-
Journal of Health and Social Behavior 1995Over the last several decades, epidemiological studies have been enormously successful in identifying risk factors for major diseases. However, most of this research has... (Review)
Review
Over the last several decades, epidemiological studies have been enormously successful in identifying risk factors for major diseases. However, most of this research has focused attention on risk factors that are relatively proximal causes of disease such as diet, cholesterol level, exercise and the like. We question the emphasis on such individually-based risk factors and argue that greater attention must be paid to basic social conditions if health reform is to have its maximum effect in the time ahead. There are two reasons for this claim. First we argue that individually-based risk factors must be contextualized, by examining what puts people at risk of risks, if we are to craft effective interventions and improve the nation's health. Second, we argue that social factors such as socioeconomic status and social support are likely "fundamental causes" of disease that, because they embody access to important resources, affect multiple disease outcomes through multiple mechanisms, and consequently maintain an association with disease even when intervening mechanisms change. Without careful attention to these possibilities, we run the risk of imposing individually-based intervention strategies that are ineffective and of missing opportunities to adopt broad-based societal interventions that could produce substantial health benefits for our citizens.
Topics: Disease; Epidemiology; Humans; Public Policy; Risk Factors; Social Environment; Sociology, Medical
PubMed: 7560851
DOI: No ID Found -
Science (New York, N.Y.) Jan 2020Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the... (Review)
Review
Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the chemical complexity of our world. To safeguard current and future generations from the increasing number of chemicals polluting our environment, a systematic and agnostic approach is needed. The "exposome" concept strives to capture the diversity and range of exposures to synthetic chemicals, dietary constituents, psychosocial stressors, and physical factors, as well as their corresponding biological responses. Technological advances such as high-resolution mass spectrometry and network science have allowed us to take the first steps toward a comprehensive assessment of the exposome. Given the increased recognition of the dominant role that nongenetic factors play in disease, an effort to characterize the exposome at a scale comparable to that of the human genome is warranted.
Topics: Dietary Supplements; Disease; Exposome; Genome, Human; Health; Humans; Organic Chemicals; Physical Phenomena; Risk Assessment; Stress, Psychological
PubMed: 31974245
DOI: 10.1126/science.aay3164 -
The EMBO Journal Mar 2021Various forms of cell death have been identified over the last decades with each relying on a different subset of proteins for the activation and execution of their... (Review)
Review
Various forms of cell death have been identified over the last decades with each relying on a different subset of proteins for the activation and execution of their respective pathway(s). In addition to the three best characterized pathways-apoptosis, necroptosis, and pyroptosis-other forms of regulated cell death including autophagy-dependent cell death (ADCD), mitochondrial permeability transition pore (MPTP)-mediated necrosis, parthanatos, NETosis and ferroptosis, and their relevance for organismal homeostasis are becoming better understood. Importantly, it is increasingly clear that none of these pathways operate alone. Instead, a more complex picture is emerging with many pathways sharing components and signaling principles. Finally, a number of cell death regulators are implicated in human diseases and represent attractive therapeutic targets. Therefore, better understanding of physiological and mechanistic aspects of cell death signaling should yield improved reagents for addressing unmet medical needs.
Topics: Cell Death; Disease; Humans; Signal Transduction
PubMed: 33439509
DOI: 10.15252/embj.2020106700 -
Science (New York, N.Y.) Oct 2022Cellular barcodes are distinct DNA sequences that enable one to track specific cells across time or space. Recent advances in our ability to detect natural or synthetic... (Review)
Review
Cellular barcodes are distinct DNA sequences that enable one to track specific cells across time or space. Recent advances in our ability to detect natural or synthetic cellular barcodes, paired with single-cell readouts of cell state, have markedly increased our knowledge of clonal dynamics and genealogies of the cells that compose a variety of tissues and organs. These advances hold promise to redefine our view of human disease. Here, we provide an overview of cellular barcoding approaches, discuss applications to gain new insights into disease mechanisms, and provide an outlook on future applications. We discuss unanticipated insights gained through barcoding in studies of cancer and blood cell production and describe how barcoding can be applied to a growing array of medical fields, particularly with the increasing recognition of clonal contributions in human diseases.
Topics: Humans; DNA Barcoding, Taxonomic; Clonal Evolution; Disease; Single-Cell Analysis
PubMed: 36227997
DOI: 10.1126/science.abm5874 -
The American Journal of Pathology Feb 2020Over the past 15 years, elegant studies have demonstrated that in certain conditions, programed cell death resembles necrosis and depends on a unique molecular pathway... (Review)
Review
Over the past 15 years, elegant studies have demonstrated that in certain conditions, programed cell death resembles necrosis and depends on a unique molecular pathway with no overlap with apoptosis. This form of regulated necrosis is represented by necroptosis, in which the receptor-interacting protein kinase-3 and its substrate mixed-lineage kinase domain-like protein play a crucial role. With the development of knockout mouse models and molecular inhibitors unique to necroptotic proteins, this cell death has been found to occur in virtually all tissues and diseases evaluated. There are different immunologic consequences depending on whether cells die through apoptosis or necroptosis. Therefore, distinguishing between these two forms of cell death may be crucial during pathologic evaluations. In this review, we provide an understanding of necroptotic cell-death and highlight diseases in which necroptosis has been found to play a role. We also discuss the inhibitors of necroptosis and the ways these inhibitors have been used in preclinical models of diseases. These two discussions offer an understanding of the role of necroptosis in diseases and will foster efforts to pharmacologically target this unique yet pervasive form of programed cell death in the clinic.
Topics: Animals; Chronic Disease; Disease; Humans; Inflammation; Necroptosis
PubMed: 31783008
DOI: 10.1016/j.ajpath.2019.10.012 -
Cell Jun 2017A central goal of genetics is to understand the links between genetic variation and disease. Intuitively, one might expect disease-causing variants to cluster into key... (Review)
Review
A central goal of genetics is to understand the links between genetic variation and disease. Intuitively, one might expect disease-causing variants to cluster into key pathways that drive disease etiology. But for complex traits, association signals tend to be spread across most of the genome-including near many genes without an obvious connection to disease. We propose that gene regulatory networks are sufficiently interconnected such that all genes expressed in disease-relevant cells are liable to affect the functions of core disease-related genes and that most heritability can be explained by effects on genes outside core pathways. We refer to this hypothesis as an "omnigenic" model.
Topics: Animals; Disease; Genetic Diseases, Inborn; Genome-Wide Association Study; Genomics; Humans; Multifactorial Inheritance; Polymorphism, Single Nucleotide
PubMed: 28622505
DOI: 10.1016/j.cell.2017.05.038 -
RNA (New York, N.Y.) Dec 2017RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has... (Review)
Review
RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has changed dramatically in recent years, to a large extent as a result of systematic efforts to map and quantify various RNA modifications in a transcriptome-wide manner, revealing that RNA modifications are reversible, dynamically regulated, far more widespread than originally thought, and involved in major biological processes, including cell differentiation, sex determination, and stress responses. Here we summarize the state of knowledge and provide a catalog of RNA modifications and their links to neurological disorders, cancers, and other diseases. With the advent of direct RNA-sequencing technologies, we expect that this catalog will help prioritize those RNA modifications for transcriptome-wide maps.
Topics: Animals; Disease; Humans; RNA; RNA Processing, Post-Transcriptional
PubMed: 28855326
DOI: 10.1261/rna.063503.117 -
Nature Reviews. Genetics Jan 2011Given the functional interdependencies between the molecular components in a human cell, a disease is rarely a consequence of an abnormality in a single gene, but... (Review)
Review
Given the functional interdependencies between the molecular components in a human cell, a disease is rarely a consequence of an abnormality in a single gene, but reflects the perturbations of the complex intracellular and intercellular network that links tissue and organ systems. The emerging tools of network medicine offer a platform to explore systematically not only the molecular complexity of a particular disease, leading to the identification of disease modules and pathways, but also the molecular relationships among apparently distinct (patho)phenotypes. Advances in this direction are essential for identifying new disease genes, for uncovering the biological significance of disease-associated mutations identified by genome-wide association studies and full-genome sequencing, and for identifying drug targets and biomarkers for complex diseases.
Topics: Databases, Genetic; Disease; Gene Expression Profiling; Gene Regulatory Networks; Genome-Wide Association Study; Humans; Metabolic Networks and Pathways
PubMed: 21164525
DOI: 10.1038/nrg2918 -
Physiological Reviews Oct 2014Extensive experimental animal studies and epidemiological observations have shown that environmental influences during early development affect the risk of later... (Review)
Review
Extensive experimental animal studies and epidemiological observations have shown that environmental influences during early development affect the risk of later pathophysiological processes associated with chronic, especially noncommunicable, disease (NCD). This field is recognized as the developmental origins of health and disease (DOHaD). We discuss the extent to which DOHaD represents the result of the physiological processes of developmental plasticity, which may have potential adverse consequences in terms of NCD risk later, or whether it is the manifestation of pathophysiological processes acting in early life but only becoming apparent as disease later. We argue that the evidence suggests the former, through the operation of conditioning processes induced across the normal range of developmental environments, and we summarize current knowledge of the physiological processes involved. The adaptive pathway to later risk accords with current concepts in evolutionary developmental biology, especially those concerning parental effects. Outside the normal range, effects on development can result in nonadaptive processes, and we review their underlying mechanisms and consequences. New concepts concerning the underlying epigenetic and other mechanisms involved in both disruptive and nondisruptive pathways to disease are reviewed, including the evidence for transgenerational passage of risk from both maternal and paternal lines. These concepts have wider implications for understanding the causes and possible prevention of NCDs such as type 2 diabetes and cardiovascular disease, for broader social policy and for the increasing attention paid in public health to the lifecourse approach to NCD prevention.
Topics: Cardiovascular Diseases; Chronic Disease; Disease; Epigenomics; Human Development; Humans; Life Style; Risk Factors; Time Factors
PubMed: 25287859
DOI: 10.1152/physrev.00029.2013 -
Nature Communications Jan 2022With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most...
With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein's genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease.
Topics: Aged; Aged, 80 and over; Blood Proteins; Cohort Studies; Disease; Female; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Iceland; Male; Polymorphism, Single Nucleotide; Quantitative Trait Loci
PubMed: 35078996
DOI: 10.1038/s41467-021-27850-z