in experimental design and tissue source as well as the low power of the studies. More recent better powered studies have shown some potential in developing gene expression profiling as a diagnostic tool in AS. True future success will rely on larger genetic and genomic studies and the combination of these datasets in eQTL studies requiring significant collaborative efforts. Such larger-scale approaches will also generate sufficient power to target specific disease stages and sites.

Autosomal Recessive Mental Retardation, Deafness, Ankylosis, and Mild Hypophosphatemia Associated with a NovelANKHMutation in a Consanguineous Family

“…This is supported by increased osteoclast numbers per trabecular bone surface in ank long bones (32). In patients affected by ankylosing spondylitis and corresponding animal models, osteopenia as a consequence of joint destruction has been well established (1,34). Normal trabecular bone values in ank vertebrae at 6 wk of age suggest that osteopenia in long bones is secondary to joint stiffness and that the joint pathology does not induce systemic bone loss at this stage.…”

“…D egenerative joint disorders like ankylosing spondylitis frequently lead to the formation of osteophytes, which finally can result in osseous ankylosis, the bridging of joints by mineralized tissue (1). This process can lead to conductive hearing loss if it affects the articulations of the hearing ossicles (2).…”

Interferon‐γ regulates discordant mechanisms of uveitis versus joint and axial disease in a murine model resembling spondylarthritis

“…AS-associated uveitis is typically anterior, meaning it most consistently affects the iris, and typically manifests as unilateral disease with recurrent episodes (3). HLA-B27 is a documented genetic susceptibility factor for AS (4), and ϳ95% of patients with AS in whom uveitis develops are HLA-B27 positive (5); however, the presence of HLA-B27 accounts for only ϳ20-40% of the genetic risk for AS. Genetics studies and clinical observations strongly suggest that uveitis is affected by additional genetic or environmental factors that distinguish it from either the axial or peripheral joint disease that is characteristic of AS (4,6).…”

The Impact of Large-Scale Genomic Methods in Orthopaedic Disorders: Insights from Genome-Wide Association Studies

“…By effect size, we refer to the strength of the signal associated with a given genetic factor. For example, HLA (human leukocyte antigen) B27 is strongly associated with ankylosing spondylitis, particularly in patients of European descent, and accounts for a major portion of the genetic risk for this condition 24 . In contrast, a recent GWAS of human height found that height is highly polygenic, with many genes contributing small effect sizes 25 .…”