Decision: Making inroads to precision medicine for the treatment of autoimmune diseases: Harnessing genomic studies to better diagnose and treat complex disorders — R1/PR9
Yuriy BaglaenkoCatriona A. WagnerVijay BhojPetter BrodinM. Eric GershwinDaniel B. GrahamPietro InvernizziKenneth K. KíddIlya KorsunskyMichael LevyAndrew L. MammenVictor NizetFrancisco Ramírez‐ValleEdward C. StitesMarc S. WilliamsMichael R. WilsonNoel R. RoseVirginia LaddMarina Sirota
0
Citation
112
Reference
10
Related Paper
Abstract:
Precision Medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle. Autoimmune diseases are those in which the body's natural defense system loses discriminating power between its own cells and foreign cells, causing the body to mistakenly attack healthy tissues. These conditions are very heterogeneous in their presentation and therefore difficult to diagnose and treat. Achieving precision medicine in autoimmune diseases has been challenging due to the complex etiologies of these conditions, involving an interplay between genetic, epigenetic, and environmental factors. However, recent technological and computational advances in molecular profiling have helped identify patient subtypes and molecular pathways which can be used to improve diagnostics and therapeutics. This review discusses the current understanding of the disease mechanisms, heterogeneity, and pathogenic autoantigens in autoimmune diseases gained from genomic and transcriptomic studies and highlights how these findings can be applied to better understand disease heterogeneity in the context of disease diagnostics and therapeutics.Keywords:
Profiling (computer programming)
Diabetes mellitus type-2 (DMT2) molecular pathophysiology is still challenging since the disease represents a complex, multifactorial metabolic disease caused by polygenic defects and environmental factors. In addition, the resulting secondary organ complications can be affected by various environmental and life-style factors over the years. The metabolic imbalance in DMT2 is manifested by the dysfunction of pancreatic β-cells in secreting insulin and the inability of other tissue cells to respond to insulin and utilize blood glucose. However, over recent years, through the advances in genomics and molecular analysis, several genes and microRNAs have been shown to be correlated as potential biomarkers with DMT2 prognosis, diagnosis, and therapy. Furthermore, drug therapy and clinical pharmacology have benefited from pharmacogenomics in a manner where the molecular knowledge can be translated into clinical information aiming to improve precision and personalized medicine therapeutic methodologies in healthcare. In this work, using systems pharmacology and network analysis approaches, we comprehensively assessed the molecular and genomics data associated with DMT2 to: (a) Better understand miRNA, gene, and drug associations; (b) Create connectivity and interaction maps of practical clinical utility; and (c) Facilitate the application of precision medicine therapeutic decisions in group and individual patients. Moreover, in order for the clinical pharmacology guidelines to be implemented in parallel with the generated molecular data, we also carried out an assessment of drug interactions in specific pharmacological classes that affect DMT2 pharmacotherapy outcomes. Overall, the proposed methodology and the results obtained: (a) Enrich our understanding of DMT2 molecular pathophysiology; (b) Unveil important biomarker and drug-gene pharmacogenomics associations; (c) Help the use of personalized therapy options; and (d) Allow precision medicine concepts to be broadly exploited in new therapeutic developments and within the clinical setting.
Pharmacogenomics
Personalized Medicine
Biomarker Discovery
Pharmacotherapy
Cite
Citations (0)
Cardiovascular disease (CVD), the main complication of diabetes mellitus (DM), accounts for a high percentage of mortality in diabetic patients. Endothelial dysfunction is a major causative event in the pathogenesis of diabetes-related vascular disease and the earliest symptom of vascular injury. Epigenetic modification plays a key role in the initiation, maintenance, and progression of both endothelial dysfunction and diabetes. Epigenetic alterations respond to the environment and mediate the 'legacy effect' of uncontrolled hyperglycaemia early in the disease despite thorough glycaemic control in a phenomenon called metabolic memory. Therefore, an understanding of the integrated system of different epigenetic mechanisms in DM and its vascular complications is urgently needed. This review summarizes aberrant epigenetic regulation under diabetic conditions, including histone modifications, DNA methylation, and non-coding RNAs (ncRNAs). Understanding the connections between these processes and DM may reveal a novel potential therapeutic target for diabetic vascular complications.
Endothelial Dysfunction
Pathogenesis
Cite
Citations (29)
Epigenetic modifications play a fundamental role in the progression of coronary artery disease (CAD). This panoramic review aims to provide an overview of the current understanding of the epigenetic mechanisms involved in CAD pathogenesis and highlights the potential implications for personalized medicine approaches. Epigenetics is the study of heritable changes that do not influence alterations in the DNA sequence of the genome. It has been shown that epigenetic processes, including DNA/histone methylation, acetylation, and phosphorylation, play an important role. Additionally, miRNAs, lncRNAs, and circRNAs are also involved in epigenetics, regulating gene expression patterns in response to various environmental factors and lifestyle choices. In the context of CAD, epigenetic alterations contribute to the dysregulation of genes involved in inflammation, oxidative stress, lipid metabolism, and vascular function. These epigenetic changes can occur during early developmental stages and persist throughout life, predisposing individuals to an increased risk of CAD. Furthermore, in recent years, the concept of personalized medicine has gained significant attention. Personalized medicine aims to tailor medical interventions based on an individual’s unique genetic, epigenetic, environmental, and lifestyle factors. In the context of CAD, understanding the interplay between genetic variants and epigenetic modifications holds promise for the development of more precise diagnostic tools, risk stratification models, and targeted therapies. This review summarizes the current knowledge of epigenetic mechanisms in CAD and discusses the fundamental principles of personalized medicine.
Personalized Medicine
Cite
Citations (5)
Abstract Migraine is a disabling common brain disorder typically characterized by attacks of severe headache and associated with autonomic and neurological symptoms. Its etiology is far from resolved. This review will focus on evidence that epigenetic mechanisms play an important role in disease etiology. Epigenetics comprise both DNA methylation and post-translational modifications of the tails of histone proteins, affecting chromatin structure and gene expression. Besides playing a role in establishing cellular and developmental stage-specific regulation of gene expression, epigenetic processes are also important for programming lasting cellular responses to environmental signals. Epigenetic mechanisms may explain how non-genetic endogenous and exogenous factors such as female sex hormones, stress hormones and inflammation trigger may modulate attack frequency. Developing drugs that specifically target epigenetic mechanisms may open up exciting new avenues for the prophylactic treatment of migraine.
Cite
Citations (99)
Epigenetics is a rapidly developing science that has gained a lot of interest in recent years due to the correlation between characteristic epigenetic marks and cardiovascular diseases (CVDs). Epigenetic modifications contribute to a change in gene expression while maintaining the DNA sequence. The analysis of these modifications provides a thorough insight into the cardiovascular system from its development to its further functioning. Epigenetics is strongly influenced by environmental factors, including known cardiovascular risk factors such as smoking, obesity, and low physical activity. Similarly, conditions affecting the local microenvironment of cells, such as chronic inflammation, worsen the prognosis in cardiovascular diseases and additionally induce further epigenetic modifications leading to the consolidation of unfavorable cardiovascular changes. A deeper understanding of epigenetics may provide an answer to the continuing strong clinical impact of cardiovascular diseases by improving diagnostic capabilities, personalized medical approaches and the development of targeted therapeutic interventions. The aim of the study was to present selected epigenetic pathways, their significance in cardiovascular diseases, and their potential as a therapeutic target in specific medical conditions.
Cite
Citations (5)
Epigenetic regulation of gene expression allows the organism to respond/adapt to environmental conditions without changing the gene coding sequence. Epigenetic modifications have also been found to control gene expression in various diseases, including diabetes. Epigenetic changes induced by hyperglycemia in multiple target organs contribute to metabolic memory of diabetic complications. The long-lasting development of diabetic complications even after achieving glucose control has been partly attributed to epigenetic changes in target cells. Specific epigenetic drugs might rescue chromatin conformation associated to hyperglycemia possibly slowing down the onset of diabetes-related complications. The current review will describe the updated epigenetics in diabetes that can be used to personalize a more focused treatment.
Epigenesis
Cite
Citations (15)
Epigenetic alterations during aging are manifested with altered gene expression linking it to lifespan regulation, genetic instability, and diseases. Diet and epigenetic modifiers exert a profound effect on the lifespan of an organism by modulating the epigenetic marks. However, our understanding of the multifactorial nature of the epigenetic process during aging and the onset of disease conditions as well as its reversal by epidrugs, diet, or environmental factors is still mystifying. This review covers the key findings in epigenetics related to aging and age-related diseases. Furthermore, it holds a discussion about the epigenetic clocks and their implications in various age-related disease conditions, including cancer. Although, epigenetics is a reversible process, how fast the epigenetic alterations can revert to normal is an intriguing question. Therefore, this article touches on the possibility of utilizing nutrition and mesenchymal stem cell secretome to accelerate the epigenetic reversal and emphasizes the identification of new therapeutic epigenetic modifiers to counter epigenetic alteration during aging.
Epigenesis
Epigenetic Therapy
Cite
Citations (4)
Epigenome
Cellular Aging
Cite
Citations (1)
The novel genome-wide assays of epigenetic marks have resulted in a greater understanding of how genetics and the environment interact in the development and inheritance of diabetes. Chronic hyperglycemia induces epigenetic changes in multiple organs, contributing to diabetic complications. Specific epigenetic-modifying compounds have been developed to erase these modifications, possibly slowing down the onset of diabetes-related complications. The current review is an update of the previously published paper, describing the most recent advances in the epigenetics of diabetes.
Inheritance
Cite
Citations (8)
Inheritance
Genomic Imprinting
Epigenesis
Epigenome
Cite
Citations (36)