Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G (original) (raw)
Journal of Investigative Dermatology, 2009
Genetic variants have long been suspected to be important in psoriasis. Recent work has suggested that HLA-Cw6 on chromosome 6 is the risk variant in the PSORS1 [MIM 177900] susceptibility locus that confers the greatest risk for early onset of psoriasis. Although numerous minor susceptibility loci have been identified by linkage analysis, few biologically relevant candidates have been discovered within these intervals. Recent large-scale genome-wide association studies have yielded new candidates in genes encoding cytokines with functional relevance to psoriasis. Polymorphisms within the genes encoding the IL-12 p40 subunit, IL12B, and one of the IL-23 receptor subunits, IL23R, have been replicated in US and European populations and overlap with risk of Crohn's disease. Polymorphisms within the gene encoding IL-13, a Th2 cytokine, also confer risk for psoriasis. Variants of the gene IL15 encoding IL-15 have been identified that associate with psoriasis in a Chinese population. These discoveries pose the challenge of elucidating the role of common genetic variants in susceptibility to and manifestations of psoriasis.
Journal of Investigative Dermatology, 2009
Psoriasis is a genetically determined inflammatory skin disease. Although the transition from uninvolved into lesional skin is accompanied by changes in the expression of multiple genes, much less is known about the difference between uninvolved skin from psoriatic patients as opposed to skin from normal individuals. Multiple biochemical and morphological changes were reported decades ago in uninvolved psoriatic skin but remain poorly understood. Here, we show dysregulation of 223 transcripts representing 179 unique genes in uninvolved psoriatic skin, 178 of which were not previously known to be altered in their expression. The proteins encoded by these transcripts are involved in lipid metabolism, antimicrobial defenses, epidermal differentiation, and control of cutaneous vasculature. Cluster analysis of transcripts with significantly altered expression identified a group of genes involved in lipid metabolism with highly correlated gene expression. Promoter analysis showed enrichment for binding sites of three transcription factors; peroxisome proliferatoractivator receptor alpha (PPARA), sterol regulatory element-binding protein (SREBF), and estrogen receptor 2 (ESR2), suggesting that the coordinate regulation of lipid metabolic genes may be related to the action of these factors. Taken together, our results identify a ''pre-psoriatic'' gene expression signature, suggesting decreased lipid biosynthesis and increased innate immunity in uninvolved psoriatic skin.
Gene from a Psoriasis Susceptibility Locus Primes the Skin for Inflammation
Science Translational Medicine, 2010
Psoriasis is a common complex genetic disease characterized by hyperplasia and inflammation in the skin; however, the relative contributions of epidermal cells and the immune system to disease pathogenesis remain unclear. Linkage studies have defined a psoriasis susceptibility locus (PSORS4) on 1q21, the epidermal differentiation complex, which includes genes for small S100 calcium-binding proteins. These proteins are involved in extracellular and intracellular signaling during epithelial host defense, linking innate and adaptive immunity. Inflammation-prone psoriatic skin constitutively expresses elevated concentrations of S100A7 (psoriasin) and S100A15 (koebnerisin) in the epidermis. Here, we report that genetically modified mice expressing elevated amounts of doxycycline-regulated mS100a7a15 in skin keratinocytes demonstrated an exaggerated inflammatory response when challenged by exogenous stimuli such as abrasion (Koebner phenomenon). This immune response was characterized by immune cell infiltration and elevated concentrations of T helper 1 (T H 1) and T H 17 proinflammatory cytokines, which have been linked to the pathogenesis of psoriasis and were further amplified upon challenge. Both inflammation priming and amplification required mS100a7a15 binding to the receptor of advanced glycation end products (RAGE). mS100a7a15 potentiated inflammation by acting directly as a chemoattractant for leukocytes, further increasing the number of inflammatory cells infiltrating the skin. This study provides a pathogenetic psoriasis model using a psoriasis candidate gene to link the epidermis and innate immune system in inflammation priming, highlighting the S100A7A15-RAGE axis as a potential therapeutic target.
Genome-wide pathway analysis identifies new genetic pathways associated with psoriasis
The Journal of investigative dermatology, 2015
Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of the present study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 SNPs in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR≤2.55e-2) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR≤3.46e-2). We found genetic pathways that had not been previously associated with psoriasis risk like retinol metabolis...
2009
Psoriasis is a common inflammatory skin disease with a prevalence of 2-3% in individuals of European ancestry 1 . In a genome-wide search for copy number variants (CNV) using a sample pooling approach, we have identified a deletion comprising LCE3B and LCE3C, members of the late cornified envelope (LCE) gene cluster 2 . The absence of LCE3B and LCE3C (LCE3C_LCE3B-del ) is significantly associated (P ¼ 1.38E-08) with risk of psoriasis in 2,831 samples from Spain, The Netherlands, Italy and the United States, and in a family-based study (P ¼ 5.4E-04). LCE3C_LCE3B-del is tagged by rs4112788 (r 2 ¼ 0.93), which is also strongly associated with psoriasis (P o 6.6E-09). LCE3C_LCE3B-del shows epistatic effects with the HLA-Cw6 allele on the development of psoriasis in Dutch samples and multiplicative effects in the other samples. LCE expression can be induced in normal epidermis by skin barrier disruption and is strongly expressed in psoriatic lesions, suggesting that compromised skin barrier function has a role in psoriasis susceptibility.