Psoriasis is a common autoimmune and hyperproliferative skin disease, characterized by thick, silvery scale patches. It usually occurs within the third decade of life, with a prevalence of 2–5% in Caucasians Citation[1] and 0.1–0.3% in Asians Citation[2]. Psoriasis can be grouped into two types: type I has an age of onset before 40 years and is HLA-associated, and type II has an age of onset after 40 years and lacks HLA associations Citation[3].
Numerous family studies have provided compelling evidence of a genetic predisposition to psoriasis, although the inheritance pattern is unclear. Within the past decade, several putative susceptibility loci for psoriasis have been reported on the basis of genome-wide linkage studies. However, few of these studies have achieved consistent results, except for the MHC locus Citation[4,5], a problem frequently encountered in the investigation of complex diseases. This may be attributed to various factors, including the low heritability of complex diseases, scattered microsatellite markers, imprecise definition of phenotypes and inadequate power of the study Citation[6]. Consequently, a strategic complement to linkage analysis is desirable.
Genome-wide association (GWA) studies are now proven to be a powerful approach for screening the susceptibility genes (loci) of complex diseases. GWA, as defined by the NIH, is the study of common genetic variation across the entire human genome to identify genetic associations with observable traits, using high-throughput technologies to genotype hundreds of thousands of single-nucleotide polymorphisms and explore their relationship with phenotypes. With no assumptions about the genomic location of the causal variants, GWA can exploit the strengths of association studies without having to guess the identity of the causal genes. Therefore, the GWA approach represents an unbiased, yet fairly comprehensive, option for identifying the susceptibility genes of complex diseases Citation[6]. Since 2005, over 700 genes for more than 100 common diseases and traits have been identified by GWA Citation[101], including those in inflammatory bowel disease, Type 2 diabetes and breast cancer, which sets a solid foundation for further study to explore disease pathogenesis Citation[7]. Recently, three GWA studies on psoriasis published in Nature Genetics have provided us with many novel clues concerning disease pathogenesis, in both immune and nonimmune pathways Citation[8,9].
Immune pathway
The MHC locus (HLA-Cw6 and other MHC variants), 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 GWA studies Citation[4,5,8,9]. IL-12, first discovered in 1989, plays an important role in the cell-mediated immune response. IL-23 is a more recently described cytokine that is closely related to IL-12 in structure and shares with it the common subunit IL-12p40. However, few studies have scrutinized the IL-12 or IL-23 genes for genetic variants that might explain susceptibility to psoriasis Citation[10]. A recent global association scan confirmed a previously reported association with IL12B (rs3212227 in its 3´UTR) Citation[11] and identified a second region of association 60 kb upstream from its mRNA start site (rs6887695) Citation[12]. An analysis of additional genes encoding components of the IL-12B pathway led to the identification of associations with IL23R (rs11209026 and rs7530511) Citation[12]. We also identified a highly significant association at the two single-nucleotide polymorphisms within the IL12B gene, and confirmed IL12B to be a susceptibility gene for psoriasis in the Chinese population Citation[9]. Furthermore, the identification of associations between variants in IL-12-related genes and disease was found not only in psoriasis, but also in asthma Citation[13], atopic dermatitis Citation[11] and Crohn’s disease Citation[14]. Recently, Nair et al. performed a GWA study in a Caucasian population and found several immune-related genes, including three genes involved in IL-23 signaling (IL23A, IL23R and IL12B), two genes that act downstream of TNF-α and regulate nuclear factor-kB signaling (TNIP1 and TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4 and IL13), which are highly associated with susceptibility to psoriasis Citation[8]. As all genes implicated here are involved in the regulation of immune responses, this, in turn, emphasizes the importance of the immune pathway in the pathogenesis of psoriasis Citation[8].
Worth mentioning are IL12B and IL23R, which are the two non-MHC genes with highly associated evidence with psoriasis in multiple studies performed so far. As potent cytokines with complex biological activities, they should be of great importance in the pathogenesis of psoriasis. Recent clinical trials, in which anti-IL-12–p40 antibodies were used for the treatment of psoriasis have provided further evidence of a role of the IL-12/23 in the pathophysiology of psoriasis, and highlighted a new road of treatment for psoriasis Citation[15].
Nonimmune pathway
Recently, we performed the first large GWA study 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, pcombined = 6.69 × 10-30; odds ratio = 0.76) Citation[9]. Meanwhile, another group also identified a deletion comprising an LCE gene cluster of LCE3B and LCE3C, which is significantly associated with a risk of psoriasis in Spain, the Netherlands, Italy and the USA (p = 1.38 × 10-08) Citation[16]. Both of these independent studies provide substantial association evidence for the LCE genes being involved in the pathogenesis of psoriasis. The LCE genes encode the stratum–corneum proteins of the cornified envelope, which play an important role in epidermal terminal differentiation. Psoriasis is a disease of the interfollicular epidermis, in which keratinocytes proliferate rapidly. In psoriatic skin, the epidermal differentiation cycle takes only 3–5 days, compared with 28–30 days in normal skin Citation[17]. This 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 Citation[18,19]. Therefore, we postulate that, by causing the production of abnormal stratum–corneum proteins and thus abnormal cornified envelope, genetic susceptibility variant(s) within the LCE genes may influence the development of psoriasis by interrupting the terminal differentiation of keratinocytes.
Perspective
What is the future direction for psoriasis genetics? As we know, psoriasis is a complex disease involving multiple genes and interactions between genes, or between genes and the environment, in its pathogenesis. The present findings from GWA studies provide us with an unprecedented view and opportunity for exploring and understanding the pathogenesis of psoriasis; however, so far, most susceptibility genes identified are immune-related genes. Noteworthy is the LCE gene, which is the first nonimmune-related locus directly involved in the pathophysiology of psoriasis. Further study of this gene will potentially extend our traditional view on the pathogenesis of psoriasis.
Although some of the highlighted genes are already targeted by effective psoriasis therapies, others could become future targets for treatments, especially the LCE genes, which will be very useful for unlocking new drug targets and tailored treatments for this painful, disfiguring skin disease. As mentioned previously, the interaction may be an important factor affecting psoriasis. Follow-up studies on interaction may allow us to further understand the disease pathogenesis and eventually establish a disease predication model, providing us with a high predication rate of disease risk, which will be very helpful for clinical use. Meanwhile, larger samples and as improved strategy for the identification of other susceptibility variants to psoriasis, as well as downstream functional study to elucidate the underlying mechanisms of diseases, are also needed. Taken together, unremitting efforts into basic research on psoriasis will lead us to achieve a better treatment and diagnosis for psoriasis in the near future.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- Nevitt GJ, Hutchinson PE. Psoriasis in the community: prevalence, severity and patients’ beliefs and attitudes towards the disease. Br. J. Dermatol.135(4), 533–537 (1996).
- Shao C, Zhang G, Wang G. Distribution of psoriasis in China: a nationwide screening. Proc. Chin. Acad. Med. Sci. Peking Union Med. Coll. (2), 59–65 (1987).
- Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J. Am. Acad. Dermatol.13(3), 450–456 (1985).
- Fan X, Yang S, Huang W et al. Fine mapping of the psoriasis susceptibility locus PSORS1 supports HLA-C as the susceptibility gene in the Han Chinese population. PLoS Genet.4(3), e1000038 (2008).
- Nair RP, Stuart PE, Nistor I et al. Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am. J. Hum. Genet.78(5), 827–851 (2006).
- Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet.6(2), 95–108 (2005).
- Donnelly P. Progress and challenges in genome-wide association studies in humans. Nature456(7223), 728–731 (2008).
- Nair RP, Duffin KC, Helms C et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat. Genet.41(2), 199–204 (2009).
- Zhang XJ, Huang W, Yang S et al. Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat. Genet.41(2), 205–210 (2009).
- Torti DC, Feldman SR. Interleukin-12, interleukin-23, and psoriasis: current prospects. J. Am. Acad. Dermatol.57(6), 1059–1068 (2007).
- Tsunemi Y, Saeki H, Nakamura K et al. Interleukin-12 p40 gene (IL12B) 3´-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. J. Dermatol. Sci.30(2), 161–166 (2002).
- Cargill M, Schrodi SJ, Chang M et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet.80(2), 273–290 (2007).
- Randolph AG, Lange C, Silverman EK et al. The IL12B gene is associated with asthma. Am. J. Hum. Genet.75(4), 709–715 (2004).
- Duerr RH, Taylor KD, Brant SR et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science314(5804), 1461–1463 (2006).
- Krueger GG, Langley RG, Leonardi C et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N. Engl. J. Med.356(6), 580–592 (2007).
- de Cid R, Riveira-Munoz E, Zeeuwen PL et al. Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat. Genet.41(2), 211–215 (2009).
- Schon MP, Boehncke WH. Psoriasis. N. Engl. J. Med.352(18), 1899–1912 (2005).
- Bowcock AM, Krueger JG. Getting under the skin: the immunogenetics of psoriasis. Nat. Rev. Immunol.5(9), 699–711 (2005).
- Krueger JG, Bowcock A. Psoriasis pathophysiology: current concepts of pathogenesis. Ann. Rheum. Dis.64(Suppl. 2), ii30–ii36 (2005).
Website
- Catalog of published genome-wide association studies www.genome.gov/26525384