Erythro-megakaryocytic transcription factors associated with hereditary anemia

Abstract Most heritable anemias are caused by mutations in genes encoding globins, red blood cell (RBC) membrane proteins, or enzymes in the glycolytic and hexose monophosphate shunt pathways. A less common class of genetic anemia is caused by mutations that alter the functions of erythroid transcription factors (TFs). Many TF mutations associated with heritable anemia cause truncations or amino acid substitutions, resulting in the production of functionally altered proteins. Characterization of these mutant proteins has provided insights into mechanisms of gene expression, hematopoietic development, and human disease. Mutations within promoter or enhancer regions that disrupt TF binding to essential erythroid genes also cause anemia and heritable variations in RBC traits, such as fetal hemoglobin content. Defining the latter may have important clinical implications for de-repressing fetal hemoglobin synthesis to treat sickle cell anemia and β thalassemia. Functionally important alterations in genes encoding TFs or their cognate cis elements are likely to occur more frequently than currently appreciated, a hypothesis that will soon be tested through ongoing genome-wide association studies and the rapidly expanding use of global genome sequencing for human diagnostics. Findings obtained through such studies of RBCs and associated diseases are likely generalizable to many human diseases and quantitative traits.

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How Cardiac Embryology Translates into Clinical Arrhythmias

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8060070 ◽

2021 ◽

Vol 8 (6) ◽

pp. 70

Author(s):

Mathilde R. Rivaud ◽

Michiel Blok ◽

Monique R. M. Jongbloed ◽

Bastiaan J. Boukens

Keyword(s):

Transcription Factors ◽

Association Studies ◽

Pulmonary Veins ◽

Atrioventricular Node ◽

Right Ventricular Outflow Tract ◽

Ventricular Outflow Tract ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Congenital Atrioventricular Block ◽

The Right

The electrophysiological signatures of the myocardium in cardiac structures, such as the atrioventricular node, pulmonary veins or the right ventricular outflow tract, are established during development by the spatial and temporal expression of transcription factors that guide expression of specific ion channels. Genome-wide association studies have shown that small variations in genetic regions are key to the expression of these transcription factors and thereby modulate the electrical function of the heart. Moreover, mutations in these factors are found in arrhythmogenic pathologies such as congenital atrioventricular block, as well as in specific forms of atrial fibrillation and ventricular tachycardia. In this review, we discuss the developmental origin of distinct electrophysiological structures in the heart and their involvement in cardiac arrhythmias.

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Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5′ olfactory receptor gene cluster

Blood ◽

10.1182/blood-2009-08-239517 ◽

2010 ◽

Vol 115 (9) ◽

pp. 1815-1822 ◽

Cited By ~ 96

Author(s):

Nadia Solovieff ◽

Jacqueline N. Milton ◽

Stephen W. Hartley ◽

Richard Sherva ◽

Paola Sebastiani ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Olfactory Receptor ◽

Association Studies ◽

Receptor Gene ◽

Fetal Hemoglobin ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Olfactory Receptor Gene ◽

Genome Wide

Abstract In a genome-wide association study of 848 blacks with sickle cell anemia, we identified single nucleotide polymorphisms (SNPs) associated with fetal hemoglobin concentration. The most significant SNPs in a discovery sample were tested in a replication set of 305 blacks with sickle cell anemia and in subjects with hemoglobin E or β thalassemia trait from Thailand and Hong Kong. A novel region on chromosome 11 containing olfactory receptor genes OR51B5 and OR51B6 was identified by 6 SNPs (lowest P = 4.7E−08) and validated in the replication set. An additional olfactory receptor gene, OR51B2, was identified by a novel SNP set enrichment analysis. Genome-wide association studies also validated a previously identified SNP (rs766432) in BCL11A, a gene known to affect fetal hemoglobin levels (P = 2.6E−21) and in Thailand and Hong Kong subjects. Elements within the olfactory receptor gene cluster might play a regulatory role in γ-globin gene expression.

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Polymorphisms Affecting Trace Element Bioavailability

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000039 ◽

2010 ◽

Vol 80 (45) ◽

pp. 314-318 ◽

Cited By ~ 3

Author(s):

John C. Mathers ◽

Catherine Méplan ◽

John E. Hesketh

Keyword(s):

Trace Element ◽

Individual Variation ◽

Association Studies ◽

Copy Number Variants ◽

Micro Rna ◽

Future Research ◽

Genome Wide Association Studies ◽

Complex Interactions ◽

Genome Wide ◽

Genes Encoding

This review outlines the nature of inter-individual variation in trace element bioavailability, focusing on genetic and epigenetic determinants. We note that pathogenic mutations responsible for dangerously high (or low) status for the micronutrient are unlikely to make large contributions to variability in bioavailability among the general population. Prospective genotyping (for variants in genes encoding selenoproteins) of participants in human studies illustrate one approach to understanding the complex interactions between genotype and trace element supply, which determine the functional bioavailability of selenium. Rapid advances in technological and bioinformatics tools; e. g., as used in Genome-Wide Association Studies, are opening new avenues for research on the genetic determinants of inter-individual variation in trace element bioavailability. This may include copy number variants in addition to the more widely studied polymorphisms. Future research on trace element bioavailability should encompass studies of epigenetic variants, including the role of non-coding (micro) RNA.

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Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107095 ◽

2020 ◽

pp. jmedgenet-2020-107095

Author(s):

William Schierding ◽

Julia A Horsfield ◽

Justin M O'Sullivan

Keyword(s):

Association Studies ◽

Genome Wide Association Studies ◽

Cohesin Complex ◽

Loss Of Function ◽

Regulatory Variants ◽

Genome Wide ◽

Genes Encoding ◽

Full Complement ◽

Transcriptional Changes ◽

Robust Regulation

Background: The cohesin complex plays an essential role in genome organisation and cell division. A full complement of the cohesin complex and its regulators is important for normal development, since heterozygous mutations in genes encoding these components can be sufficient to produce a disease phenotype. The implication that genes encoding the cohesin subunits or cohesin regulators must be tightly controlled and resistant to variability in expression has not yet been formally tested.Methods: Here, we identify spatial-regulatory connections with potential to regulate expression of cohesin loci (Mitotic: SMC1A, SMC3, STAG1, STAG2, RAD21/RAD21-AS; Meiotic: SMC1B, STAG3, REC8, RAD21L1), cohesin-ring support genes (NIPBL, MAU2, WAPL, PDS5A, PDS5B) and CTCF, including linking their expression to that of other genes. We searched the genome-wide association studies (GWAS) catalogue for SNPs mapped or attributed to cohesin genes by GWAS (GWAS-attributed) and the GTEx catalogue for SNPs mapped to cohesin genes by cis-regulatory variants in one or more of 44 tissues across the human body (expression quantitative trail locus-attributed).Results: Connections that centre on the cohesin ring subunits provide evidence of coordinated regulation that has little tolerance for perturbation. We used the CoDeS3D SNP-gene attribution methodology to identify transcriptional changes across a set of genes coregulated with the cohesin loci that include biological pathways such as extracellular matrix production and proteasome-mediated protein degradation. Remarkably, many of the genes that are coregulated with cohesin loci are themselves intolerant to loss-of-function.Conclusions: The results highlight the importance of robust regulation of cohesin genes and implicate novel pathways that may be important in the human cohesinopathy disorders.

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Personality traits and polymorphisms of genes coding neurotransmitter receptors or transporters: review of single gene and genome-wide association studies

Annals of General Psychiatry ◽

10.1186/s12991-021-00328-4 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Szymon Zmorzyński ◽

Wojciech Styk ◽

Waldemar Klinkosz ◽

Justyna Iskra ◽

Agata Anna Filip

Keyword(s):

Personality Traits ◽

Five Factor Model ◽

Association Studies ◽

Genome Wide Association ◽

Cochrane Library ◽

Neurotransmitter Receptors ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Genes Encoding ◽

The Relationship

Abstract Background The most popular tool used for measuring personality traits is the Five-Factor Model (FFM). It includes neuroticism, extraversion, openness, agreeableness and conscientiousness. Many studies indicated the association of genes encoding neurotransmitter receptors/transporters with personality traits. The relationship connecting polymorphic DNA sequences and FFM features has been described in the case of genes encoding receptors of cannabinoid and dopaminergic systems. Moreover, dopaminergic system receives inputs from other neurotransmitters, like GABAergic or serotoninergic systems. Methods We searched PubMed Central (PMC), Science Direct, Scopus, Cochrane Library, Web of Science and EBSCO databases from their inception to November 19, 2020, to identify original studies, as well as peer-reviewed studies examining the FFM and its association with gene polymorphisms affecting the neurotransmitter functions in central nervous system. Results Serotonin neurons modulate dopamine function. In gene encoding serotonin transporter protein, SLC6A4, was found polymorphism, which was correlated with openness to experience (in Sweden population), and high scores of neuroticism and low levels of agreeableness (in Caucasian population). The genome-wide association studies (GWASs) found an association of 5q34-q35, 3p24, 3q13 regions with higher scores of neuroticism, extraversion and agreeableness. However, the results for chromosome 3 regions are inconsistent, which was shown in our review paper. Conclusions GWASs on polymorphisms are being continued in order to determine and further understand the relationship between the changes in DNA and personality traits.

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Genetics of ischemic stroke: where are we now?

Orvosi Hetilap ◽

10.1556/oh.2011.29069 ◽

2011 ◽

Vol 152 (12) ◽

pp. 455-463 ◽

Cited By ~ 1

Author(s):

Anita Maász ◽

Zoltán Szolnoki ◽

László Balikó ◽

Béla Melegh

Keyword(s):

Ischemic Stroke ◽

Genetic Variants ◽

Association Studies ◽

Renin Angiotensin System ◽

Cerebrovascular Diseases ◽

Genome Wide Association Studies ◽

Angiotensin System ◽

New Approach ◽

Genome Wide ◽

Genes Encoding

As stroke is the third leading cause of death after heart failure and tumors worldwide, cerebrovascular diseases reached substantial attention. In the past few years, significant progression has been seen in identification of genetic variants in the background of stroke and other cerebrovascular and cardiovascular events. Examination of these variants is a new approach to recognize pathogenesis of disorders that hopefully helps in future prevention and prospects of screening and, optimistically, it contributes to special care of patients susceptible for stroke. In the background of ischemic stroke several genetic variants have been identified, which localize in genes encoding proteins involved in hemostasis, renin-angiotensin system and lipid metabolism. The number of these variants exponentially increases permanently due to rapid spreading of genome wide association studies. The goal of this review is to summarize the results of genetic studies on ischemic stroke. Here the authors focus on genetic variants which can have major role in personalized medicine and prevention of stroke. Orv. Hetil., 2011, 152, 455–463.

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Atlas of Transcription Factor Binding Sites from ENCODE DNase Hypersensitivity Data Across 27 Tissue Types

10.1101/252023 ◽

2018 ◽

Cited By ~ 4

Author(s):

Cory C. Funk ◽

Alex M. Casella ◽

Segun Jung ◽

Matthew A. Richards ◽

Alex Rodriguez ◽

...

Keyword(s):

Transcription Factors ◽

Human Genome ◽

Binding Sites ◽

Regulatory Networks ◽

Specific Binding ◽

Association Studies ◽

Genome Wide Association Studies ◽

Sequence Motifs ◽

Link Type ◽

Genome Wide

AbstractThere is intense interest in mapping the tissue-specific binding sites of transcription factors in the human genome to reconstruct gene regulatory networks and predict functions for non-coding genetic variation. DNase-seq footprinting provides a means to predict genome-wide binding sites for hundreds of transcription factors (TFs) simultaneously. However, despite the public availability of DNase-seq data for hundreds of samples, there is neither a unified analytical workflow nor a publicly accessible database providing the locations of footprints across all available samples. Here, we implemented a workflow for uniform processing of footprints using two state-of-the-art footprinting algorithms: Wellington and HINT. Our workflow scans the footprints generated by these algorithms for 1,530 sequence motifs to predict binding sites for 1,515 human transcription factors. We applied our workflow to detect footprints in 192 DNase-seq experiments from ENCODE spanning 27 human tissues. This collection of footprints describes an expansive landscape of potential TF occupancy. At thresholds optimized through machine learning, we report high-quality footprints covering 9.8% of the human genome. These footprints were enriched for true positive TF binding sites as defined by ChIP-seq peaks, as well as for genetic variants associated with changes in gene expression. Integrating our footprint atlas with summary statistics from genome-wide association studies revealed that risk for neuropsychiatric traits was enriched specifically at highly-scoring footprints in human brain, while risk for immune traits was enriched specifically at highly-scoring footprints in human lymphoblasts. Our cloud-based workflow is available at github.com/globusgenomics/genomics-footprint and a database with all footprints and TF binding site predictions are publicly available at http://data.nemoarchive.org/other/grant/sament/sament/footprint_atlas.

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Genetics of fetal hemoglobin in Tanzanian and British patients with sickle cell anemia

Blood ◽

10.1182/blood-2010-08-302703 ◽

2011 ◽

Vol 117 (4) ◽

pp. 1390-1392 ◽

Cited By ~ 68

Author(s):

Julie Makani ◽

Stephan Menzel ◽

Siana Nkya ◽

Sharon E. Cox ◽

Emma Drasar ◽

...

Keyword(s):

African Diaspora ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Association Studies ◽

Fetal Hemoglobin ◽

Genome Wide Association Studies ◽

Genome Wide ◽

African Populations ◽

Patient Groups ◽

Chromosome 11P

Abstract Fetal hemoglobin (HbF, α2γ2) is a major contributor to the remarkable phenotypic heterogeneity of sickle cell anemia (SCA). Genetic variation at 3 principal loci (HBB cluster on chromosome 11p, HBS1L-MYB region on chromosome 6q, and BCL11A on chromosome 2p) have been shown to influence HbF levels and disease severity in β-thalassemia and SCA. Previous studies in SCA, however, have been restricted to populations from the African diaspora, which include multiple genealogies. We have investigated the influence of these 3 loci on HbF levels in sickle cell patients from Tanzania and in a small group of African British sickle patients. All 3 loci have a significant impact on the trait in both patient groups. The results suggest the presence of HBS1L-MYB variants affecting HbF in patients who are not tracked well by European-derived markers, such as rs9399137. Additional loci may be identified through independent genome-wide association studies in African populations.

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Genome-wide association studies of 74 plasma metabolites of German shepherd dogs reveal two metabolites associated with genes encoding their enzymes

Metabolomics ◽

10.1007/s11306-019-1586-2 ◽

2019 ◽

Vol 15 (9) ◽

Cited By ~ 2

Author(s):

Pamela Xing Yi Soh ◽

Juliana Maria Marin Cely ◽

Sally-Anne Mortlock ◽

Christopher James Jara ◽

Rachel Booth ◽

...

Keyword(s):

Association Studies ◽

Genome Wide Association ◽

Plasma Metabolites ◽

Genome Wide Association Studies ◽

German Shepherd ◽

Genome Wide ◽

Genes Encoding

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Comparison of IL-33 and IL-5 Family Mediated Activation of Human Eosinophils

10.1101/645275 ◽

2019 ◽

Author(s):

Evelyn L. Angulo ◽

Elizabeth M. McKernan ◽

Paul S. Fichtinger ◽

Sameer K. Mathur

Keyword(s):

Association Studies ◽

Hypereosinophilic Syndrome ◽

Surface Protein ◽

Genome Wide Association Studies ◽

Direct Role ◽

Cytokines And Chemokines ◽

Genome Wide ◽

Genes Encoding ◽

Surface Protein Expression

ABSTRACTEosinophils are the prominent inflammatory cell involved in allergic asthma, atopic dermatitis, eosinophilic esophagitis, and hypereosinophilic syndrome and are found in high numbers in local tissue and/or circulating blood of affected patients. There is recent interest in a family of alarmins, including TSLP, IL-25 and IL-33, that are epithelial-derived and released upon stimulation of epithelial cells. Several genome wide association studies have found SNPs in genes encoding IL-33 to be risk factors for asthma. In two studies examining the direct role of IL-33 in eosinophils, there were differences in eosinophil responses. We sought to further characterize activation of eosinophils with IL-33 compared to activation by other cytokines and chemokines. We assessed IL-33 stimulated adhesion, degranulation, chemotaxis and cell surface protein expression in comparison to IL-3, IL-5, and eotaxin-1 on human eosinophils. Our results demonstrate that IL-33 can produce as potent or more eosinophil activation than IL-3, IL-5 and eotaxin-1. Thus, when considering specific cytokine targeting strategies, IL-33 will be important to consider for modulating eosinophil function.

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