Observational studies have suggested the potential associations between atopic dermatitis (AD) and psychiatric disorders. However, the causal relationship between them remains uncertain. This study aimed to evaluate the potential bidirectional causal relationship between AD and psychiatric disorders, including autism spectrum disorder (ASD), major depressive disorder (MDD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BD), anorexia nervosa (AN), Tourette syndrome (TS), schizophrenia, and anxiety.Bidirectional two-sample Mendelian randomization (MR) was employed to elucidate the causality between AD and psychiatric disorders, using summary statistics from the most comprehensive genome-wide association studies conducted on AD (Ncases = 60,653, Ncontrols = 804,329). Psychiatric disorders were derived from the Psychiatric Genomics Consortium and were independent of AD data sources. The MR analysis entailed the implementation of multiple methods, including the inverse variance weighted method, MR-Egger regression method, weighted median method, simple mode method, and weighted mode method.Bidirectional two-sample MR analysis uncovered significant causal associations between AD and severe psychiatric disorders. Specifically, liability to AD was associated with increased risk of ADHD (OR = 1.116; 95% CI: [1.009, 1.234]; P = 0.033) and ASD (OR = 1.131; 95% CI: [1.023, 1.251]; P = 0.016). Additionally, evidence suggested that liability to ADHD (OR = 1.112; 95% CI: [1.094, 1.130]; P = 9.20e-40), liability to AN (OR = 1.1; 95% CI: [1.068, 1.134]; P = 4.45e-10) and liability to BD (OR = 1.067; 95% CI: [1.009, 1.128]; P = 0.023) were associated with an increased risk of AD. Only the causal association between AD and ASD was independent of the reverse effect bias. These causal associations were robust and not affected by biases of heterogeneity and horizontal pleiotropy.Our study emphasizes the significant causal association between AD and an increased risk of ASD, and also identifying BD and AN as risk factors for AD. 

Causal relationships between atopic dermatitis and psychiatric disorders: a bidirectional two-sample Mendelian randomization study

Psoriasis and atopic dermatitis fall within the category of cutaneous immune-mediated inflammatory diseases (IMIDs). The prevalence of IMIDs is increasing in industrialized societies, influenced by both environmental changes and a genetic predisposition. However, the exact immune factors driving these chronic, progressive diseases are not fully understood. By using multi-omics techniques in cutaneous IMIDs, it is expected to advance the understanding of skin biology, uncover the underlying mechanisms of skin conditions, and potentially devise precise and personalized approaches to diagnosis and treatment. We provide a narrative review of the current knowledge in genomics, epigenomics, and proteomics of atopic dermatitis and psoriasis. A literature search was performed for articles published until 30 November 2023. Although there is still much to uncover, recent evidence has already provided valuable insights, such as proteomic profiles that permit differentiating psoriasis from mycosis fungoides and β-defensin 2 correlation to PASI and its drop due to secukinumab first injection, among others.

Multi-Omics Approach to Improved Diagnosis and Treatment of Atopic Dermatitis and Psoriasis

Background Lung adenocarcinoma (LUAD) is one of the most common types of cancer in the respiratory system, with a high mortality and recurrence rate. The role of disc large-associated protein 5 (DLGAP5) in LUAD progression and tumor microenvironment (TME) remains unclear. This study is aimed at revealing the functional role of DLGAP5 in LUAD based on bioinformatics analysis and experimental validation. Methods Differential expression analysis, protein-protein interaction (PPI) network, and Cox regression analysis were applied to screen potential prognostic biomarkers. The mRNA and protein levels of DLGAP5 were analyzed using The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA) databases. The CCK-8 and colony formation assays were performed to assess the effect of DLGAP5 on cell proliferation. RNA sequencing (RNA-seq) and enrichment analyses were utilized to explore the biological functions of DLGAP5. Furthermore, flow cytometry was used to explore the role of DLGAP5 on the cell cycle. The ssGSEA algorithm in the R package “GSVA” was applied to quantify immune infiltrating cells, and the tumor immune dysfunction and exclusion (TIDE) algorithm was used to predict the efficacy of immunotherapy. Moreover, analyses using the cBioPortal and MethSurv databases were performed to evaluate the mutation and methylation of DLGAP5, respectively. Finally, the prognostic value of DLGAP5 was estimated using the TCGA and the Gene Expression Omnibus (GEO) databases. The nomogram model was constructed using the TCGA-LUAD cohort and evaluated by adopting calibration curves, time-dependent receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Results DLGAP5 mRNA and protein abundance were significantly elevated in LUAD, and knockdown of DLGAP5 remarkably suppressed lung cancer cell proliferation through induction of cell cycle G1 arrest. In addition, DLGAP5 expression was positively correlated with Th2 cells and negatively correlated with B cells, T follicular helper cells, and mast cells. LUAD patients with high DLGAP5 expression may be resistant to immunotherapy. Hypermethylation levels of the cg23678254 site of DLGAP5 or its enhanced expression were unfavorable for the survival of LUAD patients. Meanwhile, DLGAP5 expression was associated with TNM stages, tumor status, and therapy outcome. Notably, the prognostic model constructed based on DLGAP5 expression exhibited great predictive capability, which was promising for clinical applications. Conclusion DLGAP5 promotes lung cancer cell proliferation through regulation of the cell cycle and is associated with multiple immune infiltrating cells. Furthermore, DLGAP5 predicts poor prognosis and response to immunotherapy in lung adenocarcinoma.

/pdf/high-expression-of-dlgap5-indicates-poor-prognosis-and-1kodflmi.pdf

High Expression of DLGAP5 Indicates Poor Prognosis and Immunotherapy in Lung Adenocarcinoma and Promotes Proliferation through Regulation of the Cell Cycle

Simple Summary NPAS2, short for Neuronal PAS Domain Protein 2, is a transcription factor involved in regulating the circadian rhythms and sleep–wake cycles in mammals, including humans. It is a key component of the molecular clockwork that governs daily biological processes. NPAS2 binds heme as a prosthetic group and CO at micromolar concentrations, with ensuing changes in DNA affinity. In this way, gaseous signaling plus heme-based sensing and redox balance modify NPAS2 transcriptional activity and the expression of target genes. NPAS2 plays a crucial role in metabolism regulation and in maintaining the body’s internal clock synchronized with the day–night cycle. Dysregulation of NPAS2 can lead to disruptions in circadian rhythms and may contribute to sleep disturbances, psychiatric disorders and other health issues, such as neoplastic, cardiovascular and cerebrovascular diseases. Alternatively, NPAS2 could represent a valuable predictive biomarker for prevention/stratification strategies and a promising druggable target for innovative therapeutic approaches. Abstract Neuronal PAS domain protein 2 (NPAS2) is a hemeprotein comprising a basic helix–loop–helix domain (bHLH) and two heme-binding sites, the PAS-A and PAS-B domains. This protein acts as a pyridine nucleotide-dependent and gas-responsive CO-dependent transcription factor and is encoded by a gene whose expression fluctuates with circadian rhythmicity. NPAS2 is a core cog of the molecular clockwork and plays a regulatory role on metabolic pathways, is important for the function of the central nervous system in mammals, and is involved in carcinogenesis as well as in normal biological functions and processes, such as cardiovascular function and wound healing. We reviewed the scientific literature addressing the various facets of NPAS2 and framing this gene/protein in several and very different research and clinical fields.

Role of the Circadian Gas-Responsive Hemeprotein NPAS2 in Physiology and Pathology

Loss-of-Function (LoF) variants in the filaggrin (FLG) gene are the strongest known genetic risk factor for atopic dermatitis (AD), but the impact of these variants on AD outcomes is poorly understood. We comprehensively identified genetic variants through targeted region sequencing of FLG in children (n = 438) participating in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort. Twenty FLG LoF variants were identified, including one novel variant and nine variants not previously associated with AD. FLG LoF variants were found in 13.6% of the cohort. Among these children, the presence of one or more FLG LoF variants was associated with moderate/severe AD (odds ratio (OR) = 2.00 (95% CI, 1.23-3.68) compared to those with mild AD. Children with FLG LoF variants had a higher SCORAD (SCORing for Atopic Dermatitis (SCORAD); P = 0.012) and higher likelihood of food allergy within the first 2.5 years of life (OR = 2.81, 1.50-5.26). LoF variants were associated with higher transepidermal Water Loss (TEWL) in both lesional (P = 0.018) and non-lesional skin (P = 0.015). Collectively, our study identifies established and novel AD-associated FLG LoF variants and associates FLG LoF with higher TEWL in lesional and non-lesional skin.

Filaggrin loss-of-function variants are associated with atopic dermatitis phenotypes in a diverse, early life prospective cohort.

A novel metabolic-immune related signature predicts prognosis and immunotherapy response in lung adenocarcinoma

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N=1,086,394, replication N=3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis and 15 additional loci in the multi-ancestry analysis (6 novel). All 81 variants replicated in a separate European analysis. Eleven variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African). While four variants appeared to be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL signals in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

https://www.medrxiv.org/content/medrxiv/early/2022/11/18/2022.10.05.22279072.full.pdf

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

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A novel metabolic-immune related signature predicts prognosis and immunotherapy response in lung adenocarcinoma

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation