The genetic basis of ankylosing spondylitis: new insights into disease pathogenesis

Abstract

Ankylosing spondylitis (AS) is a complex disease involving multiple risk factors, both genetic and environmental. AS patients are predominantly young men, and the disease is characterized by inflammation and ankylosis, mainly at the cartilage-bone interface and enthesis. HLA-B27 has been known to be the major AS-susceptibility gene for more than 40 years. Despite advances made in the past few years, progress in the search for non-human leukocyte antigen susceptibility genes has been hampered by the heterogeneity of the disease. Compared to other complex diseases, such as inflammatory bowel disease (IBD), fewer susceptibility loci have been identified in AS. Furthermore, non-major histocompatibility-complex susceptibility loci discovered, such as ERAP1 and IL23R, are likely contributors to joint inflammation. Identification and confirmation of functional variants remains a significant challenge of investigations involving genome-wide association studies (GWAS). It remains unclear why none of the AS-susceptibility genes identified in GWAS appear to be directly involved in the ankylosing process. Numerous reviews have recently been published on the genetics of AS. Therefore, aside from a brief summary of what AS GWAS has successfully achieved thus far, this review will focus on directions that could address unanswered questions raised by GWAS.

Keywords: ankylosing spondylitis; ankylosis; clinical subsets; genome-wide association studies; joint and gut inflammation; risk loci.

Figure 1

Summary of family-based association analyses using multiplex ankylosing spondylitis (AS) families from the North American Spondylitis Consortium (NASC). Abbreviations: ANKH, human homolog of progressive ankylosis; TNAP, tissue-nonspecific alkaline phosphatases.