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Background: Palmoplantar pustulosis (PPP) is an inflammatory disease characterized by relapsing eruptions of neutrophil-filled, sterile pustules on the palms and soles that can be clinically difficult to differentiate from non-pustular palmoplantar psoriasis (palmPP) and dyshidrotic palmoplantar eczema (DPE)., Objective: We sought to identify overlapping and unique PPP, palmPP, and DPE drivers to provide molecular insight into their pathogenesis., Methods: We performed bulk RNA sequencing of lesional PPP (n = 33), palmPP (n = 5), and DPE (n = 28) samples, as well as 5 healthy nonacral and 10 healthy acral skin samples., Results: Acral skin showed a unique immune environment, likely contributing to a unique niche for palmoplantar inflammatory diseases. Compared to healthy acral skin, PPP, palmPP, and DPE displayed a broad overlapping transcriptomic signature characterized by shared upregulation of proinflammatory cytokines (TNF, IL-36), chemokines, and T-cell-associated genes, along with unique disease features of each disease state, including enriched neutrophil processes in PPP and to a lesser extent in palmPP, and lipid antigen processing in DPE. Strikingly, unsupervised clustering and trajectory analyses demonstrated divergent inflammatory profiles within the 3 disease states. These identified putative key upstream immunologic switches, including eicosanoids, interferon responses, and neutrophil degranulation, contributing to disease heterogeneity., Conclusion: A molecular overlap exists between different inflammatory palmoplantar diseases that supersedes clinical and histologic assessment. This highlights the heterogeneity within each condition, suggesting limitations of current disease classification and the need to move toward a molecular classification of inflammatory acral diseases., Competing Interests: Disclosure statement Supported by an unrestricted research grant from Janssen. Additional support was provided by P30-AR075043 (J.E.G., L.C.T.), the Alfred A. Taubman Medical Research Institute (J.E.G., J.M.K.), and the George M. O’Brien Michigan Kidney Translational Research Core Center P30DK081943 (C.C.B.). C.F.S. is supported by K23–NIH/NIAID K23AI162661. F.W. is supported by the Taubman Institute Innovation Projects program. Disclosure of potential conflict of interest: K. R. van Straalen has received honoraria from Novartis, Boehringer-Ingelheim, and UCB. A. S. MacLeod is currently employed by Janssen Pharmaceuticals. J. M. Kahlenberg has received grant support from Q32 Bio, Celgene/Bristol Myers Squibb (BMS), Ventus Therapeutics, ROME Therapeutics, and Janssen; and has served on advisory boards for AstraZeneca, Eli Lilly, GlaxoSmithKline, BMS, Avion Pharmaceuticals, Provention Bio, Aurinia Pharmaceuticals, Ventus Therapeutics, Gilead, and EMD Serano. M. W. L. Leung is currently employed by Janssen R&D LLC, San Diego, Calif. J. E. Gudjonsson has received grant support from Celgene/BMS, Janssen, Eli Lilly, and Almirall and has served on advisory boards for AstraZeneca, Sanofi, Eli Lilly, Boehringer Ingelheim, Novartis, Janssen, Almirall, and BMS. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Multiple treatment options are available for the management of psoriasis, but clinical response varies among individual patients and no biomarkers are available to facilitate treatment selection for improved patient outcomes., Objectives: To utilize retrospective data to conduct a pharmacogenetic study to explore the potential genetic pathways associated with drug response in the treatment of psoriasis., Methods: We conducted a retrospective pharmacogenetic study using self-evaluated treatment response from 1942 genotyped patients with psoriasis. We examined 6 502 658 genetic markers to model their associations with response to six treatment options using linear regression, adjusting for cohort variables and demographic features. We further utilized an integrative approach incorporating epigenomics, transcriptomics and a longitudinal clinical cohort to provide biological implications for the topmost signals associated with drug response., Results: Two novel markers were revealed to be associated with treatment response: rs1991820 (P = 1.30 × 10-6) for anti-tumour necrosis factor (TNF) biologics; and rs62264137 (P = 2.94 × 10-6) for methotrexate, which was also associated with cutaneous mRNA expression levels of two known psoriasis-related genes KLK7 (P = 1.0 × 10-12) and CD200 (P = 5.4 × 10-6). We demonstrated that KLK7 expression was increased in the psoriatic epidermis, as shown by immunohistochemistry, as well as single-cell RNA sequencing, and its responsiveness to anti-TNF treatment was highlighted. By inhibiting the expression of KLK7, we further illustrated that keratinocytes have decreased proinflammatory responses to TNF., Conclusions: Our study implicates the genetic regulation of cytokine responses in predicting clinical drug response and supports the association between pharmacogenetic loci and anti-TNF response, as shown here for KLK7., Competing Interests: Conflicts of interest J.E.G. has served as a consultant to AbbVie, Eli Lilly, Almirall, Celgene, BMS, Janssen, Prometheus, TimberPharma, Galderma, Novartis, MiRagen and AnaptysBio, and has received research support from AbbVie, SunPharma, Eli Lilly, Kyowa Kirin, Almirall, Celgene, BMS, Janssen, Prometheus and TimberPharma. L.C.T. has received support from Novartis, Galderma and Janssen. N.L.W. has received support from Sun Pharma, and has served as a consultant to AnaptysBio and Janssen., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Psoriasis and multiple sclerosis (MS) are complex immune diseases that are mediated by T cells and share multiple comorbidities. Previous studies have suggested psoriatic patients are at higher risk of MS; however, causal relationships between the two conditions remain unclear. Through epidemiology and genetics, we provide a comprehensive understanding of the relationship, and share molecular factors between psoriasis and MS., Methods: We used logistic regression, trans-disease meta-analysis and Mendelian randomization. Medical claims data were included from 30 million patients, including 141,544 with MS and 742,919 with psoriasis. We used genome-wide association study summary statistics from 11,024 psoriatic, 14,802 MS cases, and 43,039 controls for trans-disease meta-analysis, with additional summary statistics from 5 million individuals for Mendelian randomization., Results: Psoriatic patients have a significantly higher risk of MS (4,637 patients with both diseases; odds ratio [OR] 1.07, p = 1.2 × 10 -5 ) after controlling for potential confounders. Using inverse variance and equally weighted trans-disease meta-analysis, we revealed >20 shared and opposing (direction of effect) genetic loci outside the major histocompatibility complex that showed significant genetic colocalization (in COLOC and COLOC-SuSiE v5.1.0). Co-expression analysis of genes from these loci further identified distinct clusters that were enriched among pathways for interleukin-17/tumor necrosis factor-α (OR >39, p < 1.6 × 10 -3 ) and Janus kinase-signal transducers and activators of transcription (OR 35, p = 1.1 × 10 -5 ), including genes, such as TNFAIP3, TYK2, and TNFRSF1A. Mendelian randomization found psoriasis as an exposure has a significant causal effect on MS (OR 1.04, p = 5.8 × 10 -3 ), independent of type 1 diabetes (OR 1.05, p = 4.3 × 10 -7 ), type 2 diabetes (OR 1.08, p = 2.3 × 10 -3 ), inflammatory bowel disease (OR 1.11, p = 1.6 × 10 -11 ), and vitamin D level (OR 0.75, p = 9.4 × 10 -3 )., Interpretation: By investigating the shared genetics of psoriasis and MS, along with their modifiable risk factors, our findings will advance innovations in treatment for patients suffering from comorbidities. ANN NEUROL 2023;94:384-397., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

ERAP1, ERAP2, and LNPEP are aminopeptidases implicated in autoimmune pathophysiology. In this study, we show that ERAP2 is upregulated and ERAP1 is downregulated in patients with psoriasis who are homozygous for autoimmune-linked variants of ERAP. We also demonstrate that aminopeptidase expression is not uniform in the skin. Specifically, the intracellular antigen-processing aminopeptidases ERAP1 and ERAP2 are strongly expressed in basal and early spinous layer keratinocytes, whereas granular layer keratinocytes expressed predominantly LNPEP, an aminopeptidase specialized in the processing of extracellular antigens for presentation to T cells. In psoriasis, basal keratinocytes also expressed the T-cell- and monocyte-attracting chemokine, CCL2, and the T-cell-supporting cytokine, IL-15. In contrast, TGF-β1 was the major cytokine expressed by healthy control basal keratinocytes. SFRP2-high dermal fibroblasts were also noted to have an ERAP2-high expression phenotype and elevated HLA-C. In psoriasis, the SFRP2-high fibroblast subpopulation also expressed elevated CXCL14. From these results, we postulate that (i) an increased ERAP2/ERAP1 ratio results in altered antigen processing, a potential mechanism by which ERAP risk alleles predispose individuals to autoimmunity; (ii) ERAP2-high expressing cells display a unique major histocompatibility complex-bound peptidome generated from intracellular antigens; and (iii) the granular layer peptidome is skewed toward extracellular antigens., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is incompletely understood. Here we demonstrate, using a combination of single cell and spatial RNA sequencing, IL-36 dependent amplification of IL-17A and TNF inflammatory responses in the absence of neutrophil proteases, which primarily occur within the supraspinous layer of the psoriatic epidermis. We further show that a subset of SFRP2 + fibroblasts in psoriasis contribute to amplification of the immune network through transition to a pro-inflammatory state. The SFRP2 + fibroblast communication network involves production of CCL13, CCL19 and CXCL12, connected by ligand-receptor interactions to other spatially proximate cell types: CCR2 + myeloid cells, CCR7 + LAMP3 + dendritic cells, and CXCR4 expressed on both CD8 + Tc17 cells and keratinocytes, respectively. The SFRP2 + fibroblasts also express cathepsin S, further amplifying inflammatory responses by activating IL-36G in keratinocytes. These data provide an in-depth view of psoriasis pathogenesis, which expands our understanding of the critical cellular participants to include inflammatory fibroblasts and their cellular interactions., (© 2023. The Author(s).)

Background: Observational research suggests that vitamin D levels affect psoriasis. However, observational studies are prone to potential confounding or reverse causation, which complicates interpreting the data and drawing causal conclusions., Aim: To apply Mendelian randomization (MR) methods to comprehensively assess a potential association between vitamin D and psoriasis., Methods: Genetic variants strongly associated with 25-hydroxyvitamin D (25OHD) in genome-wide association study (GWAS) data from 417 580 and 79 366 individuals from two independent studies served as instrumental variables (used as the discovery and replication datasets, respectively). As the outcome variable, we used GWAS data of psoriasis (13 229 people in the case group, 21 543 in the control group). We used (i) biologically validated genetic instruments, and (ii) polygenic genetic instruments to assess the relationship between genetically proxied vitamin D and psoriasis. We carried out inverse-variance weighted (IVW) MR analyses for the primary analysis. In sensitivity analyses, we used robust MR approaches., Results: MR analyses of both the discovery and replication datasets did not show an effect of 25OHD on psoriasis. Neither the IVW MR analysis of the biologically validated instruments [discovery dataset: odds ratio (OR) 0.99; 95% confidence interval (CI) 0.88-1.12, P = 0.873; replication dataset: OR 0.98, 95% CI 0.66-1.46, P = 0.930] nor that of the polygenic genetic instruments (discovery dataset: OR 1.00, 95% CI 0.81-1.22, P = 0.973; replication dataset: OR 0.94, 95% CI 0.64-1.38, P = 0.737) revealed an impact of 25OHD on psoriasis., Conclusion: The present MR study did not support the hypothesis that vitamin D levels, measured by 25OHD, affect psoriasis. This study was conducted on Europeans, so the conclusions may not be applicable to all ethnicities., Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Psoriasis and coronary artery disease (CAD) are related comorbidities that are well established, but whether a genetic basis underlies this is not well studied. We apply trans-disease meta-analysis to 11,024 psoriasis and 60,801 CAD cases, along with their associated controls, identifying one opposing and three shared genetic loci, which are confirmed through colocalization analysis. Combining results from Bayesian credible interval analysis with independent information from genomic, epigenomic, and spatial chromatin organization, we prioritize genes (including IFIH1 and IL23A) that have implications for common molecular mechanisms involved in psoriasis and CAD inflammatory signaling. Chronic systemic inflammation has been associated with CAD and myocardial infarction, and Mendelian randomization analysis finds that CAD as an exposure can have a significant causal effect on psoriasis (OR = 1.11; p = 3×10 -6 ) following adjustment for BMI and waist-hip ratio. Together, these findings suggest that systemic inflammation which causes CAD can increase the risk of psoriasis., (© 2022. The Author(s).)

Background: Alcohol consumption and smoking have been reported to be associated with psoriasis risk. However, a conclusion with high-quality evidence of causality could not be easily drawn from regular observational studies., Objectives: This study aims to assess the causal associations of alcohol consumption and smoking with psoriasis., Methods: Genome-wide association study (GWAS) summary-level data for alcohol consumption (N = 941 280), smoking initiation (N = 1 232 091), cigarettes per day (N = 337 334) and smoking cessation (N = 547 219) was obtained from the GSCAN consortium (Sequencing Consortium of Alcohol and Nicotine use). The GWAS results for lifetime smoking (N = 462 690) were obtained from the UK Biobank samples. Summary statistics for psoriasis were obtained from a recent GWAS meta-analysis of eight cohorts comprising 19 032 cases and 286 769 controls and the FinnGen consortium, comprising 4510 cases and 212 242 controls. Linkage disequilibrium score regression was applied to compute the genetic correlation. Bidirectional Mendelian randomization (MR) analyses were conducted to determine casual direction using independent genetic variants that reached genome-wide significance (P < 5 × 10 -8 )., Results: There were genetic correlations between smoking and psoriasis. MR revealed a causal effect of smoking initiation [odds ratio (OR) 1·46, 95% confidence interval (CI) 1·32-1·60, P = 6·24E-14], cigarettes per day (OR 1·38, 95% CI 1·13-1·67, P = 0·001) and lifetime smoking (OR 1·96, 95% CI 1·41-2·73, P = 7·32E-05) on psoriasis. Additionally, a suggestive causal effect of smoking cessation on psoriasis was observed (OR 1·39, 95% CI 1·07-1·79, P = 0·012). We found no causal relationship between alcohol consumption and psoriasis (P = 0·379). The reverse associations were not statistically significant., Conclusions: Our findings provide causal evidence for the effects of smoking on psoriasis risk. What is already known about this topic? Alcohol consumption and smoking have been reported to be associated with psoriasis risk. Whether alcohol consumption and smoking have a causal effect on psoriasis risk remains unclear. What does this study add? This Mendelian randomization study shows a causal association between smoking, but not alcohol consumption, and the risk of developing psoriasis. Restricting smoking could be helpful in reducing the burden of psoriasis., (© 2022 British Association of Dermatologists.)

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a posttranslational regulator of the LDL receptor (LDLR). Recent studies have proposed a role for PCSK9 in regulating immune responses. Using RNA-Seq-based variant discovery, we identified a possible psoriasis-susceptibility locus at 1p32.3, located within PCSK9 (rs662145 C > T). This finding was verified in independently acquired genomic and RNA-Seq data sets. Single-cell RNA-Seq (scRNA-Seq) identified keratinocytes as the primary source of PCSK9 in human skin. PCSK9 expression, however, was not uniform across keratinocyte subpopulations. scRNA-Seq and IHC demonstrated an epidermal gradient of PCSK9, with expression being highest in basal and early spinous layer keratinocytes and lowest in granular layer keratinocytes. IL36G expression followed the opposite pattern, with expression highest in granular layer keratinocytes. PCSK9 siRNA knockdown experiments confirmed this inverse relationship between PCSK9 and IL36G expression. Other immune genes were also linked to PCSK9 expression, including IL27RA, IL1RL1, ISG20, and STX3. In both cultured keratinocytes and nonlesional human skin, homozygosity for PCSK9 SNP rs662145 C > T was associated with lower PCSK9 expression and higher IL36G expression, when compared with heterozygous skin or cell lines. Together, these results support PCSK9 as a psoriasis-susceptibility locus and establish a putative link between PCSK9 and inflammatory cytokine expression.

Tape stripping is a minimally invasive, nonscarring method that can be utilized to assess gene expression in the skin but is infrequently used given technical constraints. By comparing different tape stripping technologies and full-thickness skin biopsy results of lesional and nonlesional psoriatic skin from the same patients, we demonstrate that tape stripping with optimized high-resolution transcriptomic profiling can be used to effectively assess and characterize inflammatory responses in the skin. Upon comparison with single-cell RNA-sequencing data from psoriatic full-thickness skin biopsies, we illustrate that tape-stripping efficiently captures the transcriptome of the upper layers of the epidermis with sufficient resolution to assess the molecular components of the feed-forward immune amplification pathway in psoriasis. Notably, nonlesional psoriatic skin sampled by tape stripping demonstrates activated, proinflammatory changes when compared to healthy control skin, suggesting a prepsoriatic state, which is not captured on full-thickness skin biopsy transcriptome profiling. This work illustrates an approach to assess inflammatory response in the epidermis by combining noninvasive sampling with high throughput RNA-sequencing, providing a foundation for biomarker discoveries and mechanism of action studies for inflammatory skin conditions., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: Observational research suggests that periodontitis affects psoriasis. However, observational studies are prone to reverse causation and confounding, which hampers drawing causal conclusions and the effect direction. We applied the Mendelian randomization (MR) method to comprehensively assess the potential bi-directional association between periodontitis and psoriasis., Materials and Methods: We used genetic instruments from the largest available genome-wide association study of European descent for periodontitis (17,353 cases, 28,210 controls) to investigate the relationship with psoriasis (13,229 cases, 21,543 controls), and vice versa. Causal Analysis Using Summary Effect (CAUSE) estimates and inverse variance-weighted (IVW) MR analyses were used for the primary analysis. Robust MR approaches were used for sensitivity analyses., Results: Both univariable methods, CAUSE and IVW MR analyses, did not reveal any impact of periodontitis on psoriasis (CAUSE odds ratio [OR] = 1.00, p = 1.00; IVW OR = 1.02, p = .6247), or vice versa (CAUSE OR = 1.01, p = .5135; IVW OR = 1.00, p = .7070). The null association was corroborated by pleiotropy-robust methods with ORs close to 1 and p-values >.59. Overall, MR analyses did not suggest any effect of periodontitis on psoriasis. Similarly, there was no evidence to support an effect of psoriasis on periodontitis., Conclusions: Within the limitations of this MR study, the outcomes supported neither periodontitis affecting psoriasis nor psoriasis affecting periodontitis., (© 2022 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Differences in the morphology and physiology of darkly pigmented skin compared with those of lightly pigmented skin are well-recognized. There are also disparities in the prevalence and clinical features for many inflammatory skin diseases, including atopic dermatitis and psoriasis; however, the underlying mechanisms are largely unknown. We compared the baseline gene expression in full-thickness skin biopsies from healthy individuals self-reporting as African American (AA) or as White non-Hispanic (WNH). Extensively validated RNA-sequencing analysis identified 570 differentially expressed genes in AA skin, including Igs and their receptors such as FCER1G; proinflammatory genes such as TNFα and IL32; and epidermal differentiation cluster and keratin genes. Differentially expressed genes were functionally enriched for inflammatory responses, keratinization, and cornified envelope formation. RNA-sequencing analysis of three-dimensional human skin equivalents made from AA and WNH primary keratinocytes revealed 360 differentially expressed genes (some shared with skin) that were enriched by similar functions. AA human skin equivalents appeared more responsive to TNF-α proinflammatory effects. Finally, AA-specific differentially expressed genes in the skin and human skin equivalents significantly overlapped with molecular signatures of skin in patients with atopic dermatitis and psoriasis. Overall, these findings suggest the existence of intrinsic proinflammatory circuits in AA keratinocytes/skin that may account for disease disparities and will help to build a foundation for the development of targeted skin disease prevention., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Immune-mediated skin conditions (IMSCs) are a diverse group of autoimmune diseases associated with significant disease burden. Atopic dermatitis and psoriasis are among the most common IMSCs in the United States and have disproportionate impact on racial and ethnic minorities. African American patients are more likely to develop atopic dermatitis compared to their European American counterparts; and despite lower prevalence of psoriasis among this group, African American patients can suffer from more extensive disease involvement, significant post-inflammatory changes, and a decreased quality of life. While recent studies have been focused on understanding the heterogeneity underlying disease mechanisms and genetic factors at play, little emphasis has been put on the effect of psychosocial or psychological stress on immune pathways, and how these factors contribute to differences in clinical severity, prevalence, and treatment response across ethnic groups. In this review, we explore the heterogeneity of atopic dermatitis and psoriasis between African American and European American patients by summarizing epidemiological studies, addressing potential molecular and environmental factors, with a focus on the intersection between stress and inflammatory pathways., Competing Interests: JG has served as a consultant to AbbVie, Eli Lilly, Almirall, Celgene, BMS, Janssen, Prometheus, TimberPharma, Galderma, Novatis, MiRagen, AnaptysBio and has received research support from AbbVie, SunPharma, Eli Lilly, Kyowa Kirin, Almirall, Celgene, BMS, Janssen, Prometheus, and TimberPharma. LT has received support from Janssen and Galderma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jamerson, Li, Sreeskandarajan, Budunova, He, Kang, Gudjonsson, Patrick and Tsoi.)

Background: A major issue with the current management of psoriasis is our inability to predict treatment response., Objective: Our aim was to evaluate the ability to use baseline molecular expression profiling to assess treatment outcome for patients with psoriasis., Methods: We conducted a longitudinal study of 46 patients with chronic plaque psoriasis treated with anti-TNF agent etanercept, and molecular profiles were assessed in more than 200 RNA-seq samples., Results: We demonstrated correlation between clinical response and molecular changes during the course of the treatment, particularly for genes responding to IL-17A/TNF in keratinocytes. Intriguingly, baseline gene expressions in nonlesional, but not lesional, skin were the best marker of treatment response at week 12. We identified USP18, a known regulator of IFN responses, as positively correlated with Psoriasis Area and Severity Index (PASI) improvement (P = 9.8 × 10 -4 ) and demonstrate its role in regulating IFN/TNF responses in keratinocytes. Consistently, cytokine gene signatures enriched in baseline nonlesional skin expression profiles had strong correlations with PASI improvement. Using this information, we developed a statistical model for predicting PASI75 (ie, 75% of PASI improvement) at week 12, achieving area under the receiver-operating characteristic curve value of 0.75 and up to 80% accurate PASI75 prediction among the top predicted responders., Conclusions: Our results illustrate feasibility of assessing drug response in psoriasis using nonlesional skin and implicate involvement of IFN regulators in anti-TNF responses., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Psoriasis is a common, inflammatory autoimmune skin disease. Early detection of an IFN-1 signature occurs in many psoriasis lesions, but the source of IFN production remains debated. IFN-κ is an important source of IFN-1 production in the epidermis. We identified a correlation between IFN-regulated and psoriasis-associated genes in human lesional skin. We thus wanted to explore the effects of IFN-κ in psoriasis using the well-characterized imiquimod psoriasis model. Three mouse strains aged 10 weeks were used: wild-type C57Bl/6, C57Bl/6 that overexpress Ifnk in the epidermis (i.e., transgenic), and total body Ifnk -/- (i.e., knockout) strain. Psoriasis was induced by topical application of imiquimod on both ears for 8 consecutive days. Notably, the severity of skin lesions and inflammatory cell infiltration was more significantly increased in transgenic than in wild-type than in knockout mice. Gene expression analysis identified greater upregulation of Mxa, Il1b, Tnfa, Il6, Il12, Il23, Il17, and Ifng in transgenic compared to wild-type compared to knockout mice after imiquimod treatment. Furthermore, imiquimod increased CD8 + and CD4 + T-cell infiltration more in transgenic than in wild-type than in knockout mice. In summary, we identified IFN-κ as a rheostat for initiation of psoriasiform inflammation. This suggests that targeting IFN-1s early in the disease may be an effective way of controlling psoriatic inflammation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Altered epidermal differentiation along with increased keratinocyte proliferation is a characteristic feature of psoriasis and pityriasis rubra pilaris (PRP). However, despite this large degree of overlapping clinical and histologic features, the molecular signatures these skin disorders share are unknown. Using global transcriptomic profiling, we demonstrate that plaque psoriasis and PRP skin lesions have high overlap, with all differentially expressed genes in PRP relative to normal skin having complete overlap with those in psoriasis. The major common pathway shared between psoriasis and PRP involves the phospholipases PLA2G2F, PLA2G4D, and PLA2G4E, which were found to be primarily expressed in the epidermis. Gene silencing each of the 3 PLA2s led to reduction in immune responses and epidermal thickness both in vitro and in vivo in a mouse model of psoriasis, establishing their proinflammatory roles. Lipidomic analyses demonstrated that PLA2s affect mobilization of a phospholipid-eicosanoid pool, which is altered in psoriatic lesions and functions to promote immune responses in keratinocytes. Taken together, our results highlight the important role of PLA2s as regulators of epidermal barrier homeostasis and inflammation, identify PLA2s as a shared pathogenic mechanism between PRP and psoriasis, and as potential therapeutic targets for both diseases.

The observed incidence of psoriasis has been gradually increasing over time (J Am Acad Dermatol, 03, 2009, 394), but the underlying pathogenic factors have remained unclear. Recent studies suggest the importance of epigenetic modification in the pathogenesis of psoriasis. Aberrant epigenetic patterns including changes in DNA methylation, histone modifications and non-coding RNA expression are observed in psoriatic skin. Reversing these epigenetic mechanisms has showed improvement in psoriatic phenotypes, making epigenetic therapy a potential avenue for psoriasis treatment. Here, we summarize relevant evidence for epigenetic dysregulation contributing to psoriasis susceptibility and pathogenesis, and the factors responsible for epigenetic modifications, providing directions for potential future clinical avenues., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Atopic dermatitis (AD) and psoriasis are two common chronic inflammatory skin diseases that are associated with various comorbidities. Circular RNA (circRNA) constitutes a major class of non-coding RNAs that have been implicated in many human diseases, although their potential involvement in inflammatory skin diseases remains elusive. Here, we compare and contrast the circRNA expression landscapes in paired lesional and non-lesional skin from psoriasis and AD patients relative to skin from unaffected individuals using high-depth RNA-seq data. CircRNAs and their cognate linear transcripts were quantified using the circRNA detection algorithm, CIRI2, and in situ hybridization and Sanger sequencing was used for validation purposes. We identified 39,286 circRNAs among all samples and found that psoriasis and AD lesional skin could be distinguished from non-lesional and healthy skin based on circRNA expression landscapes. In general, circRNAs were less abundant in lesional relative to non-lesional and healthy skin. Differential expression analyses revealed many significantly downregulated circRNAs, mainly in psoriasis lesional skin, and a strong correlation between psoriasis and AD-related circRNA expression changes was observed. Two individual circRNAs, ciRS-7 (also known as CDR1as) and circZRANB1, were specifically dysregulated in psoriasis and show promise as biomarkers for discriminating AD from psoriasis. In conclusion, the circRNA transcriptomes of psoriasis and AD share expression features, including a global downregulation relative to healthy skin, but this is most pronounced in psoriasis, and only psoriasis is characterized by several circRNAs being dysregulated independently of their cognate linear transcripts. Finally, specific circRNAs could potentially be used to distinguish AD from psoriasis., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Drug-drug interactions (DDIs) can result in adverse and potentially life-threatening health consequences; however, it is challenging to predict potential DDIs in advance. We introduce a new computational approach to comprehensively assess the drug pairs which may be involved in specific DDI types by combining information from large-scale gene expression (984 transcriptomic datasets), molecular structure (2159 drugs), and medical claims (150 million patients)., Materials and Methods: Features were integrated using ensemble machine learning techniques, and we evaluated the DDIs predicted with a large hospital-based medical records dataset. Our pipeline integrates information from >30 different resources, including >10 000 drugs and >1.7 million drug-gene pairs. We applied our technique to predict interactions between 37 611 drug pairs used to treat psoriasis and its comorbidities., Results: Our approach achieves >0.9 area under the receiver operator curve (AUROC) for differentiating 11 861 known DDIs from 25 750 non-DDI drug pairs. Significantly, we demonstrate that the novel DDIs we predict can be confirmed through independent data sources and supported using clinical medical records., Conclusions: By applying machine learning and taking advantage of molecular, genomic, and health record data, we are able to accurately predict potential new DDIs that can have an impact on public health., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Killer cell immunoglobulin-like receptors (KIR) regulate immune responses in NK and CD8+ T cells via interaction with HLA ligands. KIR genes, including KIR2DS1, KIR3DL1, and KIR3DS1 have previously been implicated in psoriasis susceptibility. However, these previous studies were constrained to small sample sizes, in part due to the time and expense required for direct genotyping of KIR genes. Here, we implemented KIR*IMP to impute KIR copy number from single-nucleotide polymorphisms (SNPs) on chromosome 19 in the discovery cohort (n=11,912) from the PAGE consortium, University of California San Francisco, and the University of Dundee, and in a replication cohort (n=66,357) from Kaiser Permanente Northern California. Stratified multivariate logistic regression that accounted for patient ancestry and high-risk HLA alleles revealed that KIR2DL2 copy number was significantly associated with psoriasis in the discovery cohort (p ≤ 0.05). The KIR2DL2 copy number association was replicated in the Kaiser Permanente replication cohort. This is the first reported association of KIR2DL2 copy number with psoriasis and highlights the importance of KIR genetics in the pathogenesis of psoriasis., Competing Interests: WL has received research grant funding from Abbvie, Amgen, Janssen, Leo, Novartis, Pfizer, Regeneron, and TRex Bio. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ahn, Vukcevic, Motyer, Nititham, Squire, Hollenbach, Norman, Ellinghaus, Nair, Tsoi, Oksenberg, Foerster, Lieb, Weidinger, Franke, Elder, Jorgenson, Leslie and Liao.)

Psoriasis and type 2 diabetes (T2D) are complex conditions with significant impacts on health. Patients with psoriasis have a higher risk of T2D (∼1.5 OR) and vice versa, controlling for body mass index; yet, there has been a limited study comparing their genetic architecture. We hypothesized that there are shared genetic components between psoriasis and T2D. Trans-disease meta-analysis was applied to 8,016,731 well-imputed genetic markers from large-scale meta-analyses of psoriasis (11,024 cases and 16,336 controls) and T2D (74,124 cases and 824,006 controls), adjusted for body mass index. We confirmed our findings in a hospital-based study (42,112 patients) and tested for causal relationships with multivariable Mendelian randomization. Mendelian randomization identified a causal relationship between psoriasis and T2D (P = 1.6 × 10 ‒4 , OR = 1.01) and highlighted the impact of body mass index. Trans-disease meta-analysis further revealed four genome-wide significant loci (P < 5 × 10 ‒8 ) with evidence of colocalization and shared directions of effect between psoriasis and T2D not present in body mass index. The proteins coded by genes in these loci (ACTR2, ERLIN1, TRMT112, and BECN1) are connected through NF-κB signaling. Our results provide insight into the immunological components that connect immune-mediated skin conditions and metabolic diseases, independent of confounding factors., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19) is commonly associated with skin manifestations, and may also exacerbate existing skin diseases, yet the relationship between COVID-19 and skin diseases remains unclear., Objective: By investigating this relationship through a multiomics approach, we sought to ascertain whether patients with skin conditions are more susceptible to COVID-19., Methods: We conducted an epidemiological study and then compared gene expression across 9 different inflammatory skin conditions and severe acute respiratory syndrome coronavirus 2-infected bronchial epithelial cell lines, and then performed a genome-wide association study transdisease meta-analysis between COVID-19 susceptibility and 2 skin diseases (psoriasis and atopic dermatitis)., Results: Skin conditions, including psoriasis and atopic dermatitis, increase the risk of COVID-19 (odds ratio, 1.55; P = 1.4 × 10 -9 ) but decrease the risk of mechanical ventilation (odds ratio, 0.22; P = 8.5 × 10 -5 ). We observed significant overlap in gene expression between the infected normal bronchial epithelial cells and inflammatory skin diseases, such as psoriasis and atopic dermatitis. For genes that are commonly induced in both the severe acute respiratory syndrome coronavirus 2 infection and skin diseases, there are 4 S100 family members located in the epidermal differentiation complex, and we also identified the "IL-17 signaling pathway" (P = 4.9 × 10 -77 ) as one of the most significantly enriched pathways. Furthermore, a shared genome-wide significant locus in the epidermal differentiation complex was identified between psoriasis and severe acute respiratory syndrome coronavirus 2 infection, with the lead marker being a significant expression quantitative trait locus for S100A12 (P = 3.3 × 10 -7 )., Conclusions: Together our findings suggest association between inflammatory skin conditions and higher risk of COVID-19, but with less severe course, and highlight shared components involved in anti-COVID-19 immune response., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Psoriasis is a chronic inflammatory skin condition that has a fairly wide range of clinical presentations. Plaque psoriasis, which is the most common manifestation of psoriasis, is located on one end of the spectrum, dominated by adaptive immune responses, whereas the rarer pustular psoriasis lies on the opposite end, dominated by innate and autoinflammatory immune responses. In recent years, genetic studies have identified six genetic variants that predispose to pustular psoriasis, and these have highlighted the role of IL-36 cytokines as central to pustular psoriasis pathogenesis. In this review, we discuss the presentation and clinical subtypes of pustular psoriasis, contribution of genetic predisposing variants, critical role of the IL-36 family of cytokines in disease pathophysiology, and treatment perspectives for pustular psoriasis. We further outline the application of appropriate mouse models for the study of pustular psoriasis and address the outstanding questions and issues related to our understanding of the mechanisms involved in pustular psoriasis.

Background: Psoriasis is associated with elevated risk of heart attack and increased accumulation of subclinical noncalcified coronary burden by coronary computed tomography angiography (CCTA). Machine learning algorithms have been shown to effectively analyze well-characterized data sets., Objective: In this study, we used machine learning algorithms to determine the top predictors of noncalcified coronary burden by CCTA in psoriasis., Methods: The analysis included 263 consecutive patients with 63 available variables from the Psoriasis Atherosclerosis Cardiometabolic Initiative. The random forest algorithm was used to determine the top predictors of noncalcified coronary burden by CCTA. We evaluated our results using linear regression models., Results: Using the random forest algorithm, we found that the top 10 predictors of noncalcified coronary burden were body mass index, visceral adiposity, total adiposity, apolipoprotein A1, high-density lipoprotein, erythrocyte sedimentation rate, subcutaneous adiposity, small low-density lipoprotein particle, cholesterol efflux capacity and the absolute granulocyte count. Linear regression of noncalcified coronary burden yielded results consistent with our machine learning output., Limitation: We were unable to provide external validation and did not study cardiovascular events., Conclusion: Machine learning methods identified the top predictors of noncalcified coronary burden in psoriasis. These factors were related to obesity, dyslipidemia, and inflammation, showing that these are important targets when treating comorbidities in psoriasis., (Published by Elsevier Inc.)

Objectives and Methods: With 432 513 samples from UK Biobank dataset, multivariable linear/logistic regression were used to estimate the relationship between psoriasis/psoriatic arthritis (PsA) and estimated bone mineral density (eBMD)/osteoporosis, controlling for potential confounders. Here, confounders were set in three ways: model0 (including age, height, weight, smoking and drinking), model1 (model0 +regular physical activity) and model2 (model1 +medication treatments). The eBMD was derived from heel ultrasound measurement. And 4904 patients with psoriasis and 847 patients with PsA were included in final analysis. Mendelian randomisation (MR) approach was used to evaluate the causal effect between them., Results: Lower eBMD were observed in patients with PsA than in controls in both model0 (β-coefficient=-0.014, p=0.0006) and model1 (β-coefficient=-0.013, p=0.002); however, the association disappeared when conditioning on treatment with methotrexate or ciclosporin (model2) (β-coefficient=-0.005, p=0.28), mediation analysis showed that 63% of the intermediary effect on eBMD was mediated by medication treatment (p<2E-16). Patients with psoriasis without arthritis showed no difference of eBMD compared with controls. Similarly, the significance of higher risk of osteopenia in patients with PsA (OR=1.27, p=0.002 in model0) could be eliminated by conditioning on medication treatment (p=0.244 in model2). Psoriasis without arthritis was not related to osteopenia and osteoporosis. The weighted Genetic Risk Score analysis found that genetically determined psoriasis/PsA were not associated with eBMD (p=0.24 and p=0.88). Finally, MR analysis showed that psoriasis/PsA had no causal effect on eBMD, osteoporosis and fracture., Conclusions: The effect of PsA on osteoporosis was secondary (eg, medication) but not causal. Under this hypothesis, psoriasis without arthritis was not a risk factor for osteoporosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Atopic dermatitis (AD) affects up to 20% of children and adults worldwide. To gain a deeper understanding of the pathophysiology of AD, we conducted a large-scale transcriptomic study of AD with deeply sequenced RNA-sequencing samples using long (126-bp) paired-end reads. In addition to the comparisons against previous transcriptomic studies, we conducted in-depth analysis to obtain a high-resolution view of the global architecture of the AD transcriptome and contrasted it with that of psoriasis from the same cohort. By using 147 RNA samples in total, we found striking correlation between dysregulated genes in lesional psoriasis and lesional AD skin with 81% of AD dysregulated genes being shared with psoriasis. However, we described disease-specific molecular and cellular features, with AD skin showing dominance of IL-13 pathways, but with near undetectable IL-4 expression. We also demonstrated greater disease heterogeneity and larger proportion of dysregulated long noncoding RNAs in AD, and illustrated the translational impact, including skin-type classification and drug-target prediction. This study is by far the largest study comparing the AD and psoriasis transcriptomes using RNA sequencing and demonstrating the shared inflammatory components, as well as specific discordant cytokine signatures of these two skin diseases., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Psoriasis lesions are rich in IL-17-producing T cells as well as neutrophils, which release webs of DNA-protein complexes known as neutrophil extracellular traps (NETs). Because we and others have observed increased NETosis in psoriatic lesions, we hypothesized that NETs contribute to increased T helper type 17 (Th17) cells in psoriasis. After stimulating peripheral blood mononuclear cells with anti-CD3/CD28 beads for 7 days, we found significantly higher percentages of CD3 + CD4 + IL-17 + (Th17) cells in the presence versus absence of NETs, as assessed by flow cytometry, IL-17 ELISA, and IL17A/F and RORC mRNAs. Memory, but not naïve, T cells were competent and monocytes were required for CD3/CD28-mediated Th17 induction, with or without NETs. Th17 induction was enhanced by the T allele of rs33980500 (T/C), a psoriasis risk-associated variant in the TRAF3IP2 gene encoding the D10N variant of Act1, a key mediator of IL-17 signal transduction. Global transcriptome analysis of CD3/CD28-stimulated peripheral blood mononuclear cells by RNA sequencing confirmed the stimulatory effects of NETs, demonstrated NET-induced enhancement of cytokine gene expression, and verified that the effect of Act1 D10N was greater in the presence of NETs. Collectively, these results implicate NETs and the Act1 D10N variant in human Th17 induction from peripheral blood mononuclear cells, with ramifications for immunogenetic studies of psoriasis and other autoimmune diseases., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The present paradigm of psoriasis pathogenesis revolves around the IL-23/IL-17A axis. Dual-secreting Th17 T cells presumably are the predominant sources of the psoriasis phenotype-driving cytokines, IL-17A and IL-22. We thus conducted a meta-analysis of independently acquired RNA-seq psoriasis datasets to explore the relationship between the expression of IL17A and IL22 . This analysis failed to support the existence of dual secreting IL-17A/IL-22 Th17 cells as a major source of these cytokines. However, variable relationships amongst the expression of psoriasis susceptibility genes and of IL17A, IL22 , and IL23A were identified. Additionally, to shed light on gene expression relationships in psoriasis, we applied a machine learning nonlinear dimensionality reduction strategy (t-SNE) to display the entire psoriasis transcriptome as a 2-dimensonal image. This analysis revealed a variety of gene clusters, relevant to psoriasis pathophysiology but failed to support a relationship between IL17A and IL22 . These results support existing theories on alternative sources of IL-17A and IL-22 in psoriasis such as a Th22 cells and non-T cell populations.

Background: Psoriasis is a common inflammatory skin disease that has been reported to be associated with obesity. We aimed to investigate a possible causal relationship between body mass index (BMI) and psoriasis., Methods and Findings: Following a review of published epidemiological evidence of the association between obesity and psoriasis, mendelian randomization (MR) was used to test for a causal relationship with BMI. We used a genetic instrument comprising 97 single-nucleotide polymorphisms (SNPs) associated with BMI as a proxy for BMI (expected to be much less confounded than measured BMI). One-sample MR was conducted using individual-level data (396,495 individuals) from the UK Biobank and the Nord-Trøndelag Health Study (HUNT), Norway. Two-sample MR was performed with summary-level data (356,926 individuals) from published BMI and psoriasis genome-wide association studies (GWASs). The one-sample and two-sample MR estimates were meta-analysed using a fixed-effect model. To test for a potential reverse causal effect, MR analysis with genetic instruments comprising variants from recent genome-wide analyses for psoriasis were used to test whether genetic risk for this skin disease has a causal effect on BMI. Published observational data showed an association of higher BMI with psoriasis. A mean difference in BMI of 1.26 kg/m2 (95% CI 1.02-1.51) between psoriasis cases and controls was observed in adults, while a 1.55 kg/m2 mean difference (95% CI 1.13-1.98) was observed in children. The observational association was confirmed in UK Biobank and HUNT data sets. Overall, a 1 kg/m2 increase in BMI was associated with 4% higher odds of psoriasis (meta-analysis odds ratio [OR] = 1.04; 95% CI 1.03-1.04; P = 1.73 × 10(-60)). MR analyses provided evidence that higher BMI causally increases the odds of psoriasis (by 9% per 1 unit increase in BMI; OR = 1.09 (1.06-1.12) per 1 kg/m2; P = 4.67 × 10(-9)). In contrast, MR estimates gave little support to a possible causal effect of psoriasis genetic risk on BMI (0.004 kg/m2 change in BMI per doubling odds of psoriasis (-0.003 to 0.011). Limitations of our study include possible misreporting of psoriasis by patients, as well as potential misdiagnosis by clinicians. In addition, there is also limited ethnic variation in the cohorts studied., Conclusions: Our study, using genetic variants as instrumental variables for BMI, provides evidence that higher BMI leads to a higher risk of psoriasis. This supports the prioritization of therapies and lifestyle interventions aimed at controlling weight for the prevention or treatment of this common skin disease. Mechanistic studies are required to improve understanding of this relationship., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: IBM has received grants from Arthritis Research UK during the conduct of the study; grants and personal fees from Novartis, grants and personal fees from Janssen, grants and personal fees from Celgene, grants and personal fees from Abbvie, grants from BI, grants and personal fees from UCB, personal fees from Lilly, grants and personal fees from BMS. LP has received personal fees from Merck for Scientific Input Engagement related to MR methodology. SS has received grants from Arthritis Research UK during the conduct of the study; research grants from Janssen, BMS, Celgene, UCB, Boehringer Ingelheim and consultancy/speaker’s fees from AbbVie, UCB, Celgene, Pfizer, Janssen, Boehringer Ingelheim, and Novartis. SJB has received honoraria for invited lectures at the British Association of Dermatologists’ annual meetings and the AAAAI annual meetings. GDS is a member of the Editorial Board of PLOS Medicine.

Numerous studies of relatively few patients have linked T cell receptor (TCR) genes to psoriasis but have yielded dramatically conflicting results. To resolve these discrepancies, we have chosen to mine RNA-Seq datasets for patterns of TCR gene segment usage in psoriasis. A meta-analysis of 3 existing and 1 unpublished datasets revealed a statistically significant link between the relative expression of TRAJ23 and psoriasis and the psoriasis-associated cytokine IL-17A. TRGV5, a TCR-γ segment, was also associated with psoriasis but correlated instead with IL-36A, other IL-36 family members, and IL-17C (not IL-17A). In contrast, TRAJ39 was strongly associated with healthy skin. T cell diversity measurements and analysis of CDR3 sequences were also conducted, revealing no psoriasis-associated public CDR3 sequences. Finally, in comparison with the expression of TCR-αβ genes, the expression of TCR-γδ genes was relatively low but mildly elevated in psoriatic skin. These results have implications for the development of targeted therapies for psoriasis and other autoimmune diseases. Also, the techniques employed in this study have applications in other fields, such as cancer immunology and infectious disease.

In recent years marked progress has been made in our understanding of the critical biologic and immunologic pathways involved in psoriasis. Genetic studies have demonstrated that susceptibility to psoriasis involves components of both the adaptive and innate immune system and not surprisingly activation of both of these arms of the immune system is found in psoriatic skin. While adaptive immune responses predominate in chronic plaque psoriasis, innate and autoinflammatory responses dominate in pustular forms of psoriasis, with other clinical subtypes extending on a spectrum between plaque and pustular psoriasis. This makes psoriasis a unique disease where both autoimmune and autoinflammatory responses co-exist, with the balance between the two being critical in shaping its clinical presentation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Terminally differentiating epidermal keratinocytes express a large number of structural and antimicrobial proteins that are involved in the physical barrier function of the stratum corneum and provide innate cutaneous host defense. Late cornified envelope (LCE) genes, located in the epidermal differentiation complex on chromosome 1, encode a family of 18 proteins of unknown function, whose expression is largely restricted to epidermis. Deletion of two members, LCE3B and LCE3C (LCE3B/C-del), is a widely-replicated psoriasis risk factor that interacts with the major psoriasis-psoriasis risk gene HLA-C*06. Here we performed quantitative trait locus analysis, utilizing RNA-seq data from human skin and found that LCE3B/C-del was associated with a markedly increased expression of LCE3A, a gene directly adjacent to LCE3B/C-del. We confirmed these findings in a 3-dimensional skin model using primary keratinocytes from LCE3B/C-del genotyped donors. Functional analysis revealed that LCE3 proteins, and LCE3A in particular, have defensin-like antimicrobial activity against a variety of bacterial taxa at low micromolar concentrations. No genotype-dependent effect was observed for the inside-out or outside-in physical skin barrier function. Our findings identify an unknown biological function for LCE3 proteins and suggest a role in epidermal host defense and LCE3B/C-del-mediated psoriasis risk., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted., (© The Author 2017. Published by Oxford University Press.)

miR-146a inhibits inflammatory responses in human keratinocytes and in different mouse models of skin inflammation. Little is known about the role of miR-146b in the skin. In this study, we confirmed the increased expression of miR-146a and miR-146b (miR-146a/b) in the lesional skin of patients with psoriasis. The expression of miR-146a was approximately twofold higher than that of miR-146b in healthy human skin, and it was more strongly induced by stimulation of proinflammatory cytokines in keratinocytes and fibroblasts. miR-146a/b target genes regulating inflammatory responses or proliferation were altered in the skin of patients with psoriasis, among which FERMT1 was verified as a direct target of miR-146a. In silico analysis of genome-wide data from >4,000 psoriasis cases and >8,000 controls confirmed a moderate association between psoriasis and genetic variants in the miR-146a encoding gene. Transfection of miR-146a/b suppressed and inhibition enhanced keratinocyte proliferation and the expression of psoriasis-related target genes. Enhanced expression of miR-146a/b-influenced genes was detected in cultured keratinocytes from miR-146a -/- and skin fibroblasts from miR-146a -/- and miR-146b -/- mice stimulated with psoriasis-associated cytokines as compared with wild-type mice. Our results indicate that besides miR-146a, miR-146b is expressed and might be capable of modulation of inflammatory responses and keratinocyte proliferation in psoriatic skin., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The factors involved in maintaining a localized inflammatory state in psoriatic skin remain poorly understood. Here, we demonstrate through metabolomic and transcriptomic profiling marked suppression of glucocorticoid biosynthesis in the epidermis of psoriatic skin leading to localized deficiency of cortisol. Utilizing a 3D human epidermis model, we demonstrate that glucocorticoid biosynthesis is suppressed by proinflammatory cytokines and that glucocorticoid deficiency promotes inflammatory responses in keratinocytes. Finally, we show in vitro and in vivo that treatment with topical glucocorticoids leads to rapid restoration of glucocorticoid biosynthesis gene expression coincident with normalization of epidermal differentiation and suppression of inflammatory responses. Taken together, our data suggest that localized glucocorticoid deficiency in psoriatic skin interferes with epidermal differentiation and promotes a sustained and localized inflammatory response. This may shed new light on the mechanism of action of topical steroids, and demonstrates the critical role of endogenous steroid in maintaining both inflammatory and differentiation homeostasis in the epidermis., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

TRAF3IP2 is a candidate psoriasis susceptibility gene encoding Act1, an adaptor protein with ubiquitin ligase activity that couples the IL-17 receptor to downstream signaling pathways. We investigated the role of Act1 in keratinocyte responses to IL-17 using a tetracycline inducible short hairpin RNA targeting TRAF3IP2. Tetracycline exposure for 7 days effectively silenced TRAF3IP2 mRNA and Act1 protein, resulting in 761 genes with significant changes in expression (495 down, 266 up; >1.5-fold, P < 0.05). Gene ontology analysis showed that genes affected by TRAF3IP2 silencing are involved in epidermal differentiation, with early differentiation genes (KRT1, KRT10, DSC1, DSG1) being down-regulated and late differentiation genes (SPRR2, SPRR3, LCE3) being up-regulated. AP1 binding sites were enriched upstream of genes up-regulated by TRAF3IP2 silencing. Correspondingly, nuclear expression of FosB and Fra1 was increased in TRAF3IP2-silenced cells. Many genes involved in host defense were induced by IL-17 in a TRAF3IP2-dependent fashion. Inflammatory differentiation conditions (serum addition for 4 days postconfluence) markedly amplified these IL-17 responses and increased basal levels and TRAF3IP2 silencing-dependent up-regulation of multiple late differentiation genes. These findings suggest that TRAF3IP2 may alter both epidermal homeostasis and keratinocyte defense responses to influence psoriasis risk., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size >39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFκB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8 + T-cells and CD4 + T-cells including T H 0, T H 1 and T H 17). The identified loci explain ∼28% of the genetic heritability and generate a discriminatory genetic risk score (AUC=0.76 in our sample) that is significantly correlated with age at onset (p=2 × 10 -89 ). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis.

Background: Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation and altered keratinocyte differentiation and inflammation and is caused by the interplay of genetic and environmental factors. Previous studies have revealed that DNA methylation (DNAm) and genetic makers are closely associated with psoriasis, and strong evidences have shown that DNAm can be controlled by genetic factors, which attracted us to evaluate the relationship among DNAm, genetic makers, and disease status., Methods: We utilized the genome-wide methylation data of psoriatic skin (PP, N  = 114) and unaffected control skin (NN, N  = 62) tissue samples in our previous study, and we performed whole-genome genotyping with peripheral blood of the same samples to evaluate the underlying genetic effect on skin DNA methylation. Causal inference test (CIT) was used to assess whether DNAm regulate genetic variation and gain a better understanding of the epigenetic basis of psoriasis susceptibility., Results: We identified 129 SNP-CpG pairs achieving the significant association threshold, which constituted 28 unique methylation quantitative trait loci (MethQTL) and 34 unique CpGs. There are 18 SNPs were associated with psoriasis at a Bonferoni-corrected P  < 0.05, and these 18 SNPs formed 93 SNP-CpG pairs with 17 unique CpG sites. We found that 11 of 93 SNP-CpG pairs, composed of 5 unique SNPs and 3 CpG sites, presented a methylation-mediated relationship between SNPs and psoriasis. The 3 CpG sites were located on the body of C1orf106 , the TSS1500 promoter region of DMBX1 and the body of SIK3 ., Conclusions: This study revealed that DNAm of some genes can be controlled by genetic factors and also mediate risk variation for psoriasis in Chinese Han population and provided novel molecular insights into the pathogenesis of psoriasis.

Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 × 10(-11)). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 × 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Previous studies have identified 41 independent genome-wide significant psoriasis susceptibility loci. After our first psoriasis genome-wide association study, we designed a custom genotyping array to fine-map eight genome-wide significant susceptibility loci known at that time (IL23R, IL13, IL12B, TNIP1, MHC, TNFAIP3, IL23A and RNF114) enabling genotyping of 2269 single-nucleotide polymorphisms (SNPs) in the eight loci for 2699 psoriasis cases and 2107 unaffected controls of European ancestry. We imputed these data using the latest 1000 Genome reference haplotypes, which included both indels and SNPs, to increase the marker density of the eight loci to 49 239 genetic variants. Using stepwise conditional association analysis, we identified nine independent signals distributed across six of the eight loci. In the major histocompatibility complex (MHC) region, we detected three independent signals at rs114255771 (P = 2.94 × 10(-74)), rs6924962 (P = 3.21 × 10(-19)) and rs892666 (P = 1.11 × 10(-10)). Near IL12B we detected two independent signals at rs62377586 (P = 7.42 × 10(-16)) and rs918518 (P = 3.22 × 10(-11)). Only one signal was observed in each of the TNIP1 (rs17728338; P = 4.15 × 10(-13)), IL13 (rs1295685; P = 1.65 × 10(-7)), IL23A (rs61937678; P = 1.82 × 10(-7)) and TNFAIP3 (rs642627; P = 5.90 × 10(-7)) regions. We also imputed variants for eight HLA genes and found that SNP rs114255771 yielded a more significant association than any HLA allele or amino-acid residue. Further analysis revealed that the HLA-C*06-B*57 haplotype tagged by this SNP had a significantly higher odds ratio than other HLA-C*06-bearing haplotypes. The results demonstrate allelic heterogeneity at IL12B and identify a high-risk MHC class I haplotype, consistent with the existence of multiple psoriasis effectors in the MHC.

Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (P<5 × 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.

Psoriasis has been linked to cardiometabolic diseases, but epidemiological findings are inconsistent. We investigated the association between psoriasis and cardiometabolic outcomes in a German cross-sectional study (n=4,185) and a prospective cohort of German Health Insurance beneficiaries (n=1,811,098). A potential genetic overlap was explored using genome-wide data from >22,000 coronary artery disease and >4,000 psoriasis cases, and with a dense genotyping study of cardiometabolic risk loci on 927 psoriasis cases and 3,717 controls. After controlling for major confounders, in the cross-sectional analysis psoriasis was significantly associated with type 2 diabetes (T2D, adjusted odds ratio (OR)=2.36; 95% confidence interval CI=1.26-4.41) and myocardial infarction (MI, OR=2.26; 95% CI=1.03-4.96). In the longitudinal study, psoriasis slightly increased the risk for incident T2D (adjusted relative risk (RR)=1.11; 95% CI=1.08-1.14) and MI (RR=1.14; 95% CI=1.06-1.22), with highest risk increments in systemically treated psoriasis, which accounted for 11 and 17 excess cases of T2D and MI per 10,000 person-years. Except for weak signals from within the major histocompatibility complex, there was no evidence of genetic risk loci shared between psoriasis and cardiometabolic traits. Our findings suggest that psoriasis, in particular severe psoriasis, increases the risk for T2D and MI, and that the genetic architecture of psoriasis and cardiometabolic traits is largely distinct.

Motivation: Pathway analysis to reveal biological mechanisms for results from genetic association studies have great potential to better understand complex traits with major human disease impact. However, current approaches have not been optimized to maximize statistical power to identify enriched functions/pathways, especially when the genetic data derives from studies using platforms (e.g. Immunochip and Metabochip) customized to have pre-selected markers from previously identified top-rank loci. We present here a novel approach, called Minimum distance-based Enrichment Analysis for Genetic Association (MEAGA), with the potential to address both of these important concerns., Results: MEAGA performs enrichment analysis using graphical algorithms to identify sub-graphs among genes and measure their closeness in interaction database. It also incorporates a statistic summarizing the numbers and total distances of the sub-graphs, depicting the overlap between observed genetic signals and defined function/pathway gene-sets. MEAGA uses sampling technique to approximate empirical and multiple testing-corrected P-values. We show in simulation studies that MEAGA is more powerful compared to count-based strategies in identifying disease-associated functions/pathways, and the increase in power is influenced by the shortest distances among associated genes in the interactome. We applied MEAGA to the results of a meta-analysis of psoriasis using Immunochip datasets, and showed that associated genes are significantly enriched in immune-related functions and closer with each other in the protein-protein interaction network., Availability and Implementation: http://genome.sph.umich.edu/wiki/MEAGA CONTACT: : tsoi.teen@gmail.com or goncalo@umich.edu, Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Although analysis pipelines have been developed to use RNA-seq to identify long non-coding RNAs (lncRNAs), inference of their biological and pathological relevance remains a challenge. As a result, most transcriptome studies of autoimmune disease have only assessed protein-coding transcripts., Results: We used RNA-seq data from 99 lesional psoriatic, 27 uninvolved psoriatic, and 90 normal skin biopsies, and applied computational approaches to identify and characterize expressed lncRNAs. We detect 2,942 previously annotated and 1,080 novel lncRNAs which are expected to be skin specific. Notably, over 40% of the novel lncRNAs are differentially expressed and the proportions of differentially expressed transcripts among protein-coding mRNAs and previously-annotated lncRNAs are lower in psoriasis lesions versus uninvolved or normal skin. We find that many lncRNAs, in particular those that are differentially expressed, are co-expressed with genes involved in immune related functions, and that novel lncRNAs are enriched for localization in the epidermal differentiation complex. We also identify distinct tissue-specific expression patterns and epigenetic profiles for novel lncRNAs, some of which are shown to be regulated by cytokine treatment in cultured human keratinocytes., Conclusions: Together, our results implicate many lncRNAs in the immunopathogenesis of psoriasis, and our results provide a resource for lncRNA studies in other autoimmune diseases.

Atopic dermatitis and psoriasis are the two most common immune-mediated inflammatory disorders affecting the skin. Genome-wide studies demonstrate a high degree of genetic overlap, but these diseases have mutually exclusive clinical phenotypes and opposing immune mechanisms. Despite their prevalence, atopic dermatitis and psoriasis very rarely co-occur within one individual. By utilizing genome-wide association study and ImmunoChip data from >19,000 individuals and methodologies developed from meta-analysis, we have identified opposing risk alleles at shared loci as well as independent disease-specific loci within the epidermal differentiation complex (chromosome 1q21.3), the Th2 locus control region (chromosome 5q31.1), and the major histocompatibility complex (chromosome 6p21-22). We further identified previously unreported pleiotropic alleles with opposing effects on atopic dermatitis and psoriasis risk in PRKRA and ANXA6/TNIP1. In contrast, there was no evidence for shared loci with effects operating in the same direction on both diseases. Our results show that atopic dermatitis and psoriasis have distinct genetic mechanisms with opposing effects in shared pathways influencing epidermal differentiation and immune response. The statistical analysis methods developed in the conduct of this study have produced additional insight from previously published data sets. The approach is likely to be applicable to the investigation of the genetic basis of other complex traits with overlapping and distinct clinical features., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)