While there are currently over 40 replicated genes with mapped risk alleles for Late Onset Alzheimer\'s disease (LOAD), the Apolipoprotein E locus E4 haplotype is still the biggest driver of risk, with odds ratios for neuropathologically confirmed E44 carriers exceeding 30 (95% confidence interval 16.59-58.75). We sought to address whether the APOE E4 haplotype modifies expression globally through networks of expression to increase LOAD risk. We have used the Human Brainome data to build expression networks comparing APOE E4 carriers to non-carriers using scalable mixed-datatypes Bayesian network (BN) modeling. We have found that VGF had the greatest explanatory weight. High expression of VGF is a protective signal, even on the background of APOE E4 alleles. LOAD risk signals, considering an APOE background, include high levels of SPECC1L, HLA-DRA and RANBP3L. Our findings nominate several new transcripts, taking a combined approach to network building including known LOAD risk loci.

BACKGROUND: Innate/adaptive immunity is the key to anti-tumor therapy. However, its causal relationship to Gastrointestinal (GI) cancer remains unclear.
METHODS: Immunity genes were extracted from the MSigDB database. The Genome-wide association studies (GWAS) summary data of GI cancer were integrated with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) associated with genes. Summary-data-based Mendelian randomization (SMR) and co-localization analysis were used to reveal causal relationships between genes and GI cancer. Two-sample MR analysis was used for sensitivity analysis. Single cell analysis clarified the enrichment of genes.
RESULTS: Three-step SMR analysis showed that a putative mechanism, cg17294865 CpG site regulating HLA-DRA expression was negatively associated with gastric cancer risk. HLA-DRA was significantly differentially expressed in monocyte/macrophage and myeloid cells in gastric cancer.
CONCLUSIONS: This study provides evidence that upregulating the expression level of HLA-DRA can reduce the risk of gastric cancer.

OBJECTIVE: Despite recent advances in understanding the gastric cancer (GC) biology, the precise molecular mechanism of gastric carcinogenesis and role of deregulated immune responses in GC progression are still not well understood. In this study, mRNA levels of human leukocyte antigen (HLA)-DRA and -DQA1 were assessed in GC patients to find a potential association between expression of these HLA-II molecules and gastric carcinogenesis.
METHODS: Using quantitative real-time (qRT)-PCR, mRNA levels of HLA-DRA and -DQA1 were assessed in 20 pairs of matched GC and normal tissues.
RESULTS: Our results showed that overall mRNA level of HLA-DRA was decreased in the tumor samples relative to control tissues (median fold change [FC] = 0.693; P = 0.445). Overall HLA-DQA1 level was increased in the tumor samples relative to control tissues (median FC = 1.659; P = 0.5117). However, the mentioned data were not statistically significant. Meanwhile, using a ≥ 2.5 FC as the cutoff to determine upregulation or downregulation, 35% of patients showed a downregulated expression of HLA-DRA, while 10% of those showed upregulation in HLA-DRA expression. Upregulation and downregulation of HLA-DQA1 expression were detected, respectively, in 35% and 25% of samples. A strong positive correlation was determined between HLA-DRA and HLA-DQA1 levels in tumor tissues (r = 0.7298; P = 0.0003).
CONCLUSIONS: The results reported here along with future studies can be useful to understand the interplay between immune system and GC, therefore, may be helpful to design an effective immune-based therapy.

Osteoarthritis (OA) is a progressive cartilage degradation disease, concomitant with synovitis, osteophyte formation, and subchondral bone sclerosis. Over 37% of the elderly population is affected by OA, and the number of cases is increasing as the global population ages. Therefore, the objective of this study was to identify and analyze the hub genes of OA combining with comprehensive bioinformatics analysis tools to provide theoretical basis in further OA effective therapies. Two sample sets of GSE46750 contained 12 pairs OA synovial membrane and normal samples harvested from patients as well as GSE98918 including 12 OA and non-OA patients were downloaded from the Gene Expression Omnibus database (GEO) database. Differentially expressed genes (DEGs) were identified using Gene Expression Omnibus 2R (GEO2R), followed by functional enrichment analysis, protein-protein interaction networks construction. The hub genes were identified and evaluated. An OA rat model was constructed, hematoxylin and eosin staining, safranin O/fast green staining, cytokines concentrations of serum were used to verify the model. The hub genes expression level in the knee OA samples were verified using RT-qPCR. The top 20 significantly up-regulated and down-regulated DEGs were screened out from the two datasets, respectively. The top 18 GO terms and 10 KEGG pathways were enriched. Eight hub genes were identified, namely MS4A6A, C1QB, C1QC, CD74, CSF1R, HLA-DPA1, HLA-DRA and ITGB2. Among them, the hub genes were all up-regulated in in vivo OA rat model, compared with healthy controls. The eight hub genes identified (MS4A6A, C1QB, C1QC, CD74, CSF1R, HLA-DPA1, HLA-DRA and ITGB2) were shown to be associated with OA. These genes can serve as disease markers to discriminate OA patients from healthy controls.

Hypertensive disorders in pregnancy (HDP) are the leading cause of perinatal mortality worldwide. Inflammatory responses induced by insufficient placental perfusion have become a focal point in understanding the pathogenesis and aetiology of HDP and developing reliable and consistent biomarkers. Therefore, this study aims to identify gene signatures linked to the pathophysiology of HDP (gestational hypertension and early and late-onset pre-eclampsia).
RNA was extracted from the maternal serum from the blood samples collected from different groups of HDP patients. A multiplex inflammation panel (255 inflammatory and housekeeping genes) and further gene expression analysis using NanoString Digital Direct Detection were done. The prominent expressions of these genes were further validated through qPCR techniques.
NanoString analysis identified nine unique, significantly expressed genes (MAPK1, MAPK3, MAFF, HLA-DRA, IL12B, RHOA, MASP2, MEF2A and NR3C1) between specific group comparisons of different HPD classes and the normotensive groups. The qPCR showed that the HLA-DRA gene was significantly upregulated in the early-onset pre-eclamptic and gestational hypertensive group compared to its respective normotensive group. In contrast, MAFF and MEF2A were significantly downregulated in both HDPs compared to their controls. The MAPK1 gene was significantly higher in the early-onset group compared to the gestational hypertensive and normotensive groups.
The upregulation of these distinctive genes in hypertensive groups compared to normotensives confirmed their diagnostic potential. Therefore, HLA-DRA, MAFF and MEF2A could be candidate markers of HDP, while the MAPK1 gene could be a differentiating marker between early-onset pre-eclampsia and gestational hypertension.

Postoperative immunosuppression has been recognized as an important driver of surgery-related morbidity and mortality. It is characterized by lymphocyte depression and impaired monocyte capability to present foreign antigens to T-cells via Major Histocompatibility Complex, Class II (MHC-II) molecules. In patients with postoperative abdominal sepsis, we previously detected a persisting differential binding of the CCCTC-Binding Factor (CTCF), a superordinate regulator of transcription, inside the MHC-II region with specific impact on human leucocyte antigen (HLA) gene expression. In this prospective exploratory study, we investigated to which extent major surgery affects the MHC-II region of circulating CD14+-monocytes.
In non-immunocompromised patients undergoing elective major abdominal surgery, a postoperative loss of monocyte HLA-DR surface receptor density was accompanied by a decline in the transcription levels of the classical MHC-II genes HLA-DRA, HLA-DRB1, HLA-DPA1 and HLA-DPB1. The surgical event decreased the expression of the transcriptional MHC-II regulators CIITA and CTCF and led to a lower CTCF enrichment at an intergenic sequence within the HLA-DR subregion. During the observation period, we found a slow and only incomplete restoration of monocyte HLA-DR surface receptor density as well as a partial recovery of CIITA, HLA-DRA and HLA-DRB1 expression. In contrast, transcription of HLA-DPA1, HLA-DPB1, CTCF and binding of CTCF within the MHC-II remained altered.
In circulating monocytes, major surgery does not globally affect MHC-II transcription but rather induces specific changes in the expression of selected HLA genes, followed by differential recovery patterns and accompanied by a prolonged reduction of CTCF expression and binding within the MHC-II region. Our results hint toward a long-lasting impact of a major surgical intervention on monocyte functionality, possibly mediated by epigenetic changes that endure the life span of the individual cell.

Aortic aneurysms (AA) are prevalent worldwide with a notable absence of drug therapies. Thus, identifying potential drug targets is of utmost importance. AA often presents in the elderly, coupled with consistently raised serum inflammatory markers. Given that ageing and inflammation are pivotal processes linked to the evolution of AA, we have identified key genes involved in the inflammaging process of AA development through various bioinformatics methods, thereby providing potential molecular targets for further investigation.
The transcriptome data of AA was procured from the datasets GSE140947, GSE7084, and GSE47472, sourced from the NCBI GEO database, whilst gene data of ageing and inflammation were obtained from the GeneCards Database. To identify key genes, differentially expressed analysis using the \"Limma\" package and WGCNA were implemented. Protein-protein intersection (PPI) analysis and machine learning (ML) algorithms were employed for the screening of potential biomarkers, followed by an assessment of the diagnostic value. Following the acquisition of the hub inflammaging and AA-related differentially expressed genes (IADEGs), the TFs-mRNAs-miRNAs regulatory network was established. The CIBERSORT algorithm was utilized to investigate immune cell infiltration in AA. The correlation of hub IADEGs with infiltrating immunocytes was also evaluated. Lastly, wet laboratory experiments were carried out to confirm the expression of hub IADEGs.
342 and 715 AA-related DEGs (ADEGs) recognized from GSE140947 and GSE7084 datasets were procured by intersecting the results of \"Limma\" and WGCNA analyses. After 83 IADEGs were obtained, PPI analysis and ML algorithms pinpointed 7 and 5 hub IADEGs candidates respectively, and 6 of them demonstrated a high diagnostic value. Immune cell infiltration outcomes unveiled immune dysregulation in AA. In the wet laboratory experiments, 3 hub IADEGs, including BLNK, HLA-DRA, and HLA-DQB1, finally exhibited an expression trend in line with the bioinformatics analysis result.
Our research identified three genes - BLNK, HLA-DRA, and HLA-DQB1- that play a significant role in promoting the development of AA through inflammaging, providing novel insights into the future understanding and therapeutic intervention of AA.

Immunoregulation is crucial to septic shock (SS) but has not been clearly explained. Our aim was to explore potential biomarkers for SS by pathway and transcriptional analyses of immune-related genes to improve early detection. GSE57065 and GSE95233 microarray data were used to screen differentially expressed genes (DEGs) in SS. Gene Ontology and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analyses of DEGs were performed, and correlations between immune cell and pathway enrichment scores were analyzed. The predictive value of candidate genes was evaluated by receiver operating characteristic (ROC) curves. GSE66099, GSE4607, and GSE13904 datasets were used for external validation. Blood samples from six patients and six controls were collected for validation by qRT-PCR and western blotting. In total, 550 DEGs in SS were identified; these genes were involved in the immune response, inflammation, and infection. Immune-related pathways and levels of infiltration of CD4 + TCM, CD8 + T cells, and preadipocytes differed between SS cases and controls. Seventeen genes were identified as potential biomarkers of SS (areas under ROC curves >0.9). The downregulation of CD8A, CD247, CD3G, LCK, and HLA-DRA in SS was experimentally confirmed. We identified several immune-related biomarkers in SS that may improve early identification of disease risk.

BACKGROUND: Validated assays to measure autoantigen-specific T-cell frequency and phenotypes are needed for assessing the risk of developing diabetes, monitoring disease progression, evaluating responses to treatment, and personalizing antigen-based therapies.
OBJECTIVE: Toward this end, we performed a technical validation of a tetramer assay for HLA-DRA-DRB1*04:01, a class II allele that is strongly associated with susceptibility to type 1 diabetes (T1D).
METHODS: HLA-DRA-DRB1*04:01-restricted T cells specific for immunodominant epitopes from islet cell antigens GAD65, IGRP, preproinsulin, and ZnT8, and a reference influenza epitope, were enumerated and phenotyped in a single staining tube with a tetramer assay. Single and multicenter testing was performed, using a clone-spiked specimen and replicate samples from T1D patients, with a target coefficient of variation (CV) less than 30%. The same assay was applied to an exploratory cross-sectional sample set with 24 T1D patients to evaluate the utility of the assay.
RESULTS: Influenza-specific T-cell measurements had mean CVs of 6% for the clone-spiked specimen and 11% for T1D samples in single-center testing, and 20% and 31%, respectively, for multicenter testing. Islet-specific T-cell measurements in these same samples had mean CVs of 14% and 23% for single-center and 23% and 41% for multicenter testing. The cross-sectional study identified relationships between T-cell frequencies and phenotype and disease duration, sex, and autoantibodies. A large fraction of the islet-specific T cells exhibited a naive phenotype.
CONCLUSIONS: Our results demonstrate that the assay is reproducible and useful to characterize islet-specific T cells and identify correlations between T-cell measures and clinical traits.

Sarcoidosis is a complex systemic disease. Our study aimed to (1) identify novel alleles associated with sarcoidosis susceptibility; (2) provide an in-depth evaluation of HLA alleles and sarcoidosis susceptibility and (3) integrate genetic and transcription data to identify risk loci that may more directly impact disease pathogenesis. We report a genome-wide association study of 1335 sarcoidosis cases and 1264 controls of European descent (EA) and investigate associated alleles in a study of African Americans (AA: 1487 cases and 1504 controls). The EA and AA cohort was recruited from multiple United States sites. HLA alleles were imputed and tested for association with sarcoidosis susceptibility. Expression quantitative locus and colocalization analysis were performed using a subset of subjects with transcriptome data. Forty-nine SNPs in the HLA region in HLA-DRA, -DRB9, -DRB5, -DQA1 and BRD2 genes were significantly associated with sarcoidosis susceptibility in EA, rs3129888 was also a risk variant for sarcoidosis in AA. Classical HLA alleles DRB1*0101, DQA1*0101 and DQB1*0501, which are highly correlated, were also associated with sarcoidosis. rs3135287 near HLA-DRA was associated with HLA-DRA expression in peripheral blood mononuclear cells and bronchoalveolar lavage from subjects and lung tissue and whole blood from GTEx. We identified six novel SNPs (out of the seven SNPs representing the 49 significant SNPs) and nine HLA alleles associated with sarcoidosis susceptibility in the largest EA population. We also replicated our findings in an AA population. Our study reiterates the potential role of antigen recognition and/or presentation HLA class II genes in sarcoidosis pathogenesis.