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American Family Physician Aug 2009The thalassemias are a group of inherited hematologic disorders caused by defects in the synthesis of one or more of the hemoglobin chains. Alpha thalassemia is caused... (Review)
Review
The thalassemias are a group of inherited hematologic disorders caused by defects in the synthesis of one or more of the hemoglobin chains. Alpha thalassemia is caused by reduced or absent synthesis of alpha globin chains, and beta thalassemia is caused by reduced or absent synthesis of beta globin chains. Imbalances of globin chains cause hemolysis and impair erythropoiesis. Silent carriers of alpha thalassemia and persons with alpha or beta thalassemia trait are asymptomatic and require no treatment. Alpha thalassemia intermedia, or hemoglobin H disease, causes hemolytic anemia. Alpha thalassemia major with hemoglobin Bart's usually results in fatal hydrops fetalis. Beta thalassemia major causes hemolytic anemia, poor growth, and skeletal abnormalities during infancy. Affected children will require regular lifelong blood transfusions. Beta thalassemia intermedia is less severe than beta thalassemia major and may require episodic blood transfusions. Transfusion-dependent patients will develop iron overload and require chelation therapy to remove the excess iron. Bone marrow transplants can be curative for some children with beta thalassemia major. Persons with thalassemia should be referred for preconception genetic counseling, and persons with alpha thalassemia trait should consider chorionic villus sampling to diagnose infants with hemoglobin Bart's, which increases the risk of toxemia and postpartum bleeding. Persons with the thalassemia trait have a normal life expectancy. Persons with beta thalassemia major often die from cardiac complications of iron overload by 30 years of age.
Topics: Blood Transfusion; Bone Marrow Transplantation; Chelation Therapy; Erythrocyte Indices; Erythropoiesis; Hemoglobins; Humans; alpha-Thalassemia; beta-Thalassemia
PubMed: 19678601
DOI: No ID Found -
Blood Nov 2020Fetal hemoglobin (HbF) can blunt the pathophysiology, temper the clinical course, and offer prospects for curative therapy of sickle cell disease. This review focuses on... (Review)
Review
Fetal hemoglobin (HbF) can blunt the pathophysiology, temper the clinical course, and offer prospects for curative therapy of sickle cell disease. This review focuses on (1) HbF quantitative trait loci and the geography of β-globin gene haplotypes, especially those found in the Middle East; (2) how HbF might differentially impact the pathophysiology and many subphenotypes of sickle cell disease; (3) clinical implications of person-to-person variation in the distribution of HbF among HbF-containing erythrocytes; and (4) reactivation of HbF gene expression using both pharmacologic and cell-based therapeutic approaches. A confluence of detailed understanding of the molecular basis of HbF gene expression, coupled with the ability to precisely target by genomic editing most areas of the genome, is producing important preliminary therapeutic results that could provide new options for cell-based therapeutics with curative intent.
Topics: Anemia, Sickle Cell; Fetal Hemoglobin; Gene Editing; Gene Expression Regulation; Gene Knockdown Techniques; Genetic Therapy; Genetic Vectors; Haplotypes; Humans; Hydroxyurea; Lentivirus; Microfilament Proteins; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins c-myb; Quantitative Trait Loci; RNA Interference; RNA, Small Interfering; Receptors, Cell Surface; Repressor Proteins; Stroke; beta-Globins; gamma-Globins
PubMed: 32808012
DOI: 10.1182/blood.2020007645 -
Orphanet Journal of Rare Diseases May 2010Alpha-thalassaemia is inherited as an autosomal recessive disorder characterised by a microcytic hypochromic anaemia, and a clinical phenotype varying from almost... (Review)
Review
Alpha-thalassaemia is inherited as an autosomal recessive disorder characterised by a microcytic hypochromic anaemia, and a clinical phenotype varying from almost asymptomatic to a lethal haemolytic anaemia.It is probably the most common monogenic gene disorder in the world and is especially frequent in Mediterranean countries, South-East Asia, Africa, the Middle East and in the Indian subcontinent. During the last few decades the incidence of alpha thalassaemia in North-European countries and Northern America has increased because of demographic changes. Compound heterozygotes and some homozygotes have a moderate to severe form of alpha thalassaemia called HbH disease. Hb Bart's hydrops foetalis is a lethal form in which no alpha-globin is synthesized. Alpha thalassaemia most frequently results from deletion of one or both alpha genes from the chromosome and can be classified according to its genotype/phenotype correlation. The normal complement of four functional alpha-globin genes may be decreased by 1, 2, 3 or all 4 copies of the genes, explaining the clinical variation and increasing severity of the disease. All affected individuals have a variable degree of anaemia (low Hb), reduced mean corpuscular haemoglobin (MCH/pg), reduced mean corpuscular volume (MCV/fl) and a normal/slightly reduced level of HbA2. Molecular analysis is usually required to confirm the haematological observations (especially in silent alpha-thalassaemia and alpha-thalassaemia trait). The predominant features in HbH disease are anaemia with variable amounts of HbH (0.8-40%). The type of mutation influences the clinical severity of HbH disease. The distinguishing features of the haemoglobin Bart's hydrops foetalis syndrome are the presence of Hb Bart's and the total absence of HbF. The mode of transmission of alpha thalassaemia is autosomal recessive. Genetic counselling is offered to couples at risk for HbH disease or haemoglobin Bart's Hydrops Foetalis Syndrome. Carriers of alpha+- or alpha0-thalassaemia alleles generally do not need treatment. HbH patients may require intermittent transfusion therapy especially during intercurrent illness. Most pregnancies in which the foetus is known to have the haemoglobin Bart's hydrops foetalis syndrome are terminated due to the increased risk of both maternal and foetal morbidity.
Topics: Gene Deletion; Hemoglobins, Abnormal; Humans; Mutation; alpha-Globins; alpha-Thalassemia
PubMed: 20507641
DOI: 10.1186/1750-1172-5-13 -
British Journal of Haematology Apr 2016Red blood cells (RBCs) are generated from haematopoietic stem and progenitor cells (HSPCs) through the step-wise process of differentiation known as erythropoiesis. In... (Review)
Review
Red blood cells (RBCs) are generated from haematopoietic stem and progenitor cells (HSPCs) through the step-wise process of differentiation known as erythropoiesis. In this review, we discuss our current understanding of erythropoiesis and highlight recent advances in this field. During embryonic development, erythropoiesis occurs in three distinct waves comprising first, the yolk sac-derived primitive RBCs, followed sequentially by the erythro-myeloid progenitor (EMP) and HSPC-derived definitive RBCs. Recent work has highlighted the complexity and variability that may exist in the hierarchical arrangement of progenitors responsible for erythropoiesis. Using recently defined cell surface markers, it is now possible to enrich for erythroid progenitors and precursors to a much greater extent than has been possible before. While a great deal of knowledge has been gained on erythropoiesis from model organisms, our understanding of this process is currently being refined through human genetic studies. Genes mutated in erythroid disorders can now be identified more rapidly by the use of next-generation sequencing techniques. Genome-wide association studies on erythroid traits in healthy populations have also revealed new modulators of erythropoiesis. All of these recent developments have significant promise not only for increasing our understanding of erythropoiesis, but also for improving our ability to intervene when RBC production is perturbed in disease.
Topics: Animals; Cell Communication; Cell Differentiation; Embryonic Development; Erythropoiesis; Hematologic Diseases; Hematopoietic Stem Cells; Hemoglobins; Heterografts; Humans; Mice; Models, Biological; Transcription, Genetic; Zebrafish
PubMed: 26846448
DOI: 10.1111/bjh.13938 -
Investigative Ophthalmology & Visual... Mar 2023Little is known about whether sugar intake is a risk factor for myopia, and the influence of glycemic control remains unclear, with inconsistent results reported. This...
PURPOSE
Little is known about whether sugar intake is a risk factor for myopia, and the influence of glycemic control remains unclear, with inconsistent results reported. This study aimed to clarify this uncertainty by evaluating the link between multiple glycemic traits and myopia.
METHODS
We employed a two-sample Mendelian randomization (MR) design using summary statistics from independent genome-wide association studies. A total of six glycemic traits, including adiponectin, body mass index, fasting blood glucose, fasting insulin, hemoglobin A1c (HbA1c), and proinsulin levels, were used as exposures, and myopia was used as the outcome. The inverse-variance-weighted (IVW) method was the main applied analytic tool and was complemented with comprehensive sensitivity analyses.
RESULTS
Out of the six glycemic traits studied, we found that adiponectin was significantly associated with myopia. The genetically predicted level of adiponectin was consistently negatively associated with myopia incidence: IVW (odds ratio [OR] = 0.990; P = 2.66 × 10-3), MR Egger (OR = 0.983; P = 3.47 × 10-3), weighted median method (OR = 0.989; P = 0.01), and weighted mode method (OR = 0.987; P = 0.01). Evidence from all sensitivity analyses further supported these associations. In addition, a higher HbA1c level was associated with a greater risk of myopia: IVW (OR = 1.022; P = 3.06 × 10-5).
CONCLUSIONS
Genetic evidence shows that low adiponectin levels and high HbA1c are associated with an increased risk of myopia. Given that physical activity and sugar intake are controllable variables in blood glycemia treatment, these findings provide new insights into potential strategies to delay myopia onset.
Topics: Humans; Adiponectin; Genome-Wide Association Study; Glycated Hemoglobin; Myopia; Sugars
PubMed: 36867130
DOI: 10.1167/iovs.64.3.7 -
Diabetes Care Apr 2022To examine the effects of sleep traits on glycated hemoglobin (HbA1c).
OBJECTIVE
To examine the effects of sleep traits on glycated hemoglobin (HbA1c).
RESEARCH DESIGN AND METHODS
This study triangulated evidence across multivariable regression (MVR) and one- (1SMR) and two-sample Mendelian randomization (2SMR) including sensitivity analyses on the effects of five self-reported sleep traits (i.e., insomnia symptoms [difficulty initiating or maintaining sleep], sleep duration, daytime sleepiness, napping, and chronotype) on HbA1c (in SD units) in adults of European ancestry from the UK Biobank (for MVR and 1SMR analyses) (n = 336,999; mean [SD] age 57 [8] years; 54% female) and in the genome-wide association studies from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) (for 2SMR analysis) (n = 46,368; 53 [11] years; 52% female).
RESULTS
Across MVR, 1SMR, 2SMR, and their sensitivity analyses, we found a higher frequency of insomnia symptoms (usually vs. sometimes or rarely/never) was associated with higher HbA1c (MVR 0.05 SD units [95% CI 0.04-0.06]; 1SMR 0.52 [0.42-0.63]; 2SMR 0.24 [0.11-0.36]). Associations remained, but point estimates were somewhat attenuated after excluding participants with diabetes. For other sleep traits, there was less consistency across methods, with some but not all providing evidence of an effect.
CONCLUSIONS
Our results suggest that frequent insomnia symptoms cause higher HbA1c levels and, by implication, that insomnia has a causal role in type 2 diabetes. These findings could have important implications for developing and evaluating strategies that improve sleep habits to reduce hyperglycemia and prevent diabetes.
Topics: Adult; Diabetes Mellitus, Type 2; Female; Genome-Wide Association Study; Glycated Hemoglobin; Humans; Male; Mendelian Randomization Analysis; Middle Aged; Sleep; Sleep Initiation and Maintenance Disorders
PubMed: 35349659
DOI: 10.2337/dc21-0089 -
European Journal of Epidemiology Sep 2022Age at natural menopause (ANM) is associated with a range of health-related traits, including bone health, female reproductive cancers, and cardiometabolic health. Our...
Age at natural menopause (ANM) is associated with a range of health-related traits, including bone health, female reproductive cancers, and cardiometabolic health. Our objective was to conduct a Mendelian randomization phenome-wide association study (MR-pheWAS) of ANM. We conducted a hypothesis-free analysis of the genetic risk score (GRS) for ANM with 18,961 health-related traits among 181,279 women in UK Biobank. We also stratified the GRS according to the involvement of SNPs in DNA damage response. We sought to replicate our findings in independent cohorts. We conducted a negative control MR-pheWAS among men. Among women, we identified potential effects of ANM on 221 traits (1.17% of all traits) at a false discovery rate (P value ≤ 5.83 × 10), and 91 (0.48%) potential effects when using Bonferroni threshold (P value ≤ 2.64 × 10). Our findings included 55 traits directly related to ANM (e.g. hormone replacement therapy, gynaecological conditions and menstrual conditions), and liver function, kidney function, lung function, blood-cell composition, breast cancer and bone and cardiometabolic health. Replication analyses confirmed that younger ANM was associated with HbA1c (adjusted mean difference 0.003 mmol/mol; 95% CI 0.001, 0.006 per year decrease in ANM), breast cancer (adjusted OR 0.96; 95% CI 0.95, 0.98), and bone-mineral density (adjusted mean difference - 0.05; 95% CI - 0.07, - 0.03 for lumbar spine). In men, 30 traits were associated with the GRS at a false discovery rate (P value ≤ 5.49 × 10), and 11 potential effects when using Bonferroni threshold (P value ≤ 2.75 × 10). In conclusion, our results suggest that younger ANM has potential causal effects on a range of health-related traits.
Topics: Breast Neoplasms; Cardiovascular Diseases; Female; Genome-Wide Association Study; Glycated Hemoglobin; Humans; Male; Mendelian Randomization Analysis; Menopause; Minerals; Polymorphism, Single Nucleotide
PubMed: 36057072
DOI: 10.1007/s10654-022-00903-3 -
Journal of Applied Physiology... Nov 2017High altitudes (>8,000 ft or 2,500 m) provide an experiment of nature for measuring adaptation and the physiological processes involved. Studies conducted over the past... (Review)
Review
High altitudes (>8,000 ft or 2,500 m) provide an experiment of nature for measuring adaptation and the physiological processes involved. Studies conducted over the past ~25 years in Andeans, Tibetans, and, less often, Ethiopians show varied but distinct O transport traits from those of acclimatized newcomers, providing indirect evidence for genetic adaptation to high altitude. Short-term (acclimatization, developmental) and long-term (genetic) responses to high altitude exhibit a temporal gradient such that, although all influence O content, the latter also improve O delivery and metabolism. Much has been learned concerning the underlying physiological processes, but additional studies are needed on the regulation of blood flow and O utilization. Direct evidence of genetic adaptation comes from single-nucleotide polymorphism (SNP)-based genome scans and whole genome sequencing studies that have identified gene regions acted upon by natural selection. Efforts have begun to understand the connections between the two with Andean studies on the genetic factors raising uterine blood flow, fetal growth, and susceptibility to Chronic Mountain Sickness and Tibetan studies on genes serving to lower hemoglobin and pulmonary arterial pressure. Critical for future studies will be the selection of phenotypes with demonstrable effects on reproductive success, the calculation of actual fitness costs, and greater inclusion of women among the subjects being studied. The well-characterized nature of the O transport system, the presence of multiple long-resident populations, and relevance for understanding hypoxic disorders in all persons underscore the importance of understanding how evolutionary adaptation to high altitude has occurred. Variation in O transport characteristics among Andean, Tibetan, and, when available, Ethiopian high-altitude residents supports the existence of genetic adaptations that improve the distribution of blood flow to vital organs and the efficiency of O utilization. Genome scans and whole genome sequencing studies implicate a broad range of gene regions. Future studies are needed using phenotypes of clear relevance for reproductive success for determining the mechanisms by which naturally selected genes are acting.
Topics: Acclimatization; Altitude; Arterial Pressure; Ethiopia; Hemoglobins; Humans; Hypoxia; Oxygen; Phenotype; Polymorphism, Single Nucleotide; Selection, Genetic; South America; Tibet
PubMed: 28860167
DOI: 10.1152/japplphysiol.00321.2017 -
Current Opinion in Hematology May 2017The discovery of several genetic variants associated with erythroid traits and subsequent elucidation of their functional mechanisms are exemplars of the power of the... (Review)
Review
PURPOSE OF REVIEW
The discovery of several genetic variants associated with erythroid traits and subsequent elucidation of their functional mechanisms are exemplars of the power of the new genetic and genomic technology. The present review highlights findings from recent genetic studies related to the control of erythropoiesis and dyserythropoiesis, and fetal hemoglobin, an erythroid-related trait.
RECENT FINDINGS
Identification of the genetic modulators of erythropoiesis involved two approaches: genome-wide association studies (GWASs) using single nucleotide polymorphism (SNP) arrays that revealed the common genetic variants associated with erythroid phenotypes (hemoglobin, red cell count, MCV, MCH) and fetal hemoglobin; and massive parallel sequencing such as whole genome sequencing (WGS) and whole exome sequencing (WES) that led to the discovery of the rarer variants (GFI1B, SBDS, RPS19, PKLR, EPO, EPOR, KLF1, GATA1). Functional and genomic studies aided by computational approaches and gene editing technology refined the regions encompassing the putative causative SNPs and confirmed their regulatory role at different stages of erythropoiesis.
SUMMARY
Five meta-analysis of GWASs identified 17 genetic loci associated with erythroid phenotypes, which are potential regulators of erythropoiesis. Some of these loci showed pleiotropy associated with multiple erythroid traits, suggesting undiscovered molecular mechanisms and challenges underlying erythroid biology. Other sequencing strategies (WGS and WES) further elucidated the role of rare variants in dyserythropoiesis. Integration of common and rare variant studies with functional assays involving latest genome-editing technologies will significantly improve our understanding of the genetics underlying erythropoiesis and erythroid disorders.
Topics: Animals; Biomarkers; Cell Differentiation; Erythropoiesis; Gene Expression Regulation; Genetic Variation; Genome-Wide Association Study; Hematopoietic Stem Cells; Hemoglobins; Humans; Megakaryocyte-Erythroid Progenitor Cells; Quantitative Trait Loci; Quantitative Trait, Heritable
PubMed: 28212192
DOI: 10.1097/MOH.0000000000000333 -
Journal of Diabetes and Its... Jul 2022A high hemoglobin glycation index (HGI) has been repeatedly associated with greater risk for hypoglycemia in people with diabetes and greater risk for chronic vascular... (Review)
Review
A high hemoglobin glycation index (HGI) has been repeatedly associated with greater risk for hypoglycemia in people with diabetes and greater risk for chronic vascular disease in people with or without diabetes. This review explores how different sources of analytical and biological variation in HbA1c and blood glucose individually and collectively affect the clinical information value of HGI. We conclude that HGI is a complex quantitative trait that is a clinically practical biomarker of risk for both hypoglycemia and chronic vascular disease.
Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Hemoglobins; Humans; Hypoglycemia; Vascular Diseases
PubMed: 35667965
DOI: 10.1016/j.jdiacomp.2022.108223