Pneumonia: host susceptibility and shared genetics with pulmonary function and other traits

Khadzhieva, Maryam B.; Kuzovlev, Аrtem; Salnikova, Lyubov E.

doi:10.1111/cei.13367

Cited by 6 publications

(3 citation statements)

References 65 publications

(85 reference statements)

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“…In this regard, HLA-C genetic variants are known to be associated with COVID-19 clinical outcome [37] , [38] , [39] , [40] . Importantly for the natural history of COVID-19 infection, GWAS have also shown that HLA-C constitutes a susceptibility locus for human pneumonia [ 65 , 66 ]. Similar links between the other candidate epigenetic targets identified here and immune imbalance associated with lung inflammation can be found, such as the case of IFI44L, which is overexpressed in the bronchoalveolar lavage of severe COVID-19 patients [67] and SARS-CoV-2-infected bronchial epithelial cells [68] .…”

Section: Discussionmentioning

confidence: 99%

Epigenome-wide association study of COVID-19 severity with respiratory failure

et al. 2021

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Background Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities. Methods Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery ( n = 207) and validation ( n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients. Findings The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease. Interpretation We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2. Funding The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.

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Section: Discussionmentioning

confidence: 99%

Epigenome-wide association study of COVID-19 severity with respiratory failure

et al. 2021

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“…high for the inhibiting KIR (KIR2DL1) than the activating KIR [functional KIR2DS4 ( 52 )], may cause NK cell hyporesponsiveness since the early phase of infection ( 49 ). As NK cells are at the forefront of antiviral response, particularly at that of the respiratory system ( 53 ), NK hyporesponsiveness may delay SARS‐CoV‐2 viral recognition and, subsequently, generate an inadequate immune response, supporting the virus propagation and lung damage, such as seen in severe pneumonia with a genetically predicted HLA-C low expression ( 54 ). A series of genetic studies with a Sardinian/Italian sample potentially support this hypothesis, by reporting a significantly high prevalence of both, HLA-C*04:01 allele and NK-cell inhibitor KIR2DL1 receptor, in COVID-19 cases ( 34 , 55 ).…”

Section: Discussionmentioning

confidence: 99%

HLA-C*04:01 Affects HLA Class I Heterozygosity and Predicted Affinity to SARS-CoV-2 Peptides, and in Combination With Age and Sex of Armenian Patients Contributes to COVID-19 Severity

Հովհաննիսյան

Madelian²,

Avagyan³

et al. 2022

Front. Immunol.

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The novel SARS-CoV-2 coronavirus infection has become a global health concern, causing the COVID-19 pandemic. The disease symptoms and outcomes depend on the host immunity, in which the human leukocyte antigen (HLA) molecules play a distinct role. The HLA alleles have an inter-population variability, and understanding their link to the COVID-19 in an ethnically distinct population may contribute to personalized medicine. The present study aimed at detecting associations between common HLA alleles and COVID-19 susceptibility and severity in Armenians. In 299 COVID-19 patients (75 asymptomatic, 102 mild/moderate, 122 severe), the association between disease severity and classic HLA-I and II loci was examined. We found that the advanced age, male sex of patients, and sex and age interaction significantly contributed to the severity of the disease. We observed that an age-dependent effect of HLA-B*51:01 carriage [odds ratio (OR)=0.48 (0.28-0.80), Pbonf <0.036] is protective against severe COVID-19. Contrary, the HLA-C*04:01 allele, in a dose-dependent manner, was associated with a significant increase in the disease severity [OR (95% CI) =1.73 (1.20-2.49), Pbonf <0.021] and an advancing age (P<0.013). The link between HLA-C*04:01 and age was secondary to a stronger association between HLA-C*04:01 and disease severity. However, HLA-C*04:01 exerted a sex-dependent differential distribution between clinical subgroups [females: P<0.0012; males: P=0.48]. The comparison of HLA-C*04:01 frequency between subgroups and 2,781 Armenian controls revealed a significant incidence of HLA-C*04:01 deficiency in asymptomatic COVID-19. HLA-C*04:01 homozygous genotype in patients blueprinted a decrease in heterozygosity of HLA-B and HLA class-I loci. In HLA-C*04:01 carriers, these changes translated to the SARS-CoV-2 peptide presentation predicted inefficacy by HLA-C and HLA class-I molecules, simultaneously enhancing the appropriate HLA-B potency. In patients with clinical manifestation, due to the high prevalence of HLA-C*04:01, these effects provided a decrease of the HLA class-I heterozygosity and an ability to recognize SARS-CoV-2 peptides. Based on our observations, we developed a prediction model involving demographic variables and HLA-C*04:01 allele for the identification of potential cases with the risk of hospitalization (the area under the curve (AUC) = 86.2%) or severe COVID-19 (AUC =71%).

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“…c4a is known as an allergenic toxin gene that produces an antimicrobial peptide and a mediator of local inflammation. Previous studies suggested that C4bp and C4a were associated with lung inflammation and injury (56,57).…”

Section: Discussionmentioning

confidence: 92%

Proteomics analysis of lung tissue reveals protein makers for the lung injury of adjuvant arthritis rats

Zhang

Liu

et al. 2023

Mol Med Rep

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Lung injury is one of the common extra-articular lesions in rheumatoid arthritis (RA). Due to its insidious onset and no obvious clinical symptoms, it can be easily dismissed in the early stage of diagnosis, which is one of the reasons that leads to a decline of the quality of life and subsequent death of patients with RA. However, its pathogenesis is still unclear and there is a lack of effective therapeutic targets. In the present study, tandem mass tag-labeled proteomics was used to research the lung tissue proteins in RA model (adjuvant arthritis, AA) rats that had secondary lung injury. The aim of the present study was to identify the differentially expressed proteins related to RA-lung injury, determine their potential role in the pathogenesis of RA-lung injury and provide potential targets for clinical treatment. Lung tissue samples were collected from AA-lung injury and normal rats. The differentially expressed proteins (DEPs) were identified by tandem mass spectrometry. Bioinformatic analysis was used to assess the biological processes and signaling pathways associated with these DEPs. A total of 310 DEPs were found, of which 244 were upregulated and 66 were downregulated. KEGG anlysis showed that ‘fatty acid degradation’, ‘fatty acid metabolism’, ‘fatty acid elongation’, ‘complement and coagulation cascades’, ‘peroxisome proliferator-activated receptor signaling pathway’ and ‘hypoxia-inducible factor signaling pathway’ were significantly upregulated in the lung tissues of AA-lung injury. Immunofluorescence staining confirmed the increased expression of clusterin, serine protease inhibitors and complement 1qc in lung tissue of rats with AA lung injury. In the present study, the results revealed the significance of certain DEPs (for example, C9, C1qc and Clu) in the occurrence and development of RA-lung injury and provided support through experiments to identify potential biomarkers for the early diagnosis and prevention of RA-lung injury.

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Pneumonia: host susceptibility and shared genetics with pulmonary function and other traits

Cited by 6 publications

References 65 publications

Epigenome-wide association study of COVID-19 severity with respiratory failure

Epigenome-wide association study of COVID-19 severity with respiratory failure

HLA-C*04:01 Affects HLA Class I Heterozygosity and Predicted Affinity to SARS-CoV-2 Peptides, and in Combination With Age and Sex of Armenian Patients Contributes to COVID-19 Severity

Proteomics analysis of lung tissue reveals protein makers for the lung injury of adjuvant arthritis rats

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