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1.
Int J Immunogenet ; 48(2): 211-218, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1236376

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 infection produces a wide spectrum of manifestations, ranging from no symptom to viral pneumonia. This study aimed to determine the genetic variations in cytokines and their receptors in relation to COVID-19 pathogenesis using bioinformatic tools. Single nucleotide polymorphisms (SNPs) of genes encoding the cytokines and cytokine receptors elevated in patients with COVID-19 were determined from the National Biotechnology Information Center website (using the dbSNP database). Missense variants were found in 3 cytokine genes and 10 cytokine receptor genes. Computational analyses were conducted to detect the effects of these missense SNPs via cloud-based software tools. Also, the miRSNP database was used to explore whether SNPs in the 3'-UTR altered the miRNA binding efficiency for genes of cytokines and their receptors. Our in silico studies revealed that one SNP in the vascular endothelial growth factor receptor 2 (VEGFR2) gene was predicted as deleterious using sorting intolerant from tolerant. Also, the stability of VEGFR2 decreased in the I-Mutant2.0 (biotool for predicting stability changes upon mutation from the protein sequence or structure) prediction. It was suggested that the decrease in VEGFR2 function (due to the rs1870377 polymorphism) may be correlated with the progression of COVID-19 or contribute to the pathogenesis. Moreover, 27 SNPs were determined to affect miRNA binding for the genes of cytokine receptors. CXCR2 rs1126579, TNFRSF1B rs1061624 and IL10RB rs8178562 SNPs were predicted to break the miRNA-mRNA binding sites for miR-516a-3, miR-720 and miR-328, respectively. These miRNAs play an important role in immune regulation and lung damage repair. Further studies are needed to evaluate the importance of these miRNAs and the SNPs.


Subject(s)
COVID-19/diagnosis , COVID-19/genetics , Computational Biology , Cytokines/genetics , Polymorphism, Single Nucleotide , Receptors, Cytokine/genetics , 3' Untranslated Regions , Binding Sites , Computer Simulation , Disease Progression , Humans , Interleukin-10 Receptor beta Subunit/genetics , Mutation, Missense , Receptors, Interleukin-8B/genetics , Receptors, Tumor Necrosis Factor, Type II/genetics , Software , Vascular Endothelial Growth Factor Receptor-2/genetics
2.
Hum Mol Genet ; 30(13): 1247-1258, 2021 06 17.
Article in English | MEDLINE | ID: covidwho-1216653

ABSTRACT

The systematic identification of host genetic risk factors is essential for the understanding and treatment of coronavirus disease 2019 (COVID-19). By performing a meta-analysis of two independent genome-wide association summary datasets (N = 680 128), a novel locus at 21q22.11 was identified to be associated with COVID-19 infection (rs9976829 in IFNAR2-IL10RB, odds ratio = 1.16, 95% confidence interval = 1.09-1.23, P = 2.57 × 10-6). The rs9976829 represents a strong splicing quantitative trait locus for both IFNAR2 and IL10RB genes, especially in lung tissue (P = 1.8 × 10-24). Integrative genomics analysis of combining genome-wide association study with expression quantitative trait locus data showed the expression variations of IFNAR2 and IL10RB have prominent effects on COVID-19 in various types of tissues, especially in lung tissue. The majority of IFNAR2-expressing cells were dendritic cells (40%) and plasmacytoid dendritic cells (38.5%), and IL10RB-expressing cells were mainly nonclassical monocytes (29.6%). IFNAR2 and IL10RB are targeted by several interferons-related drugs. Together, our results uncover 21q22.11 as a novel susceptibility locus for COVID-19, in which individuals with G alleles of rs9976829 have a higher probability of COVID-19 susceptibility than those with non-G alleles.


Subject(s)
COVID-19/genetics , Chromosomes, Human, Pair 21 , Interleukin-10 Receptor beta Subunit/genetics , Receptor, Interferon alpha-beta/genetics , Alleles , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Cytokines/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Genomics/methods , Humans , Molecular Targeted Therapy , Polymorphism, Single Nucleotide , Quantitative Trait Loci
3.
Nat Med ; 27(4): 668-676, 2021 04.
Article in English | MEDLINE | ID: covidwho-1174686

ABSTRACT

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10-6; IFNAR2, P = 9.8 × 10-11 and IL-10RB, P = 2.3 × 10-14) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.


Subject(s)
COVID-19/genetics , Drug Repositioning , Mendelian Randomization Analysis/methods , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , COVID-19/drug therapy , Genome-Wide Association Study , Humans , Interleukin-10 Receptor beta Subunit/genetics , Interleukin-10 Receptor beta Subunit/physiology , Quantitative Trait Loci , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/physiology
4.
Nat Med ; 27(4): 659-667, 2021 04.
Article in English | MEDLINE | ID: covidwho-1104522

ABSTRACT

To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10-8), hospitalization (OR = 0.61, P = 8 × 10-8) and susceptibility (OR = 0.78, P = 8 × 10-6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.


Subject(s)
2',5'-Oligoadenylate Synthetase/physiology , COVID-19/etiology , Genetic Predisposition to Disease , SARS-CoV-2 , 2',5'-Oligoadenylate Synthetase/genetics , Aged , Aged, 80 and over , Animals , COVID-19/genetics , Case-Control Studies , Female , Humans , Interleukin-10 Receptor beta Subunit/genetics , Male , Mendelian Randomization Analysis , Middle Aged , Neanderthals , Protein Isoforms/physiology , Quantitative Trait Loci , Severity of Illness Index
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