scholarly journals Dysregulation of the peripheral glutamatergic system: A key player in migraine pathogenesis?

Cephalalgia ◽  
2021 ◽  
pp. 033310242110178
Author(s):  
Tarique Benbow ◽  
Brian E Cairns
Keyword(s):  
Glutamate Receptors ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Drug Candidates ◽  
System A ◽  
Afferent Fibers ◽  
Migraine Episode ◽  
Genomic Studies ◽  
Migraine Pathogenesis

Background Although the role of glutamate in migraine pathogenesis remains uncertain, there has been significant interest in the development of drug candidates that target glutamate receptors. Activation of trigeminovascular afferent fibers is now recognized as a crucial step to the onset of a migraine episode. New evidence suggests a dysfunction in peripheral glutamate regulation may play a role in this process. Objective To provide a narrative review of the role of peripheral glutamate dysfunction in migraine. Method A review of recent literature from neurobiological, pharmacological and genomic studies was conducted to support peripheral glutamate dysfunction as a potential element in migraine pathogenesis. Results Studies in rats suggest that elevated blood glutamate mechanically sensitizes trigeminal afferent fibers and stimulates the release of calcitonin-gene related peptide and other neuropeptides to promote and maintain neurogenic inflammation. These effects may be driven by upregulation of glutamate receptors, and modifications to reuptake and metabolic pathways of glutamate. Furthermore, genome wide association studies have found polymorphisms in glutamate receptor and transporter genes that are associated with migraine. Conclusion The role of peripheral glutamate signalling in the onset and maintenance of migraine is not completely elucidated and future studies are still needed to confirm its role in migraine pathogenesis.

scholarly journals Towards Individualized Medicine: Insights Gained from Genomic Studies

2009 ◽  
Vol 9 (1) ◽  
pp. S11-S16 ◽  
Author(s):  
Salman Kirmani ◽  
Dusica Babovic-Vuksanovic
Keyword(s):  
Human Genetics ◽  
Association Studies ◽  
Individualized Medicine ◽  
Genetic Disorders ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Prevention Strategies ◽  
Genome Wide ◽  
Genomic Studies

Advances in the field of human genetics have made it possible to develop specific management and prevention strategies for rare genetic disorders, and tailor pharmacotherapeutic approaches to anticoagulation and certain cancers. The role that genetic variation plays in influencing the risk and outcome of the most common diseases are still unclear. Data from genome-wide association studies is just beginning to answer these questions. We review the role of genome-wide association studies in the quest towards individualized medicine, and examine the promises and challenges that lie ahead.

Migraine: Genetic Variants and Clinical Phenotypes

2019 ◽  
Vol 26 (34) ◽  
pp. 6207-6221 ◽  
Author(s):  
Innocenzo Rainero ◽  
Alessandro Vacca ◽  
Flora Govone ◽  
Annalisa Gai ◽  
Lorenzo Pinessi ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Mthfr Gene ◽  
Genome Wide Association Studies ◽  
Clinical Phenotypes ◽  
Network Analyses ◽  
Genome Wide ◽  
Genomic Studies ◽  
The Common ◽  
The Relationship

Migraine is a common, chronic neurovascular disorder caused by a complex interaction between genetic and environmental risk factors. In the last two decades, molecular genetics of migraine have been intensively investigated. In a few cases, migraine is transmitted as a monogenic disorder, and the disease phenotype cosegregates with mutations in different genes like CACNA1A, ATP1A2, SCN1A, KCNK18, and NOTCH3. In the common forms of migraine, candidate genes as well as genome-wide association studies have shown that a large number of genetic variants may increase the risk of developing migraine. At present, few studies investigated the genotype-phenotype correlation in patients with migraine. The purpose of this review was to discuss recent studies investigating the relationship between different genetic variants and the clinical characteristics of migraine. Analysis of genotype-phenotype correlations in migraineurs is complicated by several confounding factors and, to date, only polymorphisms of the MTHFR gene have been shown to have an effect on migraine phenotype. Additional genomic studies and network analyses are needed to clarify the complex pathways underlying migraine and its clinical phenotypes.

MicroRNAs as Biomarker for Breast Cancer

2020 ◽  
Vol 20 (10) ◽  
pp. 1597-1610 ◽  
Author(s):  
Taru Aggarwal ◽  
Ridhima Wadhwa ◽  
Riya Gupta ◽  
Keshav Raj Paudel ◽  
Trudi Collet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Association Studies ◽  
Large Family ◽  
Breast Cancer Diagnosis ◽  
Cell Multiplication ◽  
Cell Physiology ◽  
Gene Transcript ◽  
Genome Wide Association Studies ◽  
Non Coding Rnas

Regardless of advances in detection and treatment, breast cancer affects about 1.5 million women all over the world. Since the last decade, genome-wide association studies (GWAS) have been extensively conducted for breast cancer to define the role of miRNA as a tool for diagnosis, prognosis and therapeutics. MicroRNAs are small, non-coding RNAs that are associated with the regulation of key cellular processes such as cell multiplication, differentiation, and death. They cause a disturbance in the cell physiology by interfering directly with the translation and stability of a targeted gene transcript. MicroRNAs (miRNAs) constitute a large family of non-coding RNAs, which regulate target gene expression and protein levels that affect several human diseases and are suggested as the novel markers or therapeutic targets, including breast cancer. MicroRNA (miRNA) alterations are not only associated with metastasis, tumor genesis but also used as biomarkers for breast cancer diagnosis or prognosis. These are explained in detail in the following review. This review will also provide an impetus to study the role of microRNAs in breast cancer.

scholarly journals Genetic Determinants of Paget’s Disease of Bone

2021 ◽  
Author(s):  
Navnit S. Makaram ◽  
Stuart H. Ralston
Keyword(s):  
Genetic Factors ◽  
Association Studies ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Paget’S Disease Of Bone ◽  
Genome Wide Association Studies ◽  
Paget's Disease Of Bone ◽  
Genome Wide ◽  
Family Based

Abstract Purpose of Review To provide an overview of the role of genes and loci that predispose to Paget’s disease of bone and related disorders. Recent Findings Studies over the past ten years have seen major advances in knowledge on the role of genetic factors in Paget’s disease of bone (PDB). Genome wide association studies have identified six loci that predispose to the disease whereas family based studies have identified a further eight genes that cause PDB. This brings the total number of genes and loci implicated in PDB to fourteen. Emerging evidence has shown that a number of these genes also predispose to multisystem proteinopathy syndromes where PDB is accompanied by neurodegeneration and myopathy due to the accumulation of abnormal protein aggregates, emphasising the importance of defects in autophagy in the pathogenesis of PDB. Summary Genetic factors play a key role in the pathogenesis of PDB and the studies in this area have identified several genes previously not suspected to play a role in bone metabolism. Genetic testing coupled to targeted therapeutic intervention is being explored as a way of halting disease progression and improving outcome before irreversible skeletal damage has occurred.

scholarly journals Enteric Viruses and Inflammatory Bowel Disease

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 104
Author(s):  
Georges Tarris ◽  
Alexis de Rougemont ◽  
Maëva Charkaoui ◽  
Christophe Michiels ◽  
Laurent Martin ◽  
...  
Keyword(s):  
Association Studies ◽  
Enteric Viruses ◽  
Enteric Virus ◽  
Viral Gastroenteritis ◽  
Blood Group Antigens ◽  
Genome Wide Association Studies ◽  
Virus Infections ◽  
T Helper ◽  
Inflammatory Bowel

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a multifactorial disease in which dietary, genetic, immunological, and microbial factors are at play. The role of enteric viruses in IBD remains only partially explored. To date, epidemiological studies have not fully described the role of enteric viruses in inflammatory flare-ups, especially that of human noroviruses and rotaviruses, which are the main causative agents of viral gastroenteritis. Genome-wide association studies have demonstrated the association between IBD, polymorphisms of the FUT2 and FUT3 genes (which drive the synthesis of histo-blood group antigens), and ligands for norovirus and rotavirus in the intestine. The role of autophagy in defensin-deficient Paneth cells and the perturbations of cytokine secretion in T-helper 1 and T-helper 17 inflammatory pathways following enteric virus infections have been demonstrated as well. Enteric virus interactions with commensal bacteria could play a significant role in the modulation of enteric virus infections in IBD. Based on the currently incomplete knowledge of the complex phenomena underlying IBD pathogenesis, future studies using multi-sampling and data integration combined with new techniques such as human intestinal enteroids could help to decipher the role of enteric viruses in IBD.

Stroke Genetics: Turning Discoveries into Clinical Applications

Stroke ◽  
2021 ◽  
Author(s):  
Martin Dichgans ◽  
Nathalie Beaufort ◽  
Stephanie Debette ◽  
Christopher D. Anderson
Keyword(s):  
Mendelian Randomization ◽  
Association Studies ◽  
Clinical Applications ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Neuroprotective Agents ◽  
Experimental Systems ◽  
Genome Wide ◽  
Rapid Pace

The field of medical and population genetics in stroke is moving at a rapid pace and has led to unanticipated opportunities for discovery and clinical applications. Genome-wide association studies have highlighted the role of specific pathways relevant to etiologically defined subtypes of stroke and to stroke as a whole. They have further offered starting points for the exploration of novel pathways and pharmacological strategies in experimental systems. Mendelian randomization studies continue to provide insights in the causal relationships between exposures and outcomes and have become a useful tool for predicting the efficacy and side effects of drugs. Additional applications that have emerged from recent discoveries include risk prediction based on polygenic risk scores and pharmacogenomics. Among the topics currently moving into focus is the genetics of stroke outcome. While still at its infancy, this field is expected to boost the development of neuroprotective agents. We provide a brief overview on recent progress in these areas.

scholarly journals Current knowledge in hypertension genetics: mosaic theory, candidate genes and genome-wide association studies

2020 ◽  
Vol 26 (5) ◽  
pp. 490-500
Author(s):  
A. O. Konradi
Keyword(s):  
Candidate Genes ◽  
High Performance ◽  
New Technologies ◽  
Current Knowledge ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Modern Approach ◽  
Genome Wide

The article reviews monogenic forms of hypertension, data on the role of heredity of essential hypertension and candidate genes, as well as genome-wide association studies. Modern approach for the role of genetics is driven by implementation of new technologies and their productivity. High performance speed of new technologies like genome-wide association studies provide data for better knowledge of genetic markers of hypertension. The major goal nowadays for research is to reveal molecular pathways of blood pressure regulation, which can help to move from populational to individual level of understanding of pathogenesis and treatment targets.

Vascular contributions to cognitive impairment and dementia: the emerging role of 20-HETE

2021 ◽  
Vol 135 (15) ◽  
pp. 1929-1944
Author(s):  
Ezekiel Gonzalez-Fernandez ◽  
Yedan Liu ◽  
Alexander P. Auchus ◽  
Fan Fan ◽  
Richard J. Roman
Keyword(s):  
Cognitive Impairment ◽  
Association Studies ◽  
Amyloid Β ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Cerebrovascular Risk ◽  
Potent Vasoconstrictor ◽  
Multiple Drugs ◽  
Epidemiology Studies

Abstract The accumulation of extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated τ proteins in the brain are the hallmarks of Alzheimer’s disease (AD). Much of the research into the pathogenesis of AD has focused on the amyloid or τ hypothesis. These hypotheses propose that Aβ or τ aggregation is the inciting event in AD that leads to downstream neurodegeneration, inflammation, brain atrophy and cognitive impairment. Multiple drugs have been developed and are effective in preventing the accumulation and/or clearing of Aβ or τ proteins. However, clinical trials examining these therapeutic agents have failed to show efficacy in preventing or slowing the progression of the disease. Thus, there is a need for fresh perspectives and the evaluation of alternative therapeutic targets in this field. Epidemiology studies have revealed significant overlap between cardiovascular and cerebrovascular risk factors such as hypertension, diabetes, atherosclerosis and stroke to the development of cognitive impairment. This strong correlation has given birth to a renewed focus on vascular contributions to AD and related dementias. However, few genes and mechanisms have been identified. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that plays a complex role in hypertension, autoregulation of cerebral blood flow and blood–brain barrier (BBB) integrity. Multiple human genome-wide association studies have linked mutations in the cytochrome P450 (CYP) 4A (CYP4A) genes that produce 20-HETE to hypertension and stroke. Most recently, genetic variants in the enzymes that produce 20-HETE have also been linked to AD in human population studies. This review examines the emerging role of 20-HETE in AD and related dementias.

scholarly journals Heritability jointly explained by host genotype and microbiome: will improve traits prediction?

2020 ◽  
Author(s):  
Denis Awany ◽  
Emile R Chimusa
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Heritability Estimate ◽  
Substantial Part ◽  
Phenotypic Variance ◽  
Genome Wide Association Studies ◽  
Host Genotype ◽  
Genome Wide ◽  
Heritability Estimation

Abstract As we observe the $70$th anniversary of the publication by Robertson that formalized the notion of ‘heritability’, geneticists remain puzzled by the problem of missing/hidden heritability, where heritability estimates from genome-wide association studies (GWASs) fall short of that from twin-based studies. Many possible explanations have been offered for this discrepancy, including existence of genetic variants poorly captured by existing arrays, dominance, epistasis and unaccounted-for environmental factors; albeit these remain controversial. We believe a substantial part of this problem could be solved or better understood by incorporating the host’s microbiota information in the GWAS model for heritability estimation and may also increase human traits prediction for clinical utility. This is because, despite empirical observations such as (i) the intimate role of the microbiome in many complex human phenotypes, (ii) the overlap between genetic variants associated with both microbiome attributes and complex diseases and (iii) the existence of heritable bacterial taxa, current GWAS models for heritability estimate do not take into account the contributory role of the microbiome. Furthermore, heritability estimate from twin-based studies does not discern microbiome component of the observed total phenotypic variance. Here, we summarize the concept of heritability in GWAS and microbiome-wide association studies, focusing on its estimation, from a statistical genetics perspective. We then discuss a possible statistical method to incorporate the microbiome in the estimation of heritability in host GWAS.

The role of α-synuclein in neurodegeneration — An update

2012 ◽  
Vol 3 (2) ◽  
Author(s):  
Kurt Jellinger
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Bound States ◽  
Physiological Function ◽  
Neuronal Degeneration ◽  
Association Studies ◽  
Common Mechanism ◽  
Genome Wide Association Studies ◽  
Potential Biomarker

AbstractGenetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson’s disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson’s disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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