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Journal of Global Health Dec 2023In the aftermath of the coronavirus disease 2019 (COVID-19) pandemic, we sought to explore the causal association between COVID-19 and 17 prevalent post-COVID-19...
BACKGROUND
In the aftermath of the coronavirus disease 2019 (COVID-19) pandemic, we sought to explore the causal association between COVID-19 and 17 prevalent post-COVID-19 syndrome (PCS) symptoms using Mendelian randomisation (MR) methodology.
METHODS
We used 22 extensive genome-wide association study (GWAS) data sets, incorporating genetic variants as instrumental variables. Univariate Mendelian randomisation (UVMR) analyses involved 15 single nucleotide polymorphisms (SNPs) for COVID-19 patients, 33 for hospitalised COVID-19 patients, and 29 for patients with severe respiratory symptoms due to COVID-19. Furthermore, we further used multivariable Mendelian randomisation (MVMR) analyses based on 93 SNPs for COVID-19 patients, 105 for hospitalised COVID-19 patients, and 99 for patients with severe respiratory symptoms due to COVID-19. With these analyses, we aimed to assess the causal associations between varying levels of COVID-19 infection and 17 prevalent PCS symptoms while accounting for the influence of educational and income levels.
RESULTS
UVMR analysis identified potential causal effects of COVID-19 genetic susceptibility on myalgia and pain in various regions. Hospitalised COVID-19 was potentially linked to erectile dysfunction and alopecia areata. Very severe respiratory confirmed patients exhibited increased pain and tobacco use. Meanwhile, the MVMR analysis demonstrated a potential causal link between hospitalised COVID-19 and heart arrhythmia, and a protective effect of COVID-19 on tobacco use after adjusting for educational and income levels.
CONCLUSIONS
Our MR analysis provides compelling evidence of causal associations between genetic susceptibility to COVID-19 and specific PCS symptoms, in which educational and income levels play a mediating role. These findings shed light on PCS pathogenesis and underscore the importance of considering social factors in its management. Tailored interventions and policies are crucial for PCS-affected individuals' well-being. Further research is needed to explore the impact of social determinants on COVID-19 patients and the wider population.
Topics: Humans; Male; COVID-19; Genetic Predisposition to Disease; Genome-Wide Association Study; Pain; Post-Acute COVID-19 Syndrome; Mendelian Randomization Analysis
PubMed: 38085233
DOI: 10.7189/jogh.13.06054 -
Cells Jan 2024Driver mutations are considered the cornerstone of cancer initiation. They are defined as mutations that convey a competitive fitness advantage, and hence, their... (Review)
Review
Driver mutations are considered the cornerstone of cancer initiation. They are defined as mutations that convey a competitive fitness advantage, and hence, their mutation frequency in premalignant tissue is expected to exceed the basal mutation rate. In old terms, that translates to "the survival of the fittest" and implies that a selective process underlies the frequency of cancer driver mutations. In that sense, each tissue is its own niche that creates a molecular selective pressure that may favor the propagation of a mutation or not. At the heart of this stands one of the biggest riddles in cancer biology: the tissue-predisposition to cancer driver mutations. The frequency of cancer driver mutations among tissues is non-uniform: for instance, mutations in are particularly frequent in colorectal cancer, and 99% of chronic myeloid leukemia patients harbor the driver fusion mutation, which is rarely found in solid tumors. Here, we provide a mechanistic framework that aims to explain how tissue-specific features, ranging from epigenetic underpinnings to the expression of viral transposable elements, establish a molecular basis for selecting cancer driver mutations in a tissue-specific manner.
Topics: Humans; Precancerous Conditions; Disease Susceptibility; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mutation; Mutation Rate
PubMed: 38247798
DOI: 10.3390/cells13020106 -
Virus Research Aug 2024Coronaviruses have caused three severe epidemics since the start of the 21 century: SARS, MERS and COVID-19. The severity of the ongoing COVID-19 pandemic and increasing...
Coronaviruses have caused three severe epidemics since the start of the 21 century: SARS, MERS and COVID-19. The severity of the ongoing COVID-19 pandemic and increasing likelihood of future coronavirus outbreaks motivates greater understanding of factors leading to severe coronavirus disease. We screened ten strains from the Collaborative Cross mouse genetic reference panel and identified strains CC006/TauUnc (CC006) and CC044/Unc (CC044) as coronavirus-susceptible and resistant, respectively, as indicated by variable weight loss and lung congestion scores four days post-infection. We generated a genetic mapping population of 755 CC006xCC044 F2 mice and exposed the mice to one of three genetically distinct mouse-adapted coronaviruses: clade 1a SARS-CoV MA15 (n=391), clade 1b SARS-CoV-2 MA10 (n=274), and clade 2 HKU3-CoV MA (n=90). Quantitative trait loci (QTL) mapping in SARS-CoV MA15- and SARS-CoV-2 MA10-infected F2 mice identified genetic loci associated with disease severity. Specifically, we identified seven loci associated with variation in outcome following infection with either virus, including one, HrS43, that is present in both groups. Three of these QTL, including HrS43, were also associated with HKU3-CoV MA outcome. HrS43 overlaps with a QTL previously reported by our lab that is associated with SARS-CoV MA15 outcome in CC011xCC074 F2 mice and is also syntenic with a human chromosomal region associated with severe COVID-19 outcomes in humans GWAS. The results reported here provide: (a) additional support for the involvement of this locus in SARS-CoV MA15 infection, (b) the first conclusive evidence that this locus is associated with susceptibility across the Sarbecovirus subgenus, and (c) demonstration of the relevance of mouse models in the study of coronavirus disease susceptibility in humans.
Topics: Animals; Mice; Quantitative Trait Loci; Disease Models, Animal; SARS-CoV-2; COVID-19; Disease Susceptibility; Humans; Severe acute respiratory syndrome-related coronavirus; Chromosome Mapping; Coronavirus Infections; Female; Collaborative Cross Mice; Genetic Predisposition to Disease; Male
PubMed: 38823688
DOI: 10.1016/j.virusres.2024.199399 -
International Journal of Molecular... Mar 2024Rheumatoid arthritis (RA) is a chronic, autoimmune disease with a complex outset. Besides the genetic susceptibility in its pathogenesis, various environmental factors... (Review)
Review
Rheumatoid arthritis (RA) is a chronic, autoimmune disease with a complex outset. Besides the genetic susceptibility in its pathogenesis, various environmental factors also participate. Of these, in recent years, there have been increasing reports of the involvement of bacteria in the disease's outset and development, especially gut microbiota and oral pathogens. Most recent reports about bacteria participation in RA pathogenesis focus on and . There are also reports about the involvement of respiratory and urinary tract pathogens. The exact mechanisms leading to RA development used by bacteria are not well known; however, some mechanisms by which bacteria can interact with the immune system are known and can potentially lead to RA development. The aim of this study is to provide a comprehensive review of the potential bacteria participating in RA development and the mechanism involved in that process.
Topics: Humans; Arthritis, Rheumatoid; Porphyromonas gingivalis; Gastrointestinal Microbiome; Communicable Diseases; Genetic Predisposition to Disease
PubMed: 38542357
DOI: 10.3390/ijms25063386 -
Molecular Plant-microbe Interactions :... Sep 2023Two genes ( and ) conferring susceptibility to Fusarium head blight and tan spot, Septoria nodorum blotch, and spot blotch in wheat were targeted through wide...
Two genes ( and ) conferring susceptibility to Fusarium head blight and tan spot, Septoria nodorum blotch, and spot blotch in wheat were targeted through wide hybridization with maize expressing Cas9 and guide RNA (gRNA). For each gene, two target sites were selected and corresponding gRNA expression cassettes were synthesized and cloned into a binary vector carrying the CRISPR/Cas9-mediated genome editing machinery. The constructed binary vectors were used to transform the hybrid maize Hi-II through an -mediated approach to generate T0 and T1 plants, which were used to cross with wheat variety Dayn for targeting or the susceptible allele () of as well as with the near-isogenic line (Day-) of Dayn for targeting the resistant allele () of . Haploid embryos were rescued in vitro from the wide crosses to generate haploid plants. PCR amplification and sequencing indicated that 15 to 33% of the haploid plants contained the target gene with mutations at the target sites. This wheat × maize hybridization combined with genome editing approach provides a useful alternative tool, not only for targeting susceptibility genes to improve disease resistance without regulatory issues, but also for understanding gene function in wheat. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.
Topics: CRISPR-Cas Systems; Triticum; Zea mays; Disease Susceptibility; RNA
PubMed: 37014117
DOI: 10.1094/MPMI-01-23-0004-SC -
Ecotoxicology and Environmental Safety Oct 2023This study aimed to investigate the relationship of residential green and blue spaces with incident nonalcoholic fatty liver disease (NAFLD), and explore the potential...
BACKGROUND
This study aimed to investigate the relationship of residential green and blue spaces with incident nonalcoholic fatty liver disease (NAFLD), and explore the potential mediation effects of air pollutants and modification effect of genetic susceptibility.
METHODS
411,200 UK Biobank participants without prior liver diseases were included. Land use data were used to estimate residential green and blue spaces (land coverage percentage) at 300 m and 1000 m buffer. The study outcome was incident NAFLD, ascertained through linkage to hospital admissions and death registry records.
RESULTS
5198 NAFLD cases were documented after a median follow-up of 12.5 years. Green and blue spaces were inversely associated with the hazard of NAFLD: per standard deviation (SD) increment of green space coverage at 300 m (SD: 14.5 %; HR, 0.88, 95 %CI, 0.86-0.91) and 1000 m (SD: 14.1 %; HR, 0.88, 95 %CI, 0.86-0.91) buffer, and blue space coverage at 300 m (SD: 1.0 %; HR,0.95, 95 %CI, 0.93-0.98) and 1000 m (SD: 1.2 %; HR,0.96, 95 %CI, 0.93-0.99) buffer were related with a 4-12 % reduction of NAFLD incidence. The beneficial effects of approximately 25-52 % of green space exposure and about 5-35 % of blue space exposure on NAFLD incidence were mediated by the reduction of PM, NO and NO (All P <0.05). Moreover, genetic susceptibility of NAFLD did not modify the relationship of green and blue spaces with NAFLD incidence.
CONCLUSION
Residential green and blue spaces were inversely related to NAFLD incidence. These results suggest that green and blue spaces are modifiable factors that may help prevent NAFLD, and therefore, can be considered as a novel environmental strategy to promote liver health at the community level, rather than only at the individual level.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Air Pollutants; Genetic Predisposition to Disease; Hospitalization
PubMed: 37672940
DOI: 10.1016/j.ecoenv.2023.115436 -
Human Genomics Feb 2024Many researchers have explored the potential association between one neurosurgical disease and coronavirus disease 2019 (COVID-19), but few systematically analyzed the...
Many researchers have explored the potential association between one neurosurgical disease and coronavirus disease 2019 (COVID-19), but few systematically analyzed the association and causality between COVID-19 and various neurosurgical diseases. A Mendelian randomization analysis was conducted to evaluate the causal association between COVID-19 (including critically ill COVID-19, hospitalized COVID-19, and respiratory syndrome coronavirus 2 (SARS-CoV-2) infection) and 30 neurosurgical diseases within European populations. The consequences of inverse variance weighted models suggest that genetic susceptibility of critically ill COVID-19 may increase the risk of cerebral infarction (odds ratio [OR] = 1.02; p-value = 0.006), genetic susceptibility of SARS-CoV-2 infection may increase the risk of stroke (OR = 1.02; p-value = 0.047), and conversely, genetic susceptibility of hospitalized COVID-19 may reduce the risk of pituitary adenoma and craniopharyngioma (OR = 0.90; p-value = 0.032). In addition, evidences revealed potential associations between genetic susceptibility of COVID-19 and spinal stenosis (OR = 1.03; p-value = 0.028), diffuse brain injury (OR = 1.21; p-value = 0.040) and focal brain injury (OR = 1.12; p-value = 0.040). By testing for heterogeneity and pleiotropy, the above causal conclusions are robust. In summary, our analysis shows that COVID-19 has an independent and powerful causal influence on multiple neurosurgical disorders.
Topics: Humans; COVID-19; SARS-CoV-2; Critical Illness; Mendelian Randomization Analysis; Genetic Predisposition to Disease; Genome-Wide Association Study
PubMed: 38311757
DOI: 10.1186/s40246-024-00575-y -
Journal of Medicine and Life Feb 2024Numerous studies have established a link between gene variants within the inflammasome complex and the incidence of periodontitis and cardiovascular illness across...
Numerous studies have established a link between gene variants within the inflammasome complex and the incidence of periodontitis and cardiovascular illness across various ethnic groups. This study investigated the association between gene polymorphism and susceptibility to periodontal disease and coronary heart disease (CHD) and their correlation with clinical periodontal indices. A total of 120 participants were enrolled, categorized into four groups: 30 healthy controls (C), 30 patients with generalized periodontitis (P), 30 patients with atherosclerotic CHD but clinically healthy periodontium (AS-C), and 30 patients with both atherosclerotic CHD and generalized periodontitis (AS-P). We recorded demographic data, collected blood samples, and measured periodontal indices, including plaque index, clinical attachment loss, bleeding on probing, and pocket depth. The genomic variant of the gene was analyzed using a conventional polymerase reaction. A significant prevalence of T and G allele mutations and a higher distribution of CT and TT genotypes in C/T (rs8056505) and the AG genotype in A/G (rs372507365) were observed in groups P, AS-P, and AS-C. These single nucleotide polymorphisms (SNPs) were also positively correlated with the severity of clinical periodontitis indices. Our findings suggest that the increased frequency of T and G alleles and the distribution of CT, TT, and AG genotypes in SNPs are significantly associated with an elevated risk for periodontal disease and CHD. These SNPs may participate in the pathogenesis of these conditions. The study reinforces the potential role of these genetic markers as risk factors for both diseases in the Iraqi population.
Topics: Adult; Female; Humans; Male; Middle Aged; Alleles; CARD Signaling Adaptor Proteins; Case-Control Studies; Coronary Disease; Genetic Predisposition to Disease; Genotype; Periodontal Diseases; Periodontitis; Polymorphism, Single Nucleotide
PubMed: 38813354
DOI: 10.25122/jml-2023-0263 -
Molecular Aspects of Medicine Oct 2023Glaucoma, the leading cause of irreversible blindness worldwide, is a complex human disease, with both genetic and environmental determinants. The availability of... (Review)
Review
Glaucoma, the leading cause of irreversible blindness worldwide, is a complex human disease, with both genetic and environmental determinants. The availability of large-scale, population-based cohorts and biobanks, combining genotyping and detailed phenotyping, has greatly accelerated research into the aetiology of glaucoma in recent years. Hypothesis-free genome-wide association studies have furthered our understanding of the complex genetic architecture underpinning the disease, while epidemiological studies have provided advances in the identification and characterisation of environmental risk factors. It is increasingly recognised that the combined effects of genetic and environmental factors may confer a disease risk that reflects a departure from the simple additive effect of the two. These gene-environment interactions have been implicated in a host of complex human diseases, including glaucoma, and have several important diagnostic and therapeutic implications for future clinical practice. Importantly, the ability to modify the risk associated with a particular genetic makeup promises to lead to personalised recommendations for glaucoma prevention, as well as novel treatment approaches in years to come. Here we provide an overview of genetic and environmental risk factors for glaucoma, as well as reviewing the evidence and discussing the implications of gene-environment interactions for the disease.
Topics: Humans; Genetic Predisposition to Disease; Genome-Wide Association Study; Glaucoma; Gene-Environment Interaction; Risk Factors
PubMed: 37423164
DOI: 10.1016/j.mam.2023.101203 -
Nature Communications Nov 2023Kidney stone disease (KSD) is a complex disorder with high heritability and prevalence. We performed a large genome-wide association study (GWAS) meta-analysis for KSD... (Meta-Analysis)
Meta-Analysis
Kidney stone disease (KSD) is a complex disorder with high heritability and prevalence. We performed a large genome-wide association study (GWAS) meta-analysis for KSD to date, including 720,199 individuals with 17,969 cases in European population. We identified 44 susceptibility loci, including 28 novel loci. Cell type-specific analysis pinpointed the proximal tubule as the most relevant cells where susceptibility variants might act through a tissue-specific fashion. By integrating kidney-specific omics data, we prioritized 223 genes which strengthened the importance of ion homeostasis, including calcium and magnesium in stone formation, and suggested potential target drugs for the treatment. The genitourinary and digestive diseases showed stronger genetic correlations with KSD. In this study, we generate an atlas of candidate genes, tissue and cell types involved in the formation of KSD. In addition, we provide potential drug targets for KSD treatment and insights into shared regulation with other diseases.
Topics: Humans; Genome-Wide Association Study; Genetic Predisposition to Disease; Kidney Calculi; Genetic Loci; Polymorphism, Single Nucleotide
PubMed: 37980427
DOI: 10.1038/s41467-023-43400-1