Allelic Variants Within the ABO Blood Group Phenotype Confer Protection Against Critical COVID-19 Hospital Presentation

Introduction: Coronavirus disease 2019 (COVID-19) disease severity differs widely due to numerous factors including ABO gene-derived susceptibility or resistance. The objective of this study was to investigate the association of the ABO blood group and genetic variations of the ABO gene with COVID-19 severity in a heterogeneous hospital population sample from the United Arab Emirates, with the use of an epidemiological and candidate gene approach from a genome-wide association study (GWAS).Methods: In this cross-sectional study, a total of 646 participants who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were recruited from multiple hospitals and population-based (quarantine camps) recruitment sites from March 2020 to February 2021. The participants were divided into two groups based on the severity of COVID-19: noncritical (n = 453) and critical [intensive care unit (ICU) patients] (n = 193), as per the COVID-19 Reporting and Data System (CO-RADS) classification. The multivariate logistic regression analysis demonstrated the association of ABO blood type as well as circulating anti-A antibodies and anti-B antibodies as well as A and B antigens, in association with critical COVID-19 hospital presentation. A candidate gene analysis approach was conducted from a GWAS where we examined 240 single nucleotide polymorphisms (SNPs) (position in chr9: 136125788-136150617) in the ABO gene, in association with critical COVID-19 hospital presentation.Results: Patients with blood group O [odds ratio (OR): 0.51 (0.33, 0.79); p = 0.003] were less likely to develop critical COVID-19 symptoms. Eight alleles have been identified to be associated with a protective effect of blood group O in ABO 3'untranslated region (UTR): rs199969472 (p = 0.0052), rs34266669 (p = 0.0052), rs76700116 (p = 0.0052), rs7849280 (p = 0.0052), rs34039247 (p = 0.0104), rs10901251 (p = 0.0165), rs9411475 (p = 0.0377), and rs13291798 (p = 0.0377).Conclusion: Our findings suggest that there are novel allelic variants that link genetic variants of the ABO gene and ABO blood groups contributing to the reduced risk of critical COVID-19 disease. This study is the first study to combine genetic and serological evidence of the involvement of the ABO blood groups and the ABO gene allelic associations with COVID-19 severity within the Middle Eastern population.

Global Characterization of Metabolic Genes Regulating Survival and Immune Infiltration in Osteosarcoma

Background: The alterations in metabolic profile of tumors have been identified as one of the prognostic hallmarks of cancers, including osteosarcoma. These alterations are majorly controlled by groups of metabolically active genes. However, the regulation of metabolic gene signatures in tumor microenvironment of osteosarcoma has not been well explained.Objectives: Thus, we investigated the sets of previously published metabolic genes in osteosarcoma patients and normal samples.Methods: We applied computational techniques to identify metabolic genes involved in the immune function of tumor microenvironment (TME) and survival and prognosis of the osteosarcoma patients. Potential candidate gene PAICS (phosphoribosyl aminoimidazole carboxylase, phosphoribosyl aminoimidazole succino carboxamide synthetase) was chosen for further studies in osteosarcoma cell lines for its role in cell proliferation, migration and apoptosis.Results: Our analyses identified a list of metabolic genes differentially expressed in osteosarcoma tissues. Next, we scrutinized the list of genes correlated with survival and immune cells, followed by clustering osteosarcoma patients into three categories: C1, C2, and C3. These analyses led us to choose PAICS as potential candidate gene as its expression showed association with poor survival and negative correlation with the immune cells. Furthermore, we established that loss of PAICS induced apoptosis and inhibited proliferation, migration, and wound healing in HOS and MG-63 cell lines. Finally, the results were supported by constructing and validating a prediction model for prognosis of the osteosarcoma patients.Conclusion: Here, we conclude that metabolic genes specifically PAICS play an integral role in the immune cell infiltration in osteosarcoma TME, as well as cancer development and metastasis.

Genome-wide association study reveals white lupin candidate gene involved in anthracnose resistance

Key message GWAS identifies candidate gene controlling resistance to anthracnose disease in white lupin. Abstract White lupin (Lupinus albus L.) is a promising grain legume to meet the growing demand for plant-based protein. Its cultivation, however, is severely threatened by anthracnose disease caused by the fungal pathogen Colletotrichum lupini. To dissect the genetic architecture for anthracnose resistance, genotyping by sequencing was performed on white lupin accessions collected from the center of domestication and traditional cultivation regions. GBS resulted in 4611 high-quality single-nucleotide polymorphisms (SNPs) for 181 accessions, which were combined with resistance data observed under controlled conditions to perform a genome-wide association study (GWAS). Obtained disease phenotypes were shown to highly correlate with overall three-year disease assessments under Swiss field conditions (r > 0.8). GWAS results identified two significant SNPs associated with anthracnose resistance on gene Lalb_Chr05_g0216161 encoding a RING zinc-finger E3 ubiquitin ligase which is potentially involved in plant immunity. Population analysis showed a remarkably fast linkage disequilibrium decay, weak population structure and grouping of commercial varieties with landraces, corresponding to the slow domestication history and scarcity of modern breeding efforts in white lupin. Together with 15 highly resistant accessions identified in the resistance assay, our findings show promise for further crop improvement. This study provides the basis for marker-assisted selection, genomic prediction and studies aimed at understanding anthracnose resistance mechanisms in white lupin and contributes to improving breeding programs worldwide.

Identification of a Key Glioblastoma Candidate Gene, FUBP3, Based on Weighted Gene Co-expression Network Analysis

Background: Glioblastoma multiforme (GBM) is the most common aggressive malignant brain tumor. However, the molecular mechanism of glioblastoma formation is still poorly understood. To identify candidate genes that may be connected to glioma growth and development, weighted gene co-expression network analysis (WGCNA) was performed to construct a gene co-expression network between gene sets and clinical characteristics. We also explored the function of the key candidate gene.Methods: Two GBM datasets were selected from GEO Datasets. The R language was used to identify differentially expressed genes. WGCNA was used to construct a gene co-expression network in the GEO glioblastoma samples. A custom Venn diagram website was used to find the intersecting genes. The GEPIA website was used for survival analysis to determine the significant gene, FUBP3. OS,DSS, and PFI analyses, based on the UCSC Cancer Genomics Browser, were performed to verify the significance of FUBP3. Immunohistochemistry was performed to evaluate the expression of FUBP3 in glioblastoma and adjacent normal tissue. KEGG and GO enrichment analyses were used to reveal possible functions of FUBP3. Microenvironment analysis was used to explore the relationship between FUBP3 and immune infiltration. Immunohistochemistry was performed to verify the results of the microenvironment analysis.Results: GSE70231 and GSE108474 were selected from GEO Datasets, then 715 and 694 differentially expressed genes (DEGs) from GSE70231 and GSE108474, respectively, were identified. We then performed weighted gene co-expression network analysis (WGCNA) and identified the most downregulated gene modules of GSE70231 and GSE108474, and 659 and 3915 module genes from GSE70231 and GSE108474, respectively, were selected. Five intersection genes (FUBP3, DAD1, CLIC1, ABR, and DNM1) were calculated by Venn diagram. FUBP3 was then identified as the only significant gene by survival analysis using the GEPIA website. OS, DSS, and PFI analyses verified the significance of FUBP3. Immunohistochemical analysis revealed FUBP3 expression in GBM and adjacent normal tissue. KEGG and GO analyses uncovered the possible function of FUBP3 in GBM. Tumor microenvironment analysis showed that FUBP3 may be connected to immune infiltration, and immunohistochemistry identified a positive correlation between immune cells (CD4+ T cells, CD8+ T cells, and macrophages) and FUBP3.Conclusion: FUBP3 is associated with immune surveillance in GBM, indicating that it has a great impact on GBM development and progression. Therefore, interventions involving FUBP3 and its regulatory pathway may be a new approach for GBM treatment.

Combination of Genomic and Transcriptomic Approaches Highlights Vascular and Circadian Clock Components in Multiple Sclerosis

Aiming at exploring vascular components in multiple sclerosis (MS) with brain outflow disturbance, we combined transcriptome analysis in MS internal jugular vein (IJV) wall with WES in MS families with vertical transmission of disease. Main results were the differential expression in IJV wall of 16 MS-GWAS genes and of seven genes (GRIN2A, GRIN2B, IL20RB, IL26, PER3, PITX2, and PPARGC1A) not previously indicated by GWAS but encoding for proteins functionally interacting with MS candidate gene products. Strikingly, 22/23 genes have been previously associated with vascular or neuronal traits/diseases, nine encoded for transcriptional factors/regulators and six (CAMK2G, GRIN2A, GRIN2B, N1RD1, PER3, PPARGC1A) for circadian entrainment/rhythm components. Among the WES low-frequency (MAF ≤ 0.04) SNPs (n = 7) filtered in the 16 genes, the NR1D1 rs17616365 showed significantly different MAF in the Network for Italian Genomes affected cohort than in the 1000 Genome Project Tuscany samples. This pattern was also detected in five nonintronic variants (GRIN2B rs1805482, PER3 rs2640909, PPARGC1A rs2970847, rs8192678, and rs3755863) in genes coding for functional partners. Overall, the study proposes specific markers and low-frequency variants that might help (i) to understand perturbed biological processes in vascular tissues contributing to MS disease, and (ii) to characterize MS susceptibility genes for functional association with disease-pathways.