Génétique : les nouveaux éléments

Abstract

Spondyloarthritis (SpA) is a chronic complex disease with high heritability reflecting a predisposing genetic background. Heritability has been estimated around 90% and familial studies have established a polygenic transmission of the disease. The most important part of heritability comes from the HLA-B27 allele (explaining 25 to 50% of the heritability). More recently, large Genome Wide Association Studies (GWAS) have identified more than 20 other susceptibility loci. There is a substantial overlap between the loci associated with SpA and other inflammatory diseases frequently associated to SpA, such as inflammatory bowel disease or psoriasis. Moreover, recent genetic association studies have demonstrated that some of the polymorphisms associated with AS, the prototypical form of SpA, are also associated with the whole SpA. These results are in favour of a shared genetic background between these diseases. All these susceptibility loci highlight several pathways potentially involved in the disease pathogenesis such as the Th17 pathway or genes belonging to aminopeptidase family. Functional studies have also demonstrated consequences of several polymorphisms associated with SpA (such as rs30187 in ERAP1 or rs11209026 in IL23R). However, causal polymorphism remains to be identified for most of the susceptibility loci. Despite the recent discoveries, less than 5% of the heritability is now explained by these loci. The current challenge is to identify “missing heritability”. Next-generation sequencing could be very useful to discover rare variants, hard to identify with conventional GWAS approaches.