COVID-19 genetic risk variants are associated with expression of multiple genes in diverse immune cell types.
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ABSTRACT:
SUBMITTER: Schmiedel BJ
PROVIDER: S-EPMC8604964 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Common genetic polymorphisms associated with severity of COVID-19 illness can be utilized for discovering molecular pathways and cell types driving disease pathogenesis. Here, we assessed the effects of 679 COVID-19-risk variants on gene expression in a wide-range of immune cell types. Severe COVID-19-risk variants were significantly associated with the expression of 11 protein-coding genes, and overlapped with either target gene promoter or cis -regulatory regions that interact with target promoters in the cell types where their effects are most prominent. For example, we identified that the association between variants in the 3p21.31 risk locus and the expression of CCR2 in classical monocytes is likely mediated through an active cis-regulatory region that interacted with CCR2 promoter specifically in monocytes. The expression of several other genes showed prominent genotype-dependent effects in non-classical monocytes, NK cells, B cells, or specific T cell subtypes, highlighting the potential of COVID-19 genetic risk variants to impact the function of diverse immune cell types and influence severe disease manifestations.
| S-EPMC7724655 | biostudies-literature
Project description:PurposeTo explore the etiologic role of genetic variants in telomere pathway genes and breast cancer risk.MethodsA population-based case-control study, the Long Island Breast Cancer Study Project, was conducted, and 1,067 cases and 1,110 controls were included in the present study. Fifty-two genetic variants of nine telomere-related genes were genotyped.ResultsSeven single nucleotide polymorphisms (SNP) showed significant case-control differences at the level of P < 0.05. The top three statistically significant SNPs under a dominant model were TERT-07 (rs2736109), TERT-54 (rs3816659), and POT1-03 (rs33964002). The odds ratios (OR) were 1.56 [95% confidence interval (95% CI), 1.22-1.99] for the TERT-07 G-allele, 1.27 (95% CI, 1.05-1.52) for the TERT-54 T-allele, and 0.79 (95% CI, 0.67-0.95) for the POT1-03 A-allele. TERT-67 (rs2853669) was statistically significant under a recessive model; the OR of the CC genotype was 0.69 (95% CI, 0.69-0.93) compared with the T-allele. However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P < 0.001 (0.05/52) except for TERT-07. When restricted to Caucasians (94% of the study subjects), a stronger association for the TERT-07 G-allele was observed with an OR of 1.60 (95% CI, 1.24-2.05; P = 0.0002). No effect modifications were found for variant alleles and menopausal status, telomere length, cigarette smoking, body mass index status, and family history of breast cancer risk.ConclusionsFour SNPs in the TERT and POT1 genes were significantly related with overall breast cancer risk. This initial analysis provides valuable clues for further exploration of the biological role of telomere pathway genes in breast cancer.
| S-EPMC2805470 | biostudies-literature
Project description:Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
2022-02-01 | E-MTAB-10129 | biostudies-arrayexpress
Project description:BackgroundGenome-wide association studies have identified numerous human host genetic risk variants that play a substantial role in the host immune response to SARS-CoV-2. Although these genetic risk variants significantly increase the severity of COVID-19, their influence on body systems is poorly understood. Therefore, we aim to interpret the biological mechanisms and pathways associated with the genetic risk factors and immune responses in severe COVID-19. We perform a deep analysis of previously identified risk variants and infer the hidden interactions between their molecular networks through disease mapping and the similarity of the molecular functions between constructed networks.ResultsWe designed a four-stage computational workflow for systematic genetic analysis of the risk variants. We integrated the molecular profiles of the risk factors with associated diseases, then constructed protein-protein interaction networks. We identified 24 protein-protein interaction networks with 939 interactions derived from 109 filtered risk variants in 60 risk genes and 56 proteins. The majority of molecular functions, interactions and pathways are involved in immune responses; several interactions and pathways are related to the metabolic and cardiovascular systems, which could lead to multi-organ complications and dysfunction.ConclusionsThis study highlights the importance of analyzing molecular interactions and pathways to understand the heterogeneous susceptibility of the host immune response to SARS-CoV-2. We propose new insights into pathogenicity analysis of infections by including genetic risk information as essential factors to predict future complications during and after infection. This approach may assist more precise clinical decisions and accurate treatment plans to reduce COVID-19 complications.
| S-EPMC9977643 | biostudies-literature
Project description:BackgroundAlcohol use disorder (AUD) is one of the most common forms of substance use disorders with a strong contribution of genetic (50%-60%) and environmental factors. Genome-wide association studies (GWAS) have identified a number of AUD-associated variants, including those in alcohol metabolism genes. These genetic variants may modulate gene expression, making individuals more susceptible to AUD. A long-term alcohol consumption can also change the transcriptome patterns of subjects via epigenetic modulations.MethodsTo explore the interactive effect of genetic and epigenetic factors on AUD, we conducted a secondary analysis by integrating GWAS, CNV, brain transcriptome and DNA methylation data to unravel novel AUD-associated genes/variants. We applied the mega-analysis of OR (MegaOR) method to prioritise AUD candidate genes (AUDgenes).ResultsWe identified a consensus set of 206 AUDgenes based on the multi-omics data. We demonstrated that these AUDgenes tend to interact with each other more frequent than chance expectation. Functional annotation analysis indicated that these AUDgenes were involved in substance dependence, synaptic transmission, glial cell proliferation and enriched in neuronal and liver cells. We obtained a multidimensional evidence that AUD is a polygenic disorder influenced by both genetic and epigenetic factors as well as the interaction of them.ConclusionWe characterised multidimensional evidence of genetic, epigenetic and transcriptomic data in AUD. We found that 206 AUD associated genes were highly expressed in liver, brain cerebellum, frontal cortex, hippocampus and pituitary. Our studies provides important insights into the molecular mechanism of AUD and potential target genes for AUD treatment.
| S-EPMC7487038 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-05-10 | GSE174658 | GEO
Project description:Recent genome-wide association studies (GWASs) of COVID-19 patients of European ancestry have identified genetic loci significantly associated with disease severity. Here, we employed the detailed clinical, immunological and multi-omics dataset of the Human Functional Genomics Project (HFGP) to explore the physiological significance of the host genetic variants that influence susceptibility to severe COVID-19. A genomics investigation intersected with functional characterization of individuals with high genetic risk for severe COVID-19 susceptibility identified several major patterns: i. a large impact of genetically determined innate immune responses in COVID-19, with ii. increased susceptibility for severe disease in individuals with defective cytokine production; iii. genetic susceptibility related to ABO blood groups is probably mediated through the von Willebrand factor (VWF) and endothelial dysfunction. We further validated these identified associations at transcript and protein levels by using independent disease cohorts. These insights allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy.
| S-EPMC9133558 | biostudies-literature
Project description:Ca(2+)/nuclear factor of activated T-cells (Ca(2+)/NFAT) signaling pathway may play a crucial role in Kawasaki disease (KD). We investigated 16 genetic variants, selected by bioinformatics analyses or previous studies, in 7 key genes involved in this pathway in a Chinese population. We observed a significantly or marginally increased KD risk associated with rs2720378 GC + CC genotypes (OR = 1.39, 95% CI = 1.07-1.80, P = 0.014) or rs2069762 AC + CC genotypes (OR = 1.28, 95% CI = 0.98-1.67, P = 0.066), compared with their wild type counterparts. In classification and regression tree analysis, individuals carrying the combined genotypes of rs2720378 GC or CC genotype, rs2069762 CA or CC genotype and rs1561876 AA genotype exhibited the highest KD risk (OR = 2.12, 95% CI = 1.46-3.07, P < 0.001), compared with the lowest risk carriers of rs2720378 GG genotype. Moreover, a significant dose effect was observed among these three variants (Ptrend < 0.001). In conclusion, this study implicates that single- and multiple-risk genetic variants in this pathway might contribute to KD susceptibility. Further studies on more comprehensive single nucleotide polymorphisms, different ethnicities and larger sample sizes are warranted, and the exact biological mechanisms need to be further clarified.
| S-EPMC4047536 | biostudies-literature
Project description:Monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 stimulate inflammation response by activating and recruiting monocytes/macrophages. MCP-1 and CCR2 polymorphisms were reported to be associated with various diseases. To explore the relationship between MCP-1 and CCR2 polymorphisms and IgA nephropathy (IgAN), we conducted this case-control study by enrolling 351 IgAN patients and 310 health controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate potential associations of MCP-1 and CCR2 polymorphisms with susceptibility and clinical parameters of IgAN. No statistical differences between IgAN group and the control group in the MCP-1 -2518 and CCR2 +190 genotypic groups were observed (P > 0.05). Individuals with MCP-1 -2518 GG genotypes had a higher blood pressure (GG vs. AA+AG: OR = 1.79, 95% CI = 1.07-2.99, P = 0.026) and Lee's grade (GG vs. AA+AG: OR = 2.05, 95% CI = 1.19-3.54, P = 0.009; GG vs. AA: OR = 2.24, 95% CI = 1.19-4.20, P = 0.01), compared with patients with AA/AG genotypes. A significant association between CCR2 +190 polymorphism and Lee's grades was observed (GA+AA vs. GG: OR = 2.66, 95% CI = 1.63-4.35, P < 0.001; GA vs. AA+GG: OR = 2.27, 95% CI = 1.39-3.70, P = 0.001). Our results indicated that MCP-1 and CCR2 polymorphisms may influence the progression of IgAN, but not increase/decrease its susceptibility.
| S-EPMC5363634 | biostudies-other
Project description:Human genetic variants can influence the severity of symptoms infected with SARS-COV-2. Several genome-wide association studies have identified human genomic risk single nucleotide polymorphisms (SNPs) associated with coronavirus disease 2019 (COVID-19) severity. However, the causal tissues or cell types underlying COVID-19 severity are uncertain. In addition, candidate genes associated with these risk SNPs were investigated based on genomic proximity instead of their functional cellular contexts. Here, we compiled regulatory networks of 77 human contexts and revealed those risk SNPs' enriched cellular contexts and associated risk SNPs with transcription factors, regulatory elements, and target genes. Twenty-one human contexts were identified and grouped into two categories: immune cells and epithelium cells. We further aggregated the regulatory networks of immune cells and epithelium cells. These two aggregated regulatory networks were investigated to reveal their association with risk SNPs' regulation. Two genomic clusters, the chemokine receptors cluster and the oligoadenylate synthetase (OAS) cluster, showed the strongest association with COVID-19 severity, and they had different regulatory programs in immune and epithelium contexts. Our findings were supported by analysis of both SNP array and whole genome sequencing-based genome wide association study (GWAS) summary statistics.Supplementary informationThe online version contains supplementary material available at 10.1007/s43657-022-00066-x.
| S-EPMC9375061 | biostudies-literature