The Long and Winding Road: Searching for Non-MHC Psoriasis Susceptibility Loci

It is well recognised that the Major Histocompatibility Complex (MHC) harbours the main psoriasis susceptibility locus (PSORS1, Psoriasis Susceptibility 1). Nonetheless, linkage analyses have repeatedly shown that the PSORS1 locus account for less than 50% of the disease family clustering. On this basis, it is widely agreed that additional loci must contribute to psoriasis susceptibility, either by interacting directly with or by modifying the effect of the PSORS1 gene(s). To date, at least eight putative disease susceptibility regions have been mapped outside of the MHC (PSORS2-9). However, the search for the underlying genetic determinants has been seriously hindered by the difficulty of replicating linkage to these loci. The small disease-risk conferred by non-MHC genes and the likely occurrence of genetic heterogeneity are regarded as the main factors affecting the power of linkage studies and confounding the interpretation of experimental results. Evidence supporting some non-MHC loci has been provided by their close overlap with genomic regions conferring susceptibility to other inflammatory disorders. These observations indicate that clinically distinct autoimmune diseases might share common pathogenic pathways, suggesting that future advances in the understanding of single disorders could benefit the wider research community studying common inflammatory diseases.