Genetics and Functional Genomics of Spondyloarthritis

Spondyloarthritis (SpA) is a chronic inflammatory disorder with high heritability but with complex genetics. It encompasses several entities that share common clinical features. Most of the genetic studies in SpA have been restricted to ankylosing spondylitis (AS), the prototypical form of SpA. However, there is growing evidence of shared genetic background between all the SpA subtypes and also with some other immune-mediated diseases. The most important part of SpA heritability comes from the HLA-B27 allele in the major histocompatibility complex (MHC) that explains around 25% of the attributable heredity. Several other loci outside of the MHC have been shown to be involved in the disease. However, all these non-MHC loci explain only a small additional fraction of disease predisposition. Thus, a substantial fraction of SpA genetic basis remains poorly understood. Gene expression profiling is a complementary approach to elucidate the underlying mechanisms and pathways that drive the disease. Several expression profiling studies have been undertaken in SpA. However, results have been quite disappointing with little overlap between the studies largely due to the small sample sizes, resulting in limited power to discover small effects. In this review, we summarize current knowledge on genetic findings concerning SpA and we describe strategic approaches for identification of additional variants, with a focus on rare variants in familial forms. We also provide an overview of gene expression studies in SpA and discuss the possibilities offered by high-throughput RNA sequencing technologies, in particular in sorted cells. Finally, issues in establishing molecular mechanisms underlying genetic association hits and potential translational applications will be addressed.