[Enlightenment from genome-wide association study to genetics of psoriasis]

Psoriasis is a common autoimmune and hyper proliferative skin disease, characterized by thick, silvery scale patches. Numerous family studies have provided compelling evidence of a genetic predisposition to psoriasis, although the inheritance pattern is unclear. However, few of these studies have achieved consistent results, except for the MHC locus, a problem frequently encountered in the investigation of complex disease. Using high-throughput techniques to genotype hundreds of thousands of single nucleotide polymorphisms explore their relationship with phenotypes, genome-wide association studies (GWAS) are now proven to be a powerful approach for screening the susceptibility genes (loci) of complex disease. Recently, three GWAS on psoriasis published in Nature Genetics have provided us with many novel clues concerning disease pathogenesis, in both immune and non-immune pathways. The MHC locus (HLA-Cw6 and other MHC variance), the major locus involved in the immune reactions of human immune disease, has consistently been shown to be associated with psoriasis, both in previous linkage and present GWAS. IL-12B and IL23R, which are the two non-MHC genes with highly associated evidence with psoriasis in multiple studies performed so far and potent cytokines with complex biological activities, should be of great importance in the pathogenesis of psoriasis. Recent clinical trials, in which anti-IL-12p40 antibodies were used for the treatment of psoriasis, have provided further evidence of the role of IL-12/23 in the pathophysiology of psoriasis,and highlighted a new road of treatment for psoriasis. In 2008,we performed the first large GWAS in the Chinese population and identified a novel susceptibility locus within the late cornified envelope (LCE) gene cluster: LCE3A and LCE3D on chromosome 1q21, with conclusive evidence (rs4085613, p(combined)=6.69*10(-30); odds ratio=0.76). Meanwhile, another group also identified a deletion comprising and LCE gene cluster of LCE3B and LCE3C, which is significantly associated with a risk of psoriasis in Spain, Netherland, Italy and USA. Both of these independent studies provided substantial association evidence for the LCE genes involved in the pathogenesis of psoriasis. The LCE genes encode the stratum-corneum proteins of the cornified envelope, which plays an important role in epidermal terminal differentiation. As we know, psoriasis is a disease of interfollicular epidermis and rapid keratinocyte proliferation may cause the production of parakeratotic keratinocytes in psoriatic skin and, thus, the formation of poorly adherent stratum corneum, which in turn results in the characteristic scale or flakes of psoriasis lesions. Although some of the highlighted genes are already targeted by effective psoriasis therapies, others could become future targets for treatments,especially for the LCE genes, which will be very useful for unlocking new drug targets and tailored treatments for this painful, disfiguring skin disease. Meanwhile larger samples and improved strategy for identification of other susceptibility variants to psoriasis and downstream functional study to elucidate the underlying mechanisms of diseases are also needed. Taken together, unremitting efforts of the basic research on psoriasis will lead us to achieve a better treatment and diagnosis for psoriasis in the near future.