scholarly journals Molecular Mechanisms of Proteinuria in Minimal Change Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Shrey Purohit ◽  
Federica Piani ◽  
Flor A. Ordoñez ◽  
Carmen de Lucas-Collantes ◽  
Colin Bauer ◽  
...  
Keyword(s):  
T Cells ◽  
Minimal Change Disease ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Experimental Studies ◽  
Kidney Tissue ◽  
Disease Process ◽  
Minimal Change ◽  
Ultrastructural Changes ◽  
Genome Wide Association Studies

Minimal change disease (MCD) is the most common type of idiopathic nephrotic syndrome in childhood and represents about 15% cases in adults. It is characterized by massive proteinuria, edema, hypoalbuminemia, and podocyte foot process effacement on electron microscopy. Clinical and experimental studies have shown an association between MCD and immune dysregulation. Given the lack of inflammatory changes or immunocomplex deposits in the kidney tissue, MCD has been traditionally thought to be mediated by an unknown circulating factor(s), probably released by T cells that directly target podocytes leading to podocyte ultrastructural changes and proteinuria. Not surprisingly, research efforts have focused on the role of T cells and podocytes in the disease process. Nevertheless, the pathogenesis of the disease remains a mystery. More recently, B cells have been postulated as an important player in the disease either by activating T cells or by releasing circulating autoantibodies against podocyte targets. There are also few reports of endothelial injury in MCD, but whether glomerular endothelial cells play a role in the disease remains unexplored. Genome-wide association studies are providing insights into the genetic susceptibility to develop the disease and found a link between MCD and certain human haplotype antigen variants. Altogether, these findings emphasize the complex interplay between the immune system, glomerular cells, and the genome, raising the possibility of distinct underlying triggers and/or mechanisms of proteinuria among patients with MCD. The heterogeneity of the disease and the lack of good animal models of MCD remain major obstacles in the understanding of MCD. In this study, we will review the most relevant candidate mediators and mechanisms of proteinuria involved in MCD and the current models of MCD-like injury.

scholarly journals Uncovering the complex genetics of human temperament

2018 ◽  
Vol 25 (10) ◽  
pp. 2275-2294 ◽  
Author(s):  
Igor Zwir ◽  
Javier Arnedo ◽  
Coral Del-Val ◽  
Laura Pulkki-Råback ◽  
Bettina Konte ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Association Studies ◽  
Experimental Studies ◽  
Long Term Memory ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Complex Genetics ◽  
Associative Conditioning ◽  
Discovery Sample ◽  
Character Inventory

Abstract Experimental studies of learning suggest that human temperament may depend on the molecular mechanisms for associative conditioning, which are highly conserved in animals. The main genetic pathways for associative conditioning are known in experimental animals, but have not been identified in prior genome-wide association studies (GWAS) of human temperament. We used a data-driven machine learning method for GWAS to uncover the complex genotypic–phenotypic networks and environmental interactions related to human temperament. In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified 3 clusters of people with distinct temperament profiles measured by the Temperament and Character Inventory regardless of genotype. Third, we found 51 SNP sets that identified 736 gene loci and were significantly associated with temperament. The identified genes were enriched in pathways activated by associative conditioning in animals, including the ERK, PI3K, and PKC pathways. 74% of the identified genes were unique to a specific temperament profile. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of the 51 Finnish SNP sets in healthy Korean (90%) and German samples (89%), as well as their associations with temperament. The identified SNPs explained nearly all the heritability expected in each sample (37–53%) despite variable cultures and environments. We conclude that human temperament is strongly influenced by more than 700 genes that modulate associative conditioning by molecular processes for synaptic plasticity and long-term memory.

scholarly journals The Transcription Factor MAFF Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism

Circulation ◽  
2021 ◽  
Author(s):  
Moritz von Scheidt ◽  
Yuqi Zhao ◽  
Thomas Q. de Aguiar Vallim ◽  
Nam Che ◽  
Michael Wierer ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Prediction Models ◽  
Cholesterol Metabolism ◽  
Association Studies ◽  
Experimental Studies ◽  
Genome Wide Association Studies ◽  
Inflammatory Conditions

Background: Coronary artery disease (CAD) is a multifactorial condition with both genetic and exogenous causes. The contribution of tissue specific functional networks to the development of atherosclerosis remains largely unclear. The aim of this study was to identify and characterise central regulators and networks leading to atherosclerosis. Methods: Based on several hundred genes known to affect atherosclerosis risk in mouse (as demonstrated in knock-out models) and human (as shown by genome-wide association studies (GWAS)) liver gene regulatory networks were modeled. The hierarchical order and regulatory directions of genes within the network were based on Bayesian prediction models as well as experimental studies including chromatin immunoprecipitation DNA-Sequencing (ChIP-Seq), ChIP mass spectrometry (ChIP-MS), overexpression, siRNA knockdown in mouse and human liver cells, and knockout mouse experiments. Bioinformatics and correlation analyses were used to clarify associations between central genes and CAD phenotypes in both human and mouse. Results: The transcription factor MAFF interacted as a key driver of a liver network with three human genes at CAD GWAS loci and eleven atherosclerotic murine genes. Most importantly, expression levels of the low-density lipoprotein receptor ( LDLR ) gene correlated with MAFF in 600 CAD patients undergoing bypass surgery (STARNET) and a hybrid mouse diversity panel involving 105 different inbred mouse strains. Molecular mechanisms of MAFF were tested under non-inflammatory conditions showing a positive correlation between MAFF and LDLR in vitro and in vivo . Interestingly, after LPS stimulation (inflammatory conditions) an inverse correlation between MAFF and LDLR in vitro and in vivo was observed. ChIP-MS revealed that the human CAD GWAS candidate BACH1 assists MAFF in the presence of LPS stimulation with respective heterodimers binding at the MAF recognition element (MARE) of the LDLR promoter to transcriptionally downregulate LDLR expression. Conclusions: The transcription factor MAFF was identified as a novel central regulator of an atherosclerosis/CAD relevant liver network. MAFF triggered context specific expression of LDLR and other genes known to affect CAD risk. Our results suggest that MAFF is a missing link between inflammation, lipid and lipoprotein metabolism and a possible treatment target.

Abstract MP150: Inositol 1,4,5-trisphosphate Receptors Selectively Regulate Detrimental Cardiac Fibrosis by Modulating ER-phagy

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Gaetano Santulli ◽  
Marco Morelli ◽  
Xujun Wang ◽  
John Ferrante ◽  
Jessica Gambardella
Keyword(s):  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Ex Vivo ◽  
Myocardial Dysfunction ◽  
Association Studies ◽  
Experimental Studies ◽  
Genome Wide Association Studies ◽  
Inositol 1,4,5 Trisphosphate

Background: Therapeutic strategies that specifically target excessive post-ischemic cardiac fibrosis are lacking but desperately needed; thus, it is critical to understand the molecular mechanisms underlying these processes. Genome-wide association studies have revealed an association between inositol 1,4,5-trisphosphate receptors (IP3Rs) and ischemic heart disease. However, experimental studies examining the exact role of IP3Rs in post-ischemic cardiac fibrosis are missing. Aim: We hypothesize that IP3Rs play a key role in the regulation of cardiac myofibroblasts (myoFBs) in healing the infarcted heart after myocardial infarction (MI). Methods: We performed an integrated set of in vivo, ex vivo , and in vitro experiments aiming at identifying the functional role of cardiac myoFB IP3Rs in post-ischemic cardiac remodeling. We generated cardiac myo-FB-specific Triple IP3R knock-out (IP3R TKO ) mice ( Cre/lox recombination technique; Promoter: Periostin ), allowing us to overcome the difficulties encountered following the KO or KD of a single (of the three existent) IP3Rs, a strategy that has been shown to induce compensatory upregulation of the other isoforms. Results: After MI, IP3Rs are significantly upregulated in myoFBs of the remote regions but not in the scar area. IP3R TKO mice display a significantly reduced interstitial cardiac fibrosis and a markedly attenuated myocardial dysfunction following MI compared with control IP3R flox or Periostin Cre littermates. Moreover, FBs lacking IP3Rs exhibit significantly reduced migratory and secretory capacities, a finding confirmed both in murine and human FBs. Mechanistically, we show that IP3Rs modulate endoplasmic reticulum autophagy (ER-phagy) in primary isolated myoFBs following ischemic injury. Conclusions: Taken together, our findings indicate for the first time that IP3Rs are essential for the regulation of post-ischemic cardiac fibrosis.

scholarly journals Molecular Mechanisms of ZC3H12C/Reg-3 Biological Activity and Its Involvement in Psoriasis Pathology

2021 ◽  
Vol 22 (14) ◽  
pp. 7311
Author(s):  
Mateusz Wawro ◽  
Jakub Kochan ◽  
Weronika Sowinska ◽  
Aleksandra Solecka ◽  
Karolina Wawro ◽  
...  
Keyword(s):  
Family Member ◽  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Association Studies ◽  
Psoriasis Patient ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Transcript Levels

The members of the ZC3H12/MCPIP/Regnase family of RNases have emerged as important regulators of inflammation. In contrast to Regnase-1, -2 and -4, a thorough characterization of Regnase-3 (Reg-3) has not yet been explored. Here we demonstrate that Reg-3 differs from other family members in terms of NYN/PIN domain features, cellular localization pattern and substrate specificity. Together with Reg-1, the most comprehensively characterized family member, Reg-3 shared IL-6, IER-3 and Reg-1 mRNAs, but not IL-1β mRNA, as substrates. In addition, Reg-3 was found to be the only family member which regulates transcript levels of TNF, a cytokine implicated in chronic inflammatory diseases including psoriasis. Previous meta-analysis of genome-wide association studies revealed Reg-3 to be among new psoriasis susceptibility loci. Here we demonstrate that Reg-3 transcript levels are increased in psoriasis patient skin tissue and in an experimental model of psoriasis, supporting the immunomodulatory role of Reg-3 in psoriasis, possibly through degradation of mRNA for TNF and other factors such as Reg-1. On the other hand, Reg-1 was found to destabilize Reg-3 transcripts, suggesting reciprocal regulation between Reg-3 and Reg-1 in the skin. We found that either Reg-1 or Reg-3 were expressed in human keratinocytes in vitro. However, in contrast to robustly upregulated Reg-1 mRNA levels, Reg-3 expression was not affected in the epidermis of psoriasis patients. Taken together, these data suggest that epidermal levels of Reg-3 are negatively regulated by Reg-1 in psoriasis, and that Reg-1 and Reg-3 are both involved in psoriasis pathophysiology through controlling, at least in part different transcripts.

scholarly journals Polygenic Risk Score of Longevity Predicts Longer Survival Across an Age Continuum

2020 ◽  
Author(s):  
Niccolo’ Tesi ◽  
Sven J van der Lee ◽  
Marc Hulsman ◽  
Iris E Jansen ◽  
Najada Stringa ◽  
...  
Keyword(s):  
Older Adults ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Risk Scores ◽  
Human Longevity ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Age Related

Abstract Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N = 343), a population-matched cohort of older adults from 5 cohorts (N = 2905), and summary statistics data from genome-wide association studies on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older adults. This PRS was also associated with longer survival in an independent sample of younger individuals (p = .02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human life span is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.

scholarly journals The migraine–stroke connection: A genetic perspective

Cephalalgia ◽  
2015 ◽  
Vol 36 (7) ◽  
pp. 658-668 ◽  
Author(s):  
Rainer Malik ◽  
Bendik Winsvold ◽  
Eva Auffenberg ◽  
Martin Dichgans ◽  
Tobias Freilinger
Keyword(s):  
Ischemic Stroke ◽  
Vascular Disease ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Familial Hemiplegic Migraine ◽  
Artery Dissection ◽  
Cervical Artery Dissection ◽  
Data Sets ◽  
Genome Wide Association Studies ◽  
Disease Manifestation

Background A complex relationship between migraine and vascular disease has long been recognized. The pathophysiological basis underlying this correlation is incompletely understood. Aim The aim of this review is to focus on the migraine–vascular disorders connection from a genetic perspective, illustrating potentially shared (molecular) mechanisms. Results We first summarize the clinical presentation and genetic basis of CADASIL and other monogenic vascular syndromes with migraine as a prominent disease manifestation. Based on data from transgenic mouse models for familial hemiplegic migraine, we then discuss cortical spreading depression as a potential mechanistic link between migraine and ischemic stroke. Finally, we review data from genome-wide association studies, with a focus on overlapping findings with cervical artery dissection, ischemic stroke in general and cardiovascular disease. Conclusion A wealth of data supports a genetic link between migraine and vascular disease. Based on growing high-throughput data-sets, new genotyping techniques and in-depth phenotyping, further insights are expected for the future.

scholarly journals Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis

2019 ◽  
Author(s):  
Jing Yang ◽  
Amanda McGovern ◽  
Paul Martin ◽  
Kate Duffus ◽  
Xiangyu Ge ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
T Cells ◽  
Complex Disease ◽  
Target Genes ◽  
Disease Risk ◽  
Association Studies ◽  
Dna Interaction ◽  
Genome Wide Association Studies ◽  
Causal Genes

AbstractGenome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T-cells over 24 hours, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T-cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including FOXO1, which we confirm using CRISPR/Cas9.

scholarly journals Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells

2021 ◽  
Author(s):  
Kousuke Mouri ◽  
Michael H. Guo ◽  
Carl G. de Boer ◽  
Greg A. Newby ◽  
Matteo Gentili ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Association Studies ◽  
Regulatory Element ◽  
Genome Wide Association Studies ◽  
Expression Of Genes ◽  
Human T Cell ◽  
Allele Specific ◽  
Reporter Assays ◽  
Element Activity

Genome-wide association studies have uncovered hundreds of autoimmune disease-associated loci; however, the causal genetic variant(s) within each locus are mostly unknown. Here, we perform high-throughput allele-specific reporter assays to prioritize disease-associated variants for five autoimmune diseases. By examining variants that both promote allele-specific reporter expression and are located in accessible chromatin, we identify 60 putatively causal variants that enrich for statistically fine-mapped variants by up to 57.8-fold. We introduced the risk allele of a prioritized variant (rs72928038) into a human T cell line and deleted the orthologous sequence in mice, both resulting in reduced BACH2 expression. Naive CD8 T cells from mice containing the deletion had reduced expression of genes that suppress activation and maintain stemness. Our results represent an example of an effective approach for prioritizing variants and studying their physiologically relevant effects.

scholarly journals Enriching human interactome with functional mutations to detect high-impact network modules underlying complex diseases

2019 ◽  
Author(s):  
Hongzhu Cui ◽  
Suhas Srinivasan ◽  
Dmitry Korkin
Keyword(s):  
Biological Networks ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Genetic Diseases ◽  
Detection Methods ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Human Interactome ◽  
Module Detection ◽  
Disease Module

AbstractProgress in high-throughput -omics technologies moves us one step closer to the datacalypse in life sciences. In spite of the already generated volumes of data, our knowledge of the molecular mechanisms underlying complex genetic diseases remains limited. Increasing evidence shows that biological networks are essential, albeit not sufficient, for the better understanding of these mechanisms. The identification of disease-specific functional modules in the human interactome can provide a more focused insight into the mechanistic nature of the disease. However, carving a disease network module from the whole interactome is a difficult task. In this paper, we propose a computational framework, DIMSUM, which enables the integration of genome-wide association studies (GWAS), functional effects of mutations, and protein-protein interaction (PPI) network to improve disease module detection. Specifically, our approach incorporates and propagates the functional impact of non-synonymous single nucleotide polymorphisms (nsSNPs) on PPIs to implicate the genes that are most likely influenced by the disruptive mutations, and to identify the module with the greatest impact. Comparison against state-of-the-art seed-based module detection methods shows that our approach could yield modules that are biologically more relevant and have stronger association with the studied disease. We expect for our method to become a part of the common toolbox for disease module analysis, facilitating discovery of new disease markers.

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