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https://www.readbyqxmd.com/read/30374935/report-nia-workshop-on-translating-genetic-variants-associated-with-longevity-into-drug-targets
#1
Nicholas J Schork, Nalini Raghavachari
To date, candidate gene and genome-wide association studies (GWAS) have led to the discovery of longevity-associated variants (LAVs) in genes such as FOXO3A and APOE. Unfortunately, translating variants into drug targets is challenging for any trait, and longevity is no exception. Interdisciplinary and integrative multi-omics approaches are needed to understand how LAVs affect longevity-related phenotypes at the molecular physiologic level in order to leverage their discovery to identify new drug targets. The NIA convened a workshop in August 2017 on emerging and novel in silico (i...
October 29, 2018: GeroScience
https://www.readbyqxmd.com/read/30292915/implications-of-human-induced-pluripotent-stem-cells-in-metabolic-disorders-from-drug-discovery-toward-precision-medicine
#2
REVIEW
Agustin Cota-Coronado, P Berenice Ramírez-Rodríguez, Eduardo Padilla-Camberos, Nestor F Diaz, Jose M Flores-Fernández, Daniela Avila-Gonzalez, N Emmanuel Diaz-Martinez
Human induced pluripotent stem cells (hiPSCs) enable in vitro high-throughput pharmacological screening assays of diseased tissue. Together with recent genome-wide association studies (GWAS), hiPSCs enable the identification of key mutations for the development of effective treatments based on precise drugs. In concert with CRISPR/Cas9 systems, hiPSC technology can reveal therapeutic targets in metabolic disorders. The ex vivo CRISPR correction of autologous patient-derived hiPSCs has led to the development of replacement cell therapies, providing better patient prognoses...
October 4, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/30216917/dissecting-genetic-cross-talk-between-adhd-and-other-neurodevelopmental-disorders-evidence-from-behavioural-pharmacological-and-brain-imaging-investigations
#3
Sarojini M Sengupta, Nellie Fotopoulos, Gabriel A Devenyi, Marie-Ève Fortier, Marina Ter-Stepanian, Saba Sagliker, Sherif Karama, M Mallar Chakravarty, Aurelie Labbe, Natalie Grizenko, Ridha Joober
Several epidemiological and genetic studies have provided evidence of an overlap between neurodevelopmental disorders. However, the details of the etiological pathways remain to be elucidated. In this study, we garnered the findings of previous GWAS, conducted with schizophrenia and bipolar disorder. We conducted an exploratory study to examine the association between these SNPs and quantitative clinical/ behavioural/ cognitive/ structural brain parameters, as well as response to treatment with a fixed dose of methylphenidate, in a relatively large sample of children with ADHD...
November 2018: Psychiatry Research
https://www.readbyqxmd.com/read/30115528/foam-cell-formation-a-new-target-for-fighting-atherosclerosis-and-cardiovascular-disease
#4
REVIEW
Eithne M Maguire, Stuart W A Pearce, Qingzhong Xiao
During atherosclerosis, the gradual accumulation of lipids into the subendothelial space of damaged arteries results in several lipid modification processes followed by macrophage uptake in the arterial wall. The way in which these modified lipoproteins are dealt with determines the likelihood of cholesterol accumulation within the monocyte-derived macrophage and thus its transformation into the foam cell that makes up the characteristic fatty streak observed in the early stages of atherosclerosis. The unique expression of chemokine receptors and cellular adhesion molecules expressed on the cell surface of monocytes points to a particular extravasation route that they can take to gain entry into atherosclerotic site, in order to undergo differentiation into the phagocytic macrophage...
August 13, 2018: Vascular Pharmacology
https://www.readbyqxmd.com/read/29937318/agtr2-absence-or-antagonism-prevents-cystic-fibrosis-pulmonary-manifestations
#5
Rebecca J Darrah, Frank J Jacono, Neha Joshi, Anna L Mitchell, Abdus Sattar, Cara K Campanaro, Paul Litman, Jennifer Frey, David E Nethery, Eric S Barbato, Craig A Hodges, Harriet Corvol, Garry R Cutting, Michael R Knowles, Lisa J Strug, Mitchell L Drumm
BACKGROUND: Pulmonary disease remains the primary cause of morbidity and mortality for individuals with cystic fibrosis (CF). Variants at a locus on the X-chromosome containing the type 2 angiotensin II receptor gene (AGTR2) were identified by a large GWAS as significantly associating with lung function in CF patients. We hypothesized that manipulating the angiotensin-signaling pathway may yield clinical benefit in CF. METHODS: Genetic subset analysis was conducted on a local CF cohort to extend the GWAS findings...
June 21, 2018: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/29765977/systems-pharmacology-based-approach-of-connecting-disease-genes-in-genome-wide-association-studies-with-traditional-chinese-medicine
#6
Jihye Kim, Minjae Yoo, Jimin Shin, Hyunmin Kim, Jaewoo Kang, Aik Choon Tan
Traditional Chinese medicine (TCM) originated in ancient China has been practiced over thousands of years for treating various symptoms and diseases. However, the molecular mechanisms of TCM in treating these diseases remain unknown. In this study, we employ a systems pharmacology-based approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. We studied 102 TCM components and their target genes by analyzing microarray gene expression experiments. We constructed disease-gene networks from 2558 GWAS studies...
2018: International Journal of Genomics
https://www.readbyqxmd.com/read/29562725/genetic-and-epigenetic-regulation-in-nonalcoholic-fatty-liver-disease-nafld
#7
REVIEW
José A Del Campo, Rocío Gallego-Durán, Paloma Gallego, Lourdes Grande
Genetics and epigenetics play a key role in the development of several diseases, including nonalcoholic fatty liver disease (NAFLD). Family studies demonstrate that first degree relatives of patients with NAFLD are at a much higher risk of the disease than the general population. The development of the Genome Wide Association Study (GWAS) technology has allowed the identification of numerous genetic polymorphisms involved in the evolution of diseases (e.g., PNPLA3 , MBOAT7 ). On the other hand, epigenetic changes interact with inherited risk factors to determine an individual's susceptibility to NAFLD...
March 19, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29529423/the-genetics-of-adiposity
#8
REVIEW
Ruth Jf Loos
Genome-wide discovery efforts have identified more than 500 genetic loci associated with adiposity traits. The vast majority of these loci were found through large-scale meta-analyses for body mass index (BMI) and waist-to-hip ratio (WHR), and in European ancestry populations. However, alternative approaches, focusing on non-European ancestry populations, more refined adiposity measures, and low-frequency (minor allele frequency (MAF)<5%) coding variants, identified additional novel loci that had not been identified before...
June 2018: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/29331643/glucagon-like-peptide-1-signaling-inhibits-allergen-induced-lung-il-33-release-and-reduces-group-2-innate-lymphoid-cell-cytokine-production-in-vivo
#9
Shinji Toki, Kasia Goleniewska, Sara Reiss, Jian Zhang, Melissa H Bloodworth, Matthew T Stier, Weisong Zhou, Dawn C Newcomb, Lorraine B Ware, Gregg D Stanwood, Aurelio Galli, Kelli L Boyd, Kevin D Niswender, R Stokes Peebles
BACKGROUND: IL-33 is one of the most consistently associated gene candidates for asthma identified by using a genome-wide association study. Studies in mice and in human cells have confirmed the importance of IL-33 in inducing type 2 cytokine production from both group 2 innate lymphoid cells (ILC2s) and TH 2 cells. However, there are no pharmacologic agents known to inhibit IL-33 release from airway cells. OBJECTIVE: We sought to determine the effect of glucagon-like peptide 1 receptor (GLP-1R) signaling on aeroallergen-induced airway IL-33 production and release and on innate type 2 airway inflammation...
January 10, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29186694/large-scale-cognitive-gwas-meta-analysis-reveals-tissue-specific-neural-expression-and-potential-nootropic-drug-targets
#10
Max Lam, Joey W Trampush, Jin Yu, Emma Knowles, Gail Davies, David C Liewald, John M Starr, Srdjan Djurovic, Ingrid Melle, Kjetil Sundet, Andrea Christoforou, Ivar Reinvang, Pamela DeRosse, Astri J Lundervold, Vidar M Steen, Thomas Espeseth, Katri Räikkönen, Elisabeth Widen, Aarno Palotie, Johan G Eriksson, Ina Giegling, Bettina Konte, Panos Roussos, Stella Giakoumaki, Katherine E Burdick, Antony Payton, William Ollier, Ornit Chiba-Falek, Deborah K Attix, Anna C Need, Elizabeth T Cirulli, Aristotle N Voineskos, Nikos C Stefanis, Dimitrios Avramopoulos, Alex Hatzimanolis, Dan E Arking, Nikolaos Smyrnis, Robert M Bilder, Nelson A Freimer, Tyrone D Cannon, Edythe London, Russell A Poldrack, Fred W Sabb, Eliza Congdon, Emily Drabant Conley, Matthew A Scult, Dwight Dickinson, Richard E Straub, Gary Donohoe, Derek Morris, Aiden Corvin, Michael Gill, Ahmad R Hariri, Daniel R Weinberger, Neil Pendleton, Panos Bitsios, Dan Rujescu, Jari Lahti, Stephanie Le Hellard, Matthew C Keller, Ole A Andreassen, Ian J Deary, David C Glahn, Anil K Malhotra, Todd Lencz
Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor...
November 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/29143315/fetal-haemoglobin-induction-in-sickle-cell-disease
#11
REVIEW
Alireza Paikari, Vivien A Sheehan
Fetal haemoglobin (HbF, α2γ2) induction has long been an area of investigation, as it is known to ameliorate the clinical complications of sickle cell disease (SCD). Progress in identifying novel HbF-inducing strategies has been stymied by limited understanding of gamma (γ)-globin regulation. Genome-wide association studies (GWAS) have identified variants in BCL11A and HBS1L-MYB that are associated with HbF levels. Functional studies have established the roles of BCL11A, MYB, and KLF1 in γ-globin regulation, but this information has not yielded new pharmacological agents...
January 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29103089/hdl-cholesterol-metabolism-and-the-risk-of-chd-new-insights-from-human-genetics
#12
REVIEW
Cecilia Vitali, Sumeet A Khetarpal, Daniel J Rader
PURPOSE OF REVIEW: Elevated high-density lipoprotein cholesterol levels in the blood (HDL-C) represent one of the strongest epidemiological surrogates for protection against coronary heart disease (CHD), but recent human genetic and pharmacological intervention studies have raised controversy about the causality of this relationship. Here, we review recent discoveries from human genome studies using new analytic tools as well as relevant animal studies that have both addressed, and in some cases, fueled this controversy...
November 4, 2017: Current Cardiology Reports
https://www.readbyqxmd.com/read/29052219/pharmacogenomic-discovery-to-function-and-mechanism-breast-cancer-as-a-case-study
#13
Liewei Wang, James Ingle, Richard Weinshilboum
Biomedical research is undergoing rapid change, with the development of a series of analytical omics techniques that are capable of generating Biomedical Big Data. These developments provide an unprecedented opportunity to gain novel insight into disease pathophysiology and mechanisms of drug action and response-but they also present significant challenges. Pharmacogenomics is a discipline within Clinical Pharmacology that has been at the forefront in defining, taking advantage of, and dealing with the opportunities and challenges of this aspect of the Post-Genome Project world...
February 2018: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28731861/genetic-control-of-apoprotein-a-i-and-atheroprotection-some-insights-from-inbred-strains-of-mice
#14
REVIEW
Godfrey S Getz, Catherine A Reardon
PURPOSE OF REVIEW: Previous epidemiological studies and studies in experimental animals have provided strong evidence for the atheroprotective effect of HDL and its major apoprotein, apolipoprotein A-I (apoA-I). Identification of genetic loci associating apoA-I/HDL with cardiovascular disease is needed to establish a causal relationship. RECENT FINDINGS: Pharmacological interventions to increase apoA-I or HDL cholesterol levels in humans are not associated with reduction in atherosclerosis...
October 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28199134/genetic-control-of-fatty-acid-%C3%AE-oxidation-in-chronic-obstructive-pulmonary-disease
#15
Zhiqiang Jiang, Nelson H Knudsen, Gang Wang, Weiliang Qiu, Zun Zar Chi Naing, Yan Bai, Xingbin Ai, Chih-Hao Lee, Xiaobo Zhou
Bioenergetics homeostasis is important for cells to sustain normal functions and defend against injury. The genetic controls of bioenergetics homeostasis, especially lipid metabolism, remain poorly understood in chronic obstructive pulmonary disease (COPD), the third leading cause of death in the world. Additionally, the biological function of most of the susceptibility genes identified from genome-wide association studies (GWASs) in COPD remains unclear. Here, we aimed to address (1) how fatty acid oxidation (FAO), specifically β-oxidation, a key lipid metabolism pathway that provides energy to cells, contributes to cigarette smoke (CS)-induced COPD; and (2) whether-and if so, how-FAM13A (family with sequence similarity 13 member A), a well-replicated COPD GWAS gene, modulates the FAO pathway...
June 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28169291/hotspots-of-aberrant-enhancer-activity-punctuate-the-colorectal-cancer-epigenome
#16
Andrea J Cohen, Alina Saiakhova, Olivia Corradin, Jennifer M Luppino, Katreya Lovrenert, Cynthia F Bartels, James J Morrow, Stephen C Mack, Gursimran Dhillon, Lydia Beard, Lois Myeroff, Matthew F Kalady, Joseph Willis, James E Bradner, Ruth A Keri, Nathan A Berger, Shondra M Pruett-Miller, Sanford D Markowitz, Peter C Scacheri
In addition to mutations in genes, aberrant enhancer element activity at non-coding regions of the genome is a key driver of tumorigenesis. Here, we perform epigenomic enhancer profiling of a cohort of more than forty genetically diverse human colorectal cancer (CRC) specimens. Using normal colonic crypt epithelium as a comparator, we identify enhancers with recurrently gained or lost activity across CRC specimens. Of the enhancers highly recurrently activated in CRC, most are constituents of super enhancers, are occupied by AP-1 and cohesin complex members, and originate from primed chromatin...
February 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/27539027/connectome-and-molecular-pharmacological-differences-in-the-dopaminergic-system-in-restless-legs-syndrome-rls-plastic-changes-and-neuroadaptations-that-may-contribute-to-augmentation
#17
REVIEW
Christopher J Earley, George R Uhl, Stefan Clemens, Sergi Ferré
Restless legs syndrome (RLS) is primarily treated with levodopa and dopaminergics that target the inhibitory dopamine receptor subtypes D3 and D2. The initial success of this therapy led to the idea of a hypodopaminergic state as the mechanism underlying RLS. However, multiple lines of evidence suggest that this simplified concept of a reduced dopamine function as the basis of RLS is incomplete. Moreover, long-term medication with the D2/D3 agonists leads to a reversal of the initial benefits of dopamine agonists and augmentation, which is a worsening of symptoms under therapy...
March 2017: Sleep Medicine
https://www.readbyqxmd.com/read/27423601/genetic-insights-into-migraine-and-glutamate-a-protagonist-driving-the-headache
#18
REVIEW
Claudia F Gasparini, Robert A Smith, Lyn R Griffiths
Migraine is a complex polygenic disorder that continues to be a great source of morbidity in the developed world with a prevalence of 12% in the Caucasian population. Genetic and pharmacological studies have implicated the glutamate pathway in migraine pathophysiology. Glutamate profoundly impacts brain circuits that regulate core symptom domains in a range of neuropsychiatric conditions and thus remains a "hot" target for drug discovery. Glutamate has been implicated in cortical spreading depression (CSD), the phenomenon responsible for migraine with aura and in animal models carrying FHM mutations...
August 15, 2016: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/27302942/gene-set-analysis-based-on-the-pharmacological-profiles-of-drugs-to-identify-repurposing-opportunities-in-schizophrenia
#19
Simone de Jong, Lewis R Vidler, Younes Mokrab, David A Collier, Gerome Breen
Genome-wide association studies (GWAS) have identified thousands of novel genetic associations for complex genetic disorders, leading to the identification of potential pharmacological targets for novel drug development. In schizophrenia, 108 conservatively defined loci that meet genome-wide significance have been identified and hundreds of additional sub-threshold associations harbour information on the genetic aetiology of the disorder. In the present study, we used gene-set analysis based on the known binding targets of chemical compounds to identify the 'drug pathways' most strongly associated with schizophrenia-associated genes, with the aim of identifying potential drug repositioning opportunities and clues for novel treatment paradigms, especially in multi-target drug development...
August 2016: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/27154058/understanding-the-genetics-of-apoe-and-tomm40-and-role-of-mitochondrial-structure-and-function-in-clinical-pharmacology-of-alzheimer-s-disease
#20
REVIEW
Allen Roses, Scott Sundseth, Ann Saunders, William Gottschalk, Dan Burns, Michael Lutz
The methodology of Genome-Wide Association Screening (GWAS) has been applied for more than a decade. Translation to clinical utility has been limited, especially in Alzheimer's Disease (AD). It has become standard practice in the analyses of more than two dozen AD GWAS studies to exclude the apolipoprotein E (APOE) region because of its extraordinary statistical support, unique thus far in complex human diseases. New genes associated with AD are proposed frequently based on SNPs associated with odds ratio (OR) < 1...
June 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
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