Expert Consensus on Big Data Collection of Skin and Appendage Disease Phenotypes in Chinese.

The collection of big data on skin and appendage phenotypes has revolutionized the field of personalized diagnosis and treatment by enabling the evaluation of individual characteristics and early detection of abnormalities. To establish a standardized system for collecting and measuring big data on phenotypes, a systematic categorization of measurement entries has been undertaken, accompanied by recommendations on measurement entries, environmental equipment requirements, and collection processes, tailored to the needs of different usage scenarios. Specific collection sites have also been recommended based on different index characteristics. A multi-center, multi-regional collaboration has been initiated to collect big date on phenotypes of healthy and diseased skin in the Chinese population. This data will be correlated with patient disease information, exploring the factors influencing skin phenotype, analyzing the phenotypic data features that can predict prognosis, and ultimately promoting the exploration of the pathophysiology and pathogenesis of skin diseases and therapeutic approaches. Non-invasive skin measurement robots are also in development. This consensus aims to provide a reference for the study of phenomics and the standardization of phenotypic measurements of skin and appendages in China.

Serum dsDNA is environmentally contingent.

Psoriasis is a recurrent autoimmune disease characterized by seasonal and latitudinal variations. Double-stranded DNA (dsDNA) is a crucial component of nucleic acids and nucleosomes that provoke innate immune responses. Given the potential influence of climate on immunity and the development of autoimmune diseases, a comprehensive quantitative analysis of dsDNA levels in the population is warranted. In this case-control study conducted from 2016 to 2020, 10,110 psoriasis patients and matched controls from 12 regions in China were included. This study examined variations in serum dsDNA levels based on season and latitude. The results revealed significant associations between geographical location, climatic conditions, and season with serum dsDNA concentration. Individuals residing in Northern China exhibited significantly higher serum dsDNA levels compared to those in the South (1.00 vs. 0.96 ng/ml), and those in medium latitude regions had higher levels than their counterparts in areas with extreme latitudes (0.98 vs. 0.96 ng/ml). Furthermore, individuals in regions with low to medium ultraviolet exposure demonstrated higher serum dsDNA concentrations than those in areas with high ultraviolet levels (1.03 vs. 0.93 ng/ml), and individuals in winter showed higher levels than those in summer (1.03 vs. 0.92 ng/ml). Factors such as sex, UV index, humidity, and sunshine duration were inversely related to serum dsDNA levels, while age and daylight hours showed a positive association. These findings suggest that meteorological and climatic factors play a role in influencing serum dsDNA levels.

Genome wide association study and meta-analysis identified multiple new risk loci for freckles in 4813 Chinese individuals.

Freckle is a prevalent pigmentary dermatosis with an obvious hereditary component. Dozens of freckles risk loci have been discovered through research on multiple traits or other diseases, rather than as an independent trait. To discover novel variants associated with freckles, we performed GWAS and meta-analysis in 4813 Chinese individuals. We conducted GWAS and meta-analysis of two cohorts: 197 patients and 1603 controls (Cohort I), and 336 patients and 2677 controls (Cohort II), both from China. Then we performed linkage disequilibrium (LD) analysis, eQTL study, and enrichment analysis with association results for functional implications. Finally, we discovered 59 new SNPs and 13 novel susceptibility genes associated with freckles (Pmeta <5 × 10-8), which has enriched the genetic research on freckles.

Association of Novel Loci With Keratoconus Susceptibility in a Chinese Genome-Wide Association Study.

Purpose: Keratoconus (KC) is a progressive corneal disease that can lead to corneal blindness if not properly managed. The purpose of this study was to identify genetic associations with KC in China and to investigate whether these genetic variants are associated with corneal thickness and corneal curvature in KC cases. Methods: A genome-wide association study was conducted on 853 patients with KC and 6248 controls. The KC cases were genotyped with the Illumina Infinium Human Asian Screening Array BeadChip, and the controls were genotyped with the Illumina Infinium Human Global Screening Array BeadChip. Genetic associations with KC, as well as correlations between the positive variants and corneal parameters including central corneal thickness (CCT) and mean keratometry (Km), were compared using PLINK version 1.90. Results: Our present study identified four single-nucleotide polymorphisms (SNPs) within four risk loci (PTGER3: rs2300163, EYA1: rs1077435, ASS1: rs141365191, and CHTF8: rs3743680) associated with KC in Chinese patients that reached genome-wide significance. Among the identified SNPs with P < 1.00 × 10-4, seven SNPs (FOSL2-PLB1: rs12622211, RXRA-COL5A1: rs3118515, rs3132306, rs1536482, rs3118520, KAT6B: rs192187772, RAP2A-IPO5: rs41361245) were observed to be associated with CCT, and one SNP (USP13: rs6767552) was found to be associated with Km. Conclusions: In the first genome-wide association study of KC with a relatively large study population in China, we identified four SNPs in four risk loci associated with the disease. The findings enriched the understanding of genetic susceptibility to KC and provided new insights into the genetic etiology of the disease.

Effectiveness of guselkumab in patients with moderate-to-severe plaque psoriasis: a retrospective study from China.

Data on guselkumab as treatment for moderate-to-severe plaque psoriasis, especially in different body regions, in China is limited. This study aimed to estimate the effectiveness of guselkumab in Chinese patients with moderate-to-severe plaque psoriasis, including effectiveness at different body regions. This multicentre, observational study retrospectively enrolled patients with moderate-to-severe plaque psoriasis. Effectiveness outcome was based on Psoriasis Area and Severity Index (PASI) response and improvement in Body Surface Area (BSA) and Dermatology Life Quality Index (DLQI). A total of 51 patients were included, with a median age of 44.00 (18.00, 74.00) years and median duration of psoriasis of 10.00 (0.50, 55.00) years. After 20 weeks of treatment, PASI response with 75% improvement from baseline (PASI 75) was reported in 96.1% of patients; 72.5% of patients achieved a DLQI score of 0-1 at week 20. The percentage of affected BSA was significantly decreased at week 4 (p<0.05), week 12 (p<0.001) and week 20 (p<0.001). PASI score significantly changed from baseline after four weeks (p<0.001), 12 weeks (p<0.001) and 20 weeks of treatment (p<0.001). DLQI score significantly increased at week 4 (p<0.001), week 12 (p<0.001) and week 20 (p<0.001). PASI 75 was achieved for the upper limbs in all cases and 100% PASI improvement (PASI 100) in 89.1%. The head and lower limbs were the areas least responsive to treatment, with PASI 100 achieved in only 68.6% and 70.6%, respectively. Guselkummab provided rapid and sustained PASI improvement, especially for the skin of the upper limbs and body trunk.

Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis.

BACKGROUND AND OBJECTIVES: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a rare autoimmune neurologic disorder, the genetic etiology of which remains poorly understood. Our study aims to investigate the genetic basis of this disease in the Chinese Han population. METHODS: We performed a genome-wide association study and fine-mapping study within the major histocompatibility complex (MHC) region of 413 Chinese patients with anti-NMDAR encephalitis recruited from 6 large tertiary hospitals and 7,127 healthy controls. RESULTS: Our genome-wide association analysis identified a strong association at the IFIH1 locus on chromosome 2q24.2 (rs3747517, p = 1.06 × 10-8, OR = 1.55, 95% CI, 1.34-1.80), outside of the human leukocyte antigen (HLA) region. Furthermore, through a fine-mapping study of the MHC region, we discovered associations for 3 specific HLA class I and II alleles. Notably, HLA-DQB1*05:02 (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59) demonstrates the strongest association among classical HLA alleles, closely followed by HLA-A*11:01 (p = 4.36 × 10-7; OR, 1.52; 95% CI 1.29-1.79) and HLA-A*02:07 (p = 1.28 × 10-8; OR, 1.87; 95% CI 1.50-2.31). In addition, we uncovered 2 main HLA amino acid variation associated with anti-NMDAR encephalitis including HLA-DQß1-126H (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59), exhibiting a predisposing effect, and HLA-B-97R (p = 3.40 × 10-8; OR, 0.63; 95% CI 0.53-0.74), conferring a protective effect. Computational docking analysis suggested a close relationship between the NR1 subunit of NMDAR and DQB1*05:02. DISCUSSION: Our findings indicate that genetic variation in IFIH1, involved in the type I interferon signaling pathway and innate immunity, along with variations in the HLA class I and class II genes, has substantial implications for the susceptibility to anti-NMDAR encephalitis in the Chinese Han population.

Cutaneous Calcium/Calmodulin-Dependent Protein Kinase II-γ-Positive Sympathetic Nerves Secreting Norepinephrine Dictate Psoriasis.

Cutaneous sympathetic nerve is a crucial part of neuropsychiatric factors contributing to skin immune response, but its role in the psoriasis pathogenesis remains unclear. It is found that cutaneous calcium/calmodulin-dependent protein kinase II-γ (CAMK2γ), expressed mainly in sympathetic nerves, is activated by stress and imiquimod in mouse skin. Camk2g-deficient mice exhibits attenuated imiquimod-induced psoriasis-like manifestations and skin inflammation. CaMK2γ regulates dermal γδT-cell interleukin-17 production in imiquimod-treated mice, dependent on norepinephrine production following cutaneous sympathetic nerve activation. Adrenoceptor ß1, the primary skin norepinephrine receptor, colocalises with γδT cells. CaMK2γ aggravates psoriasiform inflammation via sympathetic nerve-norepinephrine-γδT cell-adrenoceptor ß1-nuclear factor-κB and -p38 axis activation. Application of alcaftadine, a small-molecule CaMK2γ inhibitor, relieves imiquimod-induced psoriasis-like manifestations in mice. This study reveals the mechanisms of sympathetic-nervous-system regulation of γδT-cell interleukin-17 secretion, and provides insight into neuropsychiatric factors dictating psoriasis pathogenesis and new potential targets for clinical psoriasis treatment.

The genome of Stephania japonica provides insights into the biosynthesis of cepharanthine.

Stephania japonica is an early-diverging eudicotyledon plant with high levels of cepharanthine, proven to be effective in curing coronavirus infections. Here, we report a high-quality S. japonica genome. The genome size is 688.52 Mb, and 97.37% sequences anchor to 11 chromosomes. The genome comprises 67.46% repetitive sequences and 21,036 genes. It is closely related to two Ranunculaceae species, which diverged from their common ancestor 55.90-71.02 million years ago (Mya) with a whole-genome duplication 85.59-96.75 Mya. We further reconstruct ancestral karyotype of Ranunculales. Several cepharanthine biosynthesis genes are identified and verified by western blot. Two genes (Sja03G0243 and Sja03G0241) exhibit catalytic activity as shown by liquid chromatography-mass spectrometry. Then, cepharanthine biosynthesis genes, transcription factors, and CYP450 family genes are used to construct a comprehensive network. Finally, we construct an early-diverging eudicotyledonous genome resources (EEGR) database. As the first genome of the Menispermaceae family to be released, this study provides rich resources for genomic studies.

Correlation between double-stranded DNA and acute urticaria.

BACKGROUND: Acute urticaria is a prevalent inflammatory dermatosis characterized by fulminant wheals, often accompanied by severe pruritis. It may also cause nausea, vomiting, and abdominal pain. Numerous studies have substantiated the pivotal involvement of double-stranded DNA (dsDNA) in autoimmunity. However, the role of dsDNA in the pathogenesis of acute urticaria is unclear. METHODS: We measured serum dsDNA levels in patients and controls. The relationship between dsDNA levels and environmental exposures (temperature, ultraviolet [UV] index, and season) was investigated by correlating disease onset dates with archived meteorological data. Finally, we used quantitative PCR to determine the expressions of genes encoding dsDNA receptors, single-stranded RNA (ssRNA) receptors, exosome formation, and type I interferon in the peripheral blood of patients and controls. RESULTS: Serum dsDNA levels were significantly higher in patients with acute urticaria compared with controls (mean values 1.38 and 0.94 ng/ml, respectively, P < 0.001). dsDNA levels were higher in patients exposed to higher environmental temperatures and UV indices and were higher during the summer months. We also found that the expressions of genes encoding dsDNA receptors, ssRNA receptors, absent in melanoma factor 2 (AIM2)-related inflammatory factors, and interferon alpha were up-regulated in patients. CONCLUSIONS: We demonstrated that serum dsDNA levels are elevated in acute urticaria and are influenced by climatic factors such as temperature, ultraviolet index, and season. We also found that elevated dsDNA promotes the expression of AIM2-related factors and type I interferons. This study generates new hypotheses regarding the pathogenesis of acute urticaria and suggests novel therapeutic targets.

Genome-Wide Meta-Analysis Identifies 11 Susceptibility Variants of Vitiligo in the Chinese Han Population.

Vitiligo is an autoimmune disease involving loss of melanocytes. Although several genetic studies have confirmed that genetic factors play an important role, its pathogenesis remains incompletely characterized. In this study, a genome-wide meta-analysis was conducted to search for more susceptibility variants of vitiligo. Tang et al performed a GWAS for cohort I (1117 vitiligo cases and 1701 healthy controls) previously, and we conducted a GWAS for cohort II (3323 vitiligo cases and 7186 healthy controls) in this study, with the results subjected to a genome-wide meta-analysis and linkage disequilibrium analysis. We identify, to our knowledge, 11 previously unreported susceptibility variants, of which 6 variants are located in the intronic regions, and the remaining 5 variants are located within intergenic regions between genes. In addition, the results of polygenic risk score show that the best evaluated effect for target data is among significant SNVs of the base data. The susceptibility genes of vitiligo are mainly enriched in the immune-related functions and pathways. The susceptibility variants expand the role of genetic factors associated with vitiligo. The bioinformatics analysis for risk genes provides further insight into the pathogenesis of vitiligo.

Stress aggravates imiquimod-induced psoriasiform inflammation by promoting M1 macrophage polarization.

Psychological stress has long been considered to cause the aggravation and recurrence of psoriasis, but the underlying mechanism remains largely unknown. Here, we used a mouse model of restraint-induced stress and imiquimod (IMQ)-induced psoriasiform inflammation to investigate the crosstalk between stress and the skin immune system and their functions in the pathogenesis of psoriasis. We found that stress aggravated skin inflammation and elevated serum corticosterone (CORT) levels in mice. Stress also increased the number of macrophages and glucocorticoid receptor (GR) expression in IMQ-treated mouse skin. GR agonist CORT upregulated the phosphorylation of STAT1 to promote M1 macrophage polarization in vitro. Additionally, GR deletion in macrophages and pharmacologic inhibition of GR improved skin inflammation and reduced M1 macrophage polarization under stress. Taken together, these results indicate that stress aggravates psoriasiform inflammation by promoting CORT/GR signaling-induced M1 macrophage polarization, suggesting that blocking the GR signaling has great potential as an adjuvant treatment for psoriasis patients with chronic stress.

RasGRP1 influences imiquimod-induced psoriatic inflammation via T-cell activation in mice.

The vascular endothelial growth factor (VEGF) signal transduction pathway has been shown to be a potential target for the treatment of psoriasis. Ras guanyl-releasing protein 1 (RasGRP1), a downstream target gene of VEGF, regulates the development, homeostasis, and differentiation of T cells, but the contribution of RasGRP1 to psoriasis is limited. In this manuscript, we aimed to investigate the role of RasGRP1 in psoriasis. The RNA-Seq transcriptome sequencing data from the mouse model of psoriasis treated with IMQ (imiquimod) were analyzed. The effect of RasGRP1 was investigated through in vivo injection of activators or small molecular inhibitors, as well as adeno-associated virus injections. Gene knockout and NB-UVB (narrow-band ultraviolet B) treatments were utilized to interfere with the psoriatic mouse model. By transfection of lentivirus in vitro, the effect of RasGRP1 gene function on the secretion of psoriasis-related cytokines by T cells was confirmed. We showed that cutaneous VEGF and RasGRP1 were strongly activated in human psoriatic lesions and the skin of mice with IMQ-induced psoriasis. RasGRP1 deficiency and overexpression influence IMQ-induced psoriasis-like manifestations and skin inflammation in mice. VEGF, secreted mainly by epidermal cells, mediates psoriatic inflammation through the RasGRP1-AKT-NF-κB pathway. RasGRP1 is required for psoriasis development mediated by VEGF. These results confirmed the role of RasGRP1 in the pathogenesis of psoriasis and provided potential targets for clinical psoriasis treatment.

Genome-wide meta-analyses identify five new risk loci for nonsyndromic orofacial clefts in the Chinese Han population.

BACKGROUND: Nonsyndromic orofacial clefts (NSOFCs) are the most common craniofacial birth malformations in humans and are generally classified as nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO). Genome-wide association studies (GWASs) of NSOFCs have demonstrated multiple risk loci and candidate genes; however, published risk factors are able to explain only a small fraction of the observed NSOFCs heritability. METHODS: Here, we performed GWASs of 1615 NSCPO cases and 2340 controls, and then conducted genome-wide meta-analyses of NSOFCs, totaling 6812 NSCL/P cases, 2614 NSCPO cases, and 19,165 controls from the Chinese Han population. RESULTS: We identify 47 risk loci with genome-wide pmeta -value <5.0 × 10-8 , 5 risk loci (1p32.1, 3p14.1, 3p14.3, 3p21.31, and 13q22.1) of which are new. All of the 47 susceptibility loci conjointly account for 44.12% of the NSOFCs' heritability in the Chinese Han population. CONCLUSION: Our results improve the comprehending of genetic susceptibility to NSOFCs and provide new views into the genetic etiology of craniofacial anomalies.

Multifactor dimensionality reduction reveals the effect of interaction between ERAP1 and IFIH1 polymorphisms in psoriasis susceptibility genes.

Background: Psoriasis is a common immune-mediated hyperproliferative skin dysfunction with known genetic predisposition. Gene-gene interaction (e.g., between HLA-C and ERAP1) in the psoriasis context has been reported in various populations. As ERAP1 has been recognized as a psoriasis susceptibility gene and plays a critical role in antigen presentation, we performed this study to identify interactions between ERAP1 and other psoriasis susceptibility gene variants. Methods: We validated psoriasis susceptibility gene variants in an independent cohort of 5,414 patients with psoriasis and 5,556 controls. Multifactor dimensionality reduction (MDR) analysis was performed to identify the interaction between variants significantly associated with psoriasis in the validation cohort and ERAP1 variants. We then conducted a meta-analysis of those variants with datasets from exome sequencing, target sequencing, and validation analyses and used MDR to identify the best gene-gene interaction model, including variants that were significant in the meta-analysis and ERAP1 variants. Results: We found that 19 of the replicated variants were identified with p < 0.05 and detected six single-nucleotide polymorphisms of psoriasis susceptibility genes in the meta-analysis. MDR analysis revealed that the best predictive model was that between the rs27044 polymorphism of ERAP1 and the rs7590692 polymorphism of IFIH1 (cross-validation consistency = 9/10, test accuracy = 0.53, odds ratio = 1.32 (95% CI, 1.09-1.59), p < 0.01). Conclusion: Our findings suggest that the interaction between ERAP1 and IFIH1 affects the development of psoriasis. This hypothesis needs to be tested in basic biological studies.

Calcium/calmodulin-dependent protein kinase IV promotes imiquimod-induced psoriatic inflammation via macrophages and keratinocytes in mice.

CaMK4 has an important function in autoimmune diseases, and the contribution of CaMK4 in psoriasis remains obscure. Here, we show that CaMK4 expression is significantly increased in psoriatic lesional skin from psoriasis patients compared to healthy human skin as well as inflamed skin from an imiquimod (IMQ)-induced mouse model of psoriasis compared to healthy mouse skin. Camk4-deficient (Camk4-/-) mice treated with IMQ exhibit reduced severity of psoriasis compared to wild-type (WT) mice. There are more macrophages and fewer IL-17A+γδ TCR+ cells in the skin of IMQ-treated Camk4-/- mice compared to IMQ-treated WT mice. CaMK4 inhibits IL-10 production by macrophages, thus allowing excessive psoriatic inflammation. Deletion of Camk4 in macrophages alleviates IMQ-induced psoriatic inflammation in mice. In keratinocytes, CaMK4 inhibits apoptosis as well as promotes cell proliferation and the expression of pro-inflammatory genes such as S100A8 and CAMP. Taken together, these data indicate that CaMK4 regulates IMQ-induced psoriasis by sustaining inflammation and provides a potential target for psoriasis treatment.

Rare mutations in NLRP3 and NLRP12 associated with familial cold autoinflammatory syndrome: two Chinese pedigrees.

Familial cold autoinflammatory syndrome (FCAS) is the mildest subtype of cryopyrin-associated periodic syndrome (CAPS) and is a rare inherited systemic autoinflammatory disease (SAID). CAPS is the consequence of a rare group of genetic disorders that are mostly reported in European and American populations, but scarcely reported in Chinese populations. NLRP3, NLRP12, PLCG2, and NLRC4 are known pathogenic genes associated with FCAS, and the aim of this study was to identify pathogenic mutations in two intact pedigrees of Chinese FCAS. We performed Sanger sequencing of genomic DNA samples from 25 affected and 32 unaffected members of the two intact pedigrees and analyzed the pathogenic mutations for their conservativeness using multiple sequence alignment tools. In addition, we reviewed previously reported pathogenic genes of FCAS and their pathogenicity classification and summarized the characteristics of different genotypes and phenotypes of FCAS. This study reported two intact FCAS pedigrees with different genotypes and phenotypes, the heterozygous mutation (p.V72M) in NLRP3 in pedigree 1 and the heterozygous mutation (p.R754H) in NLRP12 in pedigree 2. There are no reports targeting p.V72M in NLRP3 in FCAS1, and there are relatively few relevant phenotypic data on the clinical manifestations identified in previous pedigrees. Multiple sequence comparisons of NLRP3 indicate that the p.V72M mutation is highly conserved during evolution. Our study has enriched the understanding of the pathogenesis of FCAS, a rare disease especially in Asian populations. KEY POINTS: •The NLRP3 (p.V72M) variant was first discovered in the Chinese pedigree of FCAS1 •NLRP12 (p.R754H) variants are not conserved in multiple sequence alignments, but they are still co-segregated and expressed in the big Chinese diseased pedigree.

Imputation of the major histocompatibility complex region identifies major independent variants associated with bullous pemphigoid and dermatomyositis in Han Chinese.

As autoimmune skin diseases, both bullous pemphigoid (BP) and dermatomyositis (DM) show significant associations with the major histocompatibility complex (MHC) region. In fact, the coexistence of BP and DM has been previously reported. Therefore, we hypothesized that there may be a potential genetic correlation between BP and DM. Based on data for 312 BP patients, 128 DM patients, and 6793 healthy control subjects, in the MHC region, we imputed single-nucleotide polymorphisms (SNP), insertions and deletions (INDEL), and copy number variations (CNV) using the 1KGP phase 3 dataset and amino acids (AA) and SNP using a Han-MHC reference database. An association study revealed the most significant SNP associated with BP, namely, rs580921 (p = 1.06E-08, odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.37-1.90), which is located in the C6orf10 gene, and the most significant classic human leukocyte antigen (HLA) allele associated with DM, namely, HLA-DPB1*1701 (p = 6.56E-10, OR = 3.61, 95% CI = 2.40-5.42). Further stepwise regression analyses with rs580921 identified a threonine at position 163 of the HLA-B gene as a new independent disease-associated AA, and HLA-DPB1*1701 indicated that no loci were significant. Three-dimensional ribbon models revealed that the HLA-B AA position 163 (p = 3.93E-07, OR = 1.64, 95% CI = 1.35-1.98) located in the α2 domain of the HLA-B molecule was involved in the process of specific antigen presentation. The calculations showed that there was no significant genetic correlation between BP and DM. Our study identified three significant loci in the MHC region, proving that the HLA region was significantly correlated with BP and DM separately. Our research highlights the key role of the MHC region in disease susceptibility.