The association between human leukocyte antigen (HLA) B27 and ankylosing spondylitis (AS) is among the strongest associations known between a disease and a genetic marker. Genes, both within and outside the major histocompatibility complex, are believed to account for more than 90% of the population variance in AS. While these associations clearly indicates strong genetic contributions to the susceptibility to AS, whether genes influence the severity, of AS is unknown. The severity of AS varies widely among patients, with some having severe persistent joint inflammation, functional limitation, premature work disability, and early spinal fusion. We hypothesize that the severity of -AS is genetically determined, and that genes that influence susceptibility to AS, genes that influence the severity of inflammatory responses, and genes regulating transforming growth factor-beta are among the genes that also influence its severity. We propose a model of AS severity in which genetic differences among patients influence the immune response and consequently the persistence and severity of joint inflammation. Persistent severe joint inflammation thereafter leads to spinal ankylosis and poorer long-term health outcomes. We will test this model in two stages. First, we will identify genetic markers associated with worse radiological outcomes, greater functional disability, work disability and need for total hip arthroplasty in a retrospective cohort study of 400 patients with AS of 20 years or longer. Second, we will test these genetic markers for associations with persistent active inflammation in a prospective cohort study of 200 patients with early AS who will be repeatedly assessed over 2 years. The model will be supported if the genetic markers that are associated with persistent active inflammation are also associated with poorer long-term health outcomes. In addition, the prospective cohort will enable the development and assessment of new clinical and radiographic measures of disease activity in AS for use in clinical trials. Understanding the contribution of genetic factors to differences in the severity of AS and in the health outcomes of patients would further our understanding of the pathogenesis of AS, provide important prognostic information, and could identify subgroups at high risk for poor outcomes who could then be targeted for more aggressive interventions.
