Using multi-tissue transcriptome-wide association study to identify candidate susceptibility genes for respiratory infectious diseases

Objective: We explore the candidate susceptibility genes for influenza A virus (IAV), measles, rubella, and mumps and their underlying biological mechanisms.Methods: We downloaded the genome-wide association study summary data of four virus-specific immunoglobulin G (IgG) level data sets (anti-IAV IgG, anti-measles IgG, anti-rubella IgG, and anti-mumps virus IgG levels) and integrated them with reference models of three potential tissues from the Genotype-Tissue Expression (GTEx) project, namely, whole blood, lung, and transformed fibroblast cells, to identify genes whose expression is predicted to be associated with IAV, measles, mumps, and rubella.Results: We identified 19 significant genes (ULK4, AC010132.11, SURF1, NIPAL2, TRAP1, TAF1C, AC000078.5, RP4-639F20.1, RMDN2, ATP1B3, SRSF12, RP11-477D19.2, TFB1M, XXyac-YX65C7_A.2, TAF1C, PCGF2, and BNIP1) associated with IAV at a Bonferroni-corrected threshold of p < 0.05; 14 significant genes (SOAT1, COLGALT2, AC021860.1, HCG11, METTL21B, MRPL10, GSTM4, PAQR6, RP11-617D20.1, SNX8, METTL21B, ANKRD27, CBWD2, and TSFM) associated with measles at a Bonferroni-corrected threshold of p < 0.05; 15 significant genes (MTOR, LAMC1, TRIM38, U91328.21, POLR2J, SCRN2, Smpd4, UBN1, CNTROB, SCRN2, HOXB-AS1, SLC14A1, AC007566.10, AC093668.2, and CPD) associated with mumps at a Bonferroni-corrected threshold of p < 0.05; and 13 significant genes (JAGN1, RRP12, RP11-452K12.7, CASP7, AP3S2, IL17RC, FAM86HP, AMACR, RRP12, PPP2R1B, C11orf1, DLAT, and TMEM117) associated with rubella at a Bonferroni-corrected threshold of p < 0.05.Conclusions: We have identified several candidate genes for IAV, measles, mumps, and rubella in multiple tissues. Our research may further our understanding of the pathogenesis of infectious respiratory diseases

The relationship between obstructive sleep apnea and osteoarthritis: evidence from an observational and Mendelian randomization study

ObjectivesObstructive sleep apnea (OSA) and osteoarthritis (OA) are common comorbidities that significantly impact individuals’ quality of life. However, the relationship between OSA and OA remains unclear. This study aims to explore the connection between OSA and OA and evaluate causality using Mendelian randomization (MR).MethodsA total of 12,454 participants from the National Health and Nutrition Examination Survey (2009–2012) were included. OSA participants were identified based on self-reported interviews. The association between OA and OSA was assessed through multivariable logistic regression analysis. A two-sample MR was employed to investigate the relationship between OSA and OA, specifically hip OA and knee OA, utilizing the inverse variance-weighted (IVW) approach.ResultsBased on the observational study, individuals with OSA exhibited a higher risk of OA (OR = 1.67, 95% CI = 1.40–1.98). IVW demonstrated that the risk of OA (OR = 1.13, 95% CI: 1.05–1.21, p = 0.001), hip OA (OR = 1.11, 95% CI: 1.04–1.18, p = 0.002), and knee OA (OR = 1.08, 95% CI: 1.02–1.14, p = 0.005) was significantly associated with OSA. Reverse MR analyses indicated no effect of OA on OSA. Additionally, body mass index (BMI) was found to mediate 36.9% (95% CI, 4.64–73.2%, p = 0.026) of the OSA effects on OA risk.ConclusionThe cross-sectional observational analysis unveiled noteworthy associations between OSA and OA. Meanwhile, findings from the MR study provide support for a causal role

Functional studies on Vps74p, a novel protein sorting regulator in sacchromyces[sic] cerevisiae

Deletion of the VPS74 (V̲acuolar P̲rotein S̲orting 74) gene in yeast Sacchromyces cerevisiae results in a modest defect in carboxypeptidase Y (CPY) sorting. I found that null mutants of VPS74 were sensitive to Calcofluor white, indicating that the cell walls of these cells were defective. Consistent with this, processing of the GPI-anchored protein Gas1p, which is required for proper cell wall assembly and morphogenesis, was altered in vps74Δ cells. I have established that the defects of cell wall integrity and Gas1p processing observed in vps74Δ cells are attributable to the mislocalization and rapid degradation of a subset of Golgi mannosyltransferases, and in particular, Kre2p. Using a yeast two hybrid assay, I have demonstrated that Vps74p interacts with the cytoplasmic tail of Kre2p and that the FLS amino acid sequence in Kre2p is required to mediate this binding. Mammalian homologues of Vps74p, GMx33α/GPP34 and GMx33β/GPP34R, can complement the Gas1p processing and Calcofluor white sensitivity defects of vps74Δ cells to varying degrees indicating that some of Vps74p’s activities are evolutionarily conserved. My findings suggest that Vps74p functions as a protein sorting receptor mediating the retrieval and hence steady-state distribution of a subset of Golgi mannosyltransferases. To further investigate the function of VPS74, I performed a synthetic lethal screen. From this screen I identified three mutants that showed synthetic lethal interactions with cells lacking the VPS74 gene. The mutations responsible for the synthetic lethal phenotypes all mapped to a single locus - YIL039W (GPS1, G̲as1 P̲rotein S̲orting 1) an uncharacterized, non-essential yeast gene. Null, or temperature-sensitive mutations in GPS1, cause a transport delay of the GPI-anchored protein Gas1p from the endoplasmic reticulum, which suggests a role for Gps1p in ER-to-Golgi traffic. Gps1p contains a presumptive calcineurin-like phosphoesterase domain in its C-terminus and I attempted to identify candidate substrates for Gps1p by looking for dosage suppressors of the temperature-sensitive growth defect of vps74Δgps1ts cells. One such suppressor, termed DCR2 (d̲osage c̲ell cycle r̲egulator 2) also contains a calcineurin-like phosphoesterase domain, which suggests that Gps1p and Dcr2p belong to the same calcineurin-like phosphoesterase protein family. Consistent with this, cells that lack both DCR2 and GPS1 are inviable. I have established that Gps1p and Dcr2p are integral membrane proteins that localize to the ER / Golgi, and that the presumptive catalytic domains of these proteins are located in the lumen of these organelles. Characterization of the gps1-1 temperature-sensitive allele in both vps74Δ and dcr2Δ genetic backgrounds revealed a defect in cell polarity; cells show abnormal actin cytoskeleton organization, depolarized chitin deposition and fail to respond to alpha factor. In addition, I have determined that vps74Δgps1ts cells show a temperature-dependent remedial osmo-resistance phenotype under conditions that induce high osmotic stress

A Conserved N-terminal Arginine-Motif in GOLPH3-Family Proteins Mediates Binding to Coatomer

Vps74p, a member of the GOLPH3 protein family, binds directly to coatomer and the cytoplasmic tails of a subset of Golgi-resident glycosyltransferases to mediate their Golgi retention. We identify a cluster of arginine residues at the N-terminal end of GOLPH3 proteins that are necessary and sufficient to mediate coatomer binding. While loss of coatomer binding renders Vps74p non-functional for glycosyltransferase retention, the Golgi membrane-binding capabilities of the mutant protein are not significantly reduced. We establish that the oligomerization status and phosphatidylinositol-4-phosphate-binding properties of Vps74p largely account for the membrane-binding capacity of the protein and identify an Arf1pVps74p interaction as a potential contributing factor in Vps74p Golgi membrane association

Signal-Mediated Dynamic Retention of Glycosyltransferases in the Golgi

Golgi-resident glycosyltransferases are a family of enzymes that sequentially modify glycoproteins in a subcompartment-specific manner. These type II integral membrane proteins are characterized by a short cytoplasmically exposed amino-terminal tail and a luminal enzymatic domain. The cytoplasmic tails play a role in the localization of glycosyltransferases, and coat protein complex I (COPI) vesicle-mediated retrograde transport is also involved in their Golgi localization. However, the tails of these enzymes lack known COPI-binding motifs. Here, we found that Vps74p bound to a pentameric motif present in the cytoplasmic tails of the majority of yeast Golgi-localized glycosyltransferases, as well as to COPI. We propose that Vps74p maintains the steady-state localization of Golgi glycosyltransferases dynamically, by promoting their incorporation into COPI-coated vesicles

Transcriptomics and Metabolomics Analysis of <i>Sclerotium rolfsii</i> Fermented with Differential Carbon Sources

Scleroglucan is obtained from Sclerotium rolfsii and is widely used in many fields. In this study, transcriptomics combined with metabolomics were used to study the global metabolites and gene changes. The results of the joint analysis showed that the DEGs (differentially expressed genes) and DEMs (differentially expressed metabolites) of SEPS_48 (fermented with sucrose as a carbon source for 48 h) and GEPS_48 (fermented with glucose as a carbon source for 48 h) comparison groups were mainly related to cell metabolism, focusing on carbohydrate metabolism, amino acid metabolism, and amino sugar and nucleoside sugar metabolism. We therefore hypothesized that the significant differences in these metabolic processes were responsible for the differences in properties. Moreover, the joint analysis provides a scientific theoretical basis for fungal polysaccharides biosynthesis and provides new insights into the effects of carbon sources on the production. As an excellent bioenergy and biological product, scleroglucan can be better applied in different fields, such as the food industry

Gut microbial features may influence antiviral IgG levels after vaccination against viral respiratory infectious diseases: the evidence from two-sample bidirectional mendelian randomization

Abstract Background Vaccination is effective in preventing viral respiratory infectious diseases through protective antibodies and the gut microbiome has been proven to regulate human immunity. This study explores the causal correlations between gut microbial features and serum-specific antiviral immunoglobulin G (IgG) levels. Methods We conduct a two-sample bidirectional Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary data to explore the causal relationships between 412 gut microbial features and four antiviral IgG (for influenza A, measles, rubella, and mumps) levels. To make the results more reliable, we used four robust methods and performed comprehensive sensitivity analyses. Results The MR analyses revealed 26, 13, 20, and 18 causal associations of the gut microbial features influencing four IgG levels separately. ​Interestingly, ten microbial features, like genus Collinsella, species Bifidobacterium longum, and the biosynthesis of L-alanine have shown the capacity to regulate multiple IgG levels with consistent direction (rise or fall). The ​reverse MR analysis suggested several potential causal associations of IgG levels affecting microbial features. Conclusions The human immune response against viral respiratory infectious diseases could be modulated by changing the abundance of gut microbes, which provided new approaches for the intervention of viral respiratory infections

Image1_Using multi-tissue transcriptome-wide association study to identify candidate susceptibility genes for respiratory infectious diseases.TIF

Objective: We explore the candidate susceptibility genes for influenza A virus (IAV), measles, rubella, and mumps and their underlying biological mechanisms.Methods: We downloaded the genome-wide association study summary data of four virus-specific immunoglobulin G (IgG) level data sets (anti-IAV IgG, anti-measles IgG, anti-rubella IgG, and anti-mumps virus IgG levels) and integrated them with reference models of three potential tissues from the Genotype-Tissue Expression (GTEx) project, namely, whole blood, lung, and transformed fibroblast cells, to identify genes whose expression is predicted to be associated with IAV, measles, mumps, and rubella.Results: We identified 19 significant genes (ULK4, AC010132.11, SURF1, NIPAL2, TRAP1, TAF1C, AC000078.5, RP4-639F20.1, RMDN2, ATP1B3, SRSF12, RP11-477D19.2, TFB1M, XXyac-YX65C7_A.2, TAF1C, PCGF2, and BNIP1) associated with IAV at a Bonferroni-corrected threshold of p Conclusions: We have identified several candidate genes for IAV, measles, mumps, and rubella in multiple tissues. Our research may further our understanding of the pathogenesis of infectious respiratory diseases.</p