Gene co-expression in the interactome: moving from correlation toward causation via an integrated approach to disease module discovery

In this study, we integrate the outcomes of co-expression network analysis with the human interactome network to predict novel putative disease genes and modules. We first apply the SWItch Miner (SWIM) methodology, which predicts important (switch) genes within the co-expression network that regulate disease state transitions, then map them to the human protein–protein interaction network (PPI, or interactome) to predict novel disease–disease relationships (i.e., a SWIM-informed diseasome). Although the relevance of switch genes to an observed phenotype has been recently assessed, their performance at the system or network level constitutes a new, potentially fascinating territory yet to be explored. Quantifying the interplay between switch genes and human diseases in the interactome network, we found that switch genes associated with specific disorders are closer to each other than to other nodes in the network, and tend to form localized connected subnetworks. These subnetworks overlap between similar diseases and are situated in different neighborhoods for pathologically distinct phenotypes, consistent with the well-known topological proximity property of disease genes. These findings allow us to demonstrate how SWIM-based correlation network analysis can serve as a useful tool for efficient screening of potentially new disease gene associations. When integrated with an interactome-based network analysis, it not only identifies novel candidate disease genes, but also may offer testable hypotheses by which to elucidate the molecular underpinnings of human disease and reveal commonalities between seemingly unrelated diseases

Bone Morphogenetic Protein‐2 Decreases MicroRNA‐30b and MicroRNA‐30c to Promote Vascular Smooth Muscle Cell Calcification

Background: Vascular calcification resembles bone formation and involves vascular smooth muscle cell (SMC) transition to an osteoblast‐like phenotype to express Runx2, a master osteoblast transcription factor. One possible mechanism by which Runx2 protein expression is induced is downregulation of inhibitory microRNAs (miR). Methods and Results: Human coronary artery SMCs (CASMCs) treated with bone morphogenetic protein‐2 (BMP‐2; 100 ng/mL) demonstrated a 1.7‐fold (P<0.02) increase in Runx2 protein expression at 24 hours. A miR microarray and target prediction database analysis independently identified miR‐30b and miR‐30c (miR‐30b‐c) as miRs that regulate Runx2 expression. Real‐time–polymerase chain reaction confirmed that BMP‐2 decreased miR‐30b and miR‐30c expression. A luciferase reporter assay verified that both miR‐30b and miR‐30c bind to the 3′‐untranslated region of Runx2 mRNA to regulate its expression. CASMCs transfected with antagomirs to downregulate miR‐30b‐c demonstrated significantly increased Runx2, intracellular calcium deposition, and mineralization. Conversely, forced expression of miR‐30b‐c by transfection with pre–miR‐30b‐c prevented the increase in Runx2 expression and mineralization of SMCs. Calcified human coronary arteries demonstrated higher levels of BMP‐2 and lower levels of miR‐30b than did noncalcified donor coronary arteries. Conclusions: BMP‐2 downregulates miR‐30b and miR‐30c to increase Runx2 expression in CASMCs and promote mineralization. Strategies that modulate expression of miR‐30b and miR‐30c may influence vascular calcification

Analyzing networks of phenotypes in complex diseases: methodology and applications in COPD

Background: The investigation of complex disease heterogeneity has been challenging. Here, we introduce a network-based approach, using partial correlations, that analyzes the relationships among multiple disease-related phenotypes. Results: We applied this method to two large, well-characterized studies of chronic obstructive pulmonary disease (COPD). We also examined the associations between these COPD phenotypic networks and other factors, including case-control status, disease severity, and genetic variants. Using these phenotypic networks, we have detected novel relationships between phenotypes that would not have been observed using traditional epidemiological approaches. Conclusion: Phenotypic network analysis of complex diseases could provide novel insights into disease susceptibility, disease severity, and genetic mechanisms

DiseaseConnect: a comprehensive web server for mechanism-based disease–disease connections

The DiseaseConnect (http://disease-connect.org) is a web server for analysis and visualization of a comprehensive knowledge on mechanism-based disease connectivity. The traditional disease classification system groups diseases with similar clinical symptoms and phenotypic traits. Thus, diseases with entirely different pathologies could be grouped together, leading to a similar treatment design. Such problems could be avoided if diseases were classified based on their molecular mechanisms. Connecting diseases with similar pathological mechanisms could inspire novel strategies on the effective repositioning of existing drugs and therapies. Although there have been several studies attempting to generate disease connectivity networks, they have not yet utilized the enormous and rapidly growing public repositories of disease-related omics data and literature, two primary resources capable of providing insights into disease connections at an unprecedented level of detail. Our DiseaseConnect, the first public web server, integrates comprehensive omics and literature data, including a large amount of gene expression data, Genome-Wide Association Studies catalog, and text-mined knowledge, to discover disease–disease connectivity via common molecular mechanisms. Moreover, the clinical comorbidity data and a comprehensive compilation of known drug–disease relationships are additionally utilized for advancing the understanding of the disease landscape and for facilitating the mechanism-based development of new drug treatments

Clinical epigenetics settings for cancer and cardiovascular diseases: real-life applications of network medicine at the bedside

Despite impressive efforts invested in epigenetic research in the last 50&nbsp;years, clinical applications are still lacking. Only a few university hospital centers currently use epigenetic biomarkers at the bedside. Moreover, the overall concept of precision medicine is not widely recognized in routine medical practice and the reductionist approach remains predominant in treating patients affected by major diseases such as cancer and cardiovascular diseases. By its’ very nature, epigenetics is integrative of genetic networks. The study of epigenetic biomarkers has led to the identification of numerous drugs with an increasingly significant role in clinical therapy especially of cancer patients. Here, we provide an overview of clinical epigenetics within the context of network analysis. We illustrate achievements to date and discuss how we can move from traditional medicine into the era of network medicine (NM), where pathway-informed molecular diagnostics will allow treatment selection following the paradigm of precision medicine

Selenoprotein gene nomenclature

The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4 and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine-R-sulfoxide reductase 1) and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15 kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV) and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates

The Role of Quantitative Pharmacology in an Academic Translational Research Environment

Translational research is generally described as the application of basic science discoveries to the treatment or prevention of disease or injury. Its value is usually determined based on the likelihood that exploratory or developmental research can yield effective therapies. While the pharmaceutical industry has evolved into a highly specialized sector engaged in translational research, the academic medical research community has similarly embraced this paradigm largely through the motivation of the National Institute of Health (NIH) via its Roadmap initiative. The Clinical and Translational Science Award (CTSA) has created opportunities for institutions which can provide the multidisciplinary environment required to engage such research. A key component of the CTSA and an element of both the NIH Roadmap and the FDA Critical Path is the bridging of bench and bedside science via quantitative pharmacologic relationships. The infrastructure of the University of Pennsylvania/Children’s Hospital of Philadelphia CTSA is highlighted relative to both research and educational objectives reliant upon quantitative pharmacology. A case study, NIH-sponsored research program exploring NK1r antagonism for the treatment NeuroAIDS is used to illustrate the application of quantitative pharmacology in a translational research paradigm

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs