C-reactive protein upregulates the whole blood expression of CD59 - an integrative analysis

Elevated C-reactive protein (CRP) concentrations in the blood are associated with acute and chronic infections and inflammation. Nevertheless, the functional role of increased CRP in multiple bacterial and viral infections as well as in chronic inflammatory diseases remains unclear. Here, we studied the relationship between CRP and gene expression levels in the blood in 491 individuals from the Estonian Biobank cohort, to elucidate the role of CRP in these inflammatory mechanisms. As a result, we identified a set of 1,614 genes associated with changes in CRP levels with a high proportion of interferon-stimulated genes. Further, we performed likelihood-based causality model selection and Mendelian randomization analysis to discover causal links between CRP and the expression of CRP-associated genes. Strikingly, our computational analysis and cell culture stimulation assays revealed increased CRP levels to drive the expression of complement regulatory protein CD59, suggesting CRP to have a critical role in protecting blood cells from the adverse effects of the immune defence system. Our results show the benefit of integrative analysis approaches in hypothesis-free uncovering of causal relationships between traits.</p

Haiguspõhjuslike geenide tuvastamine statistiliste meetoditega

Väitekirja elektrooniline versioon ei sisalda publikatsiooneHaiguste mõistmiseks ja ravimiseks on keskseks eelduseks põhjuslike, haigusprotsessides osalevate geenide väljaselgitamine – selliste geenide poolt kodeeritud valkude tööd saab ravimite abil haigustele pärssivalt ümber korraldada. Põhjuslike seoste leidmisel on peamiseks standardiks laboratoorsed katsed ja kontrollgrupiga kliinilised uuringud, kuid nende läbiviimine on kulukas ja aeganõudev. Käesolevas doktoritöös näitame, et haigusi ja teisi kompleksseid fenotüübilisi tunnuseid põhjuslikult mõjutavaid geene saab märksa efektiivsemalt tuvastada statistiliste meetoditega. Geneetikas on põhjuslik analüüs alles hiljuti hoo sisse saanud seoses rahvuslike biopankade poolt kogutud suurte andmemahtude rakendamisega. Valdkond on uudne ja suure potentsiaaliga, mistõttu on vastav matemaatiline teooria alles kujunemisjärgus ja kiiresti arenev. Pühendame doktoritöös märkimisväärset tähelepanu nii selle teooria süstemaatilisele esitusele kui ka praktilistele edasiarendustele. Põhjusliku statistilise analüüsi alusprintsiipe rakendades töötame välja metoodika põhjuslike geenide tuvastamiseks väikestest valimitest (n ≈ 500), informeerides põletikumarkeri C-reaktiivse valgu funktsiooni immuunvastuses. Domeeniteadmistele tuginedes loome põhjuslike mudelite eelduste suhtes robustse algoritmi, mis võimaldab mistahes haiguse või komplekstunnuse toimemehhanismides olulist rolli omavaid geene avastada hüpoteesivabalt üle terve genoomi. Süvitsi vaatleme ühes haigustega seotud genoomipiirkonnas (16p11.2) leiduvate geenide mõju reproduktiivtervisele, osutades just funktsionaalselt olulistele geenidele. Personaalmeditsiini arenguid silmas pidades uurime ka põhjuslike geenide sõltuvust soost. Samuti hüpotiseerime, kas populaarsed assotsiatsiooniuuringud geenide ja haiguste vahel tuvastavad põhjuslikke geene, haigustest tingitud muutusi geeniekspressioonis või pelgalt juhuslikku müra. Peamised teadustöö tulemused verifitseerime laboris katseliselt.A prerequisite in understanding and curing disease is the identification of genes active in disease processes – drugs could be developed to target the proteins encoded by such causal genes. The main standard in discovering causal relationships between traits is provided by lab experiments and randomized clinical trials but these can be time-consuming and expensive to undertake. In this dissertation, we show that functionally relevant genes in the development of diseases and other complex traits can be more effectively identified using statistical methods. Causal statistical analysis in genetics has only recently been propelled by taking advantage of the vast amount of data collected by national biobanks. Due to the novelty and projected impact of the field, the corresponding mathematical theory is still evolving and rapidly so. We direct considerable attention to systematically introduce this theory and then further expand on it in practical applications. We apply the principles of causal analysis to develop methodology for identifying causal genes in small samples (n ≈ 500), ascertaining the function of an inflammatory biomarker C-reactive protein in immune response. By utilizing domain knowledge, we create an algorithm – robust to the assumptions of causal models – for hypothesis-free identification of causal genes to arbitrary complex traits over the entire genome. Furthermore, we take an in-depth look into a specific disease-associated genomic region (16p11.2) and are able to pinpoint genes responsible for reproductive health. With respect to the personalized medicine movement, we study whether the causal genes differ between sexes. Finally, we hypothesize whether the popular association studies between gene expression and complex traits identify causal genes, disease-induced changes in gene expression or simply random noise. We validate our primary research results with lab experiments.https://www.ester.ee/record=b541721

SARS-CoV-2 and miRNA-like inhibition power

(1) Background: RNA viruses and especially coronaviruses could act inside host cells not only by building their own proteins, but also by perturbing the cell metabolism. We show the possibility of miRNA-like inhibitions by the SARS-CoV-2 concerning for example the hemoglobin and type I interferons syntheses, hence highly perturbing oxygen distribution in vital organs and immune response as described by clinicians; (2) Methods: We compare RNA subsequences of SARS-CoV-2 protein S and RNA-dependent RNA polymerase genes to mRNA sequences of beta-globin and type I interferons; (3) Results: RNA subsequences longer than eight nucleotides from SARS-CoV-2 genome could hybridize subsequences of the mRNA of beta-globin and of type I interferons; (4) Conclusions: Beyond viral protein production, Covid-19 might affect vital processes like host oxygen transport and immune response.Comment: 14 pages, 12 figure

A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease

Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology

Transcriptomic analysis of milk somatic cells in mastitis resistant and susceptible sheep upon challenge with Staphylococcus epidermidis and Staphylococcus aureus

<p>Abstract</p> <p>Background</p> <p>The existence of a genetic basis for host responses to bacterial intramammary infections has been widely documented, but the underlying mechanisms and the genes are still largely unknown. Previously, two divergent lines of sheep selected for high/low milk somatic cell scores have been shown to be respectively susceptible and resistant to intramammary infections by <it>Staphylococcus spp</it>. Transcriptional profiling with an 15K ovine-specific microarray of the milk somatic cells of susceptible and resistant sheep infected successively by <it>S. epidermidis </it>and <it>S. aureus </it>was performed in order to enhance our understanding of the molecular and cellular events associated with mastitis resistance.</p> <p>Results</p> <p>The bacteriological titre was lower in the resistant than in the susceptible animals in the 48 hours following inoculation, although milk somatic cell concentration was similar. Gene expression was analysed in milk somatic cells, mainly represented by neutrophils, collected 12 hours post-challenge. A high number of differentially expressed genes between the two challenges indicated that more T cells are recruited upon inoculation by <it>S. aureus </it>than <it>S. epidermidis</it>. A total of 52 genes were significantly differentially expressed between the resistant and susceptible animals. Further Gene Ontology analysis indicated that differentially expressed genes were associated with immune and inflammatory responses, leukocyte adhesion, cell migration, and signal transduction. Close biological relationships could be established between most genes using gene network analysis. Furthermore, gene expression suggests that the cell turn-over, as a consequence of apoptosis/granulopoiesis, may be enhanced in the resistant line when compared to the susceptible line.</p> <p>Conclusions</p> <p>Gene profiling in resistant and susceptible lines has provided good candidates for mapping the biological pathways and genes underlying genetically determined resistance and susceptibility towards <it>Staphylococcus </it>infections, and opens new fields for further investigation.</p

Transcriptomic analysis of milk somatic cells in mastitis resistant and susceptible sheep upon challenge with Staphylococcus epidermidis and Staphylococcus aureus

<p>Abstract</p> <p>Background</p> <p>The existence of a genetic basis for host responses to bacterial intramammary infections has been widely documented, but the underlying mechanisms and the genes are still largely unknown. Previously, two divergent lines of sheep selected for high/low milk somatic cell scores have been shown to be respectively susceptible and resistant to intramammary infections by <it>Staphylococcus spp</it>. Transcriptional profiling with an 15K ovine-specific microarray of the milk somatic cells of susceptible and resistant sheep infected successively by <it>S. epidermidis </it>and <it>S. aureus </it>was performed in order to enhance our understanding of the molecular and cellular events associated with mastitis resistance.</p> <p>Results</p> <p>The bacteriological titre was lower in the resistant than in the susceptible animals in the 48 hours following inoculation, although milk somatic cell concentration was similar. Gene expression was analysed in milk somatic cells, mainly represented by neutrophils, collected 12 hours post-challenge. A high number of differentially expressed genes between the two challenges indicated that more T cells are recruited upon inoculation by <it>S. aureus </it>than <it>S. epidermidis</it>. A total of 52 genes were significantly differentially expressed between the resistant and susceptible animals. Further Gene Ontology analysis indicated that differentially expressed genes were associated with immune and inflammatory responses, leukocyte adhesion, cell migration, and signal transduction. Close biological relationships could be established between most genes using gene network analysis. Furthermore, gene expression suggests that the cell turn-over, as a consequence of apoptosis/granulopoiesis, may be enhanced in the resistant line when compared to the susceptible line.</p> <p>Conclusions</p> <p>Gene profiling in resistant and susceptible lines has provided good candidates for mapping the biological pathways and genes underlying genetically determined resistance and susceptibility towards <it>Staphylococcus </it>infections, and opens new fields for further investigation.</p

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Fc γ

Rheumatoid arthritis (RA) is a highly disabling disease that affects all structures of the joint and significantly impacts on morbidity and mortality in RA patients. RA is characterized by persistent inflammation of the synovial membrane lining the joint associated with infiltration of immune cells. Eighty to 90% of the leukocytes infiltrating the synovia are neutrophils. The specific role that neutrophils play in the onset of RA is not clear, but recent studies have evidenced that they have an important participation in joint damage and disease progression through the release of proteolytic enzymes, reactive oxygen species (ROS), cytokines, and neutrophil extracellular traps, in particular during frustrated phagocytosis of immune complexes (ICs). In addition, the local and systemic activation of the complement system contributes to the pathogenesis of RA and other IC-mediated diseases. This review discusses (i) the participation of Fcγ and complement receptors in mediating the effector functions of neutrophils in RA; (ii) the contribution of the complement system and ROS-dependent and ROS-independent mechanisms to joint damage in RA; and (iii) the use of plant extracts, dietary compounds, and isolated natural compounds in the treatment of RA, focusing on modulation of the effector functions of neutrophils and the complement system activity and/or activation

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.</p

Molecular Pathways in Cancers

This book includes some recent works providing the readers with novel relevant findings about the main signaling pathways that govern the molecular pathogenesis of some of the highest prevalent human tumors, which are the basis for developing alternative therapeutic strategies to improve patient outcomes