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Molecular Genetics and Metabolism... Jun 2024Our study evaluated the association of the polymorphism rs724016 in the gene, previously associated with height in other populations, with predictors of height,...
OBJECTIVES
Our study evaluated the association of the polymorphism rs724016 in the gene, previously associated with height in other populations, with predictors of height, clinical outcomes, and laboratory parameters in sickle cell anemia (SCA).
METHODS
Cross-sectional study with individuals with SCA and aged between 3 and 20 years. Clinical, laboratory, molecular, and bone age (BA) data were evaluated. Levels of IGF-1 and IGFBP-3 were adjusted for BA, target height (TH) was calculated as the mean parental height standard deviation score (SDS), and predicted adult height (PAH) SDS was calculated using BA.
RESULTS
We evaluated 80 individuals with SCA. The homozygous genotype of the G allele of rs724016 was associated with a lower height SDS ( < 0.001) and, in a additive genetic model, was negatively associated with HbF levels ( = 0.016). Lower adjusted IGF-1 levels were associated with co-inheritance of alpha-thalassemia and with the absence of HU therapy. Elevated HbF levels were associated with a lower deficit in adjusted growth potential (TH minus PAH).
CONCLUSION
Our analysis shows that SNP rs724016 in the is associated with shorter height and lower HbF levels, an important modifier of SCA.
PubMed: 38800625
DOI: 10.1016/j.ymgmr.2024.101086 -
International Journal of Molecular... May 2024Sickle cell nephropathy (SCN) is a common complication of sickle cell disease (SCD) that significantly contributes to morbidity and mortality. In addition to clinical... (Review)
Review
Sickle cell nephropathy (SCN) is a common complication of sickle cell disease (SCD) that significantly contributes to morbidity and mortality. In addition to clinical and life-style factors, genetic variants influence this risk. We performed a systematic review, searching five databases. Studies evaluating the effect of genetic modifiers on SCN were eligible. Twenty-eight studies (fair-to-good quality) were included: one genome-wide association study, twenty-six case-control studies, and one article combining both approaches. was significantly associated with albuminuria and hyperfiltration in children and with worse glomerular filtration in adults. On the other hand, alpha-thalassemia protected patients against albuminuria and hyperfiltration, while variants were protective against albuminuria alone. The long GT-tandem repeat polymorphism led to a lower glomerular filtration rate. No modifiers for the risk of hyposthenuria were identified. A genome-wide association approach identified three new loci for proteinuria (, , and ) and nine loci were linked with eGFR (, , , , , , , , and ). In conclusion, this systematic review supports the role of genetic modifiers in influencing the risk and progression of SCN. Incorporating and expanding this knowledge is crucial to improving the management and clinical outcomes of patients at risk.
Topics: Humans; Anemia, Sickle Cell; Genome-Wide Association Study; Genetic Predisposition to Disease; Kidney Diseases; Apolipoprotein L1; Disease Progression; Genes, Modifier; Glomerular Filtration Rate
PubMed: 38791464
DOI: 10.3390/ijms25105427 -
BioRxiv : the Preprint Server For... May 2024Alpha-thalassemia is an autosomal recessive disease with increasing worldwide prevalence. The molecular basis is due to mutation or deletion of one or more duplicated...
Alpha-thalassemia is an autosomal recessive disease with increasing worldwide prevalence. The molecular basis is due to mutation or deletion of one or more duplicated α-globin genes, and disease severity is directly related to the number of allelic copies compromised. The most severe form, α-thalassemia major (αTM), results from loss of all four copies of α-globin and has historically resulted in fatality . However, transfusions now enable survival to birth. Postnatally, patients face challenges similar to β-thalassemia, including severe anemia and erythrotoxicity due to imbalance of β-globin and α-globin chains. While curative, hematopoietic stem cell transplantation (HSCT) is limited by donor availability and potential transplant-related complications. Despite progress in genome editing treatments for β-thalassemia, there is no analogous curative option for patients suffering from α-thalassemia. To address this, we designed a novel Cas9/AAV6-mediated genome editing strategy that integrates a functional α-globin gene into the β-globin locus in αTM patient-derived hematopoietic stem and progenitor cells (HSPCs). Incorporation of a truncated erythropoietin receptor transgene into the α-globin integration cassette dramatically increased erythropoietic output from edited HSPCs and led to the most robust production of α-globin, and consequently normal hemoglobin. By directing edited HSPCs toward increased production of clinically relevant RBCs instead of other divergent cell types, this approach has the potential to mitigate the limitations of traditional HSCT for the hemoglobinopathies, including low genome editing and low engraftment rates. These findings support development of a definitive autologous genome editing strategy that may be curative for α-thalassemia.
PubMed: 38766216
DOI: 10.1101/2023.09.01.555926 -
HemaSphere May 2024α-Thalassemia represents one of the most important genetic modulators of β-hemoglobinopathies. During this last decade, the ongoing interest in characterizing...
α-Thalassemia represents one of the most important genetic modulators of β-hemoglobinopathies. During this last decade, the ongoing interest in characterizing genotype-phenotype relationships has yielded incredible insights into α-globin gene regulation and its impact on β-hemoglobinopathies. In this review, we provide a holistic update on α-globin gene expression stemming from DNA to RNA to protein, as well as epigenetic mechanisms that can impact gene expression and potentially influence phenotypic outcomes. Here, we highlight defined α-globin targeted strategies and rationalize the use of distinct molecular targets based on the restoration of balanced α/β-like globin chain synthesis. Considering the therapies that either increase β-globin synthesis or reactivate γ-globin gene expression, the modulation of α-globin chains as a disease modifier for β-hemoglobinopathies still remains largely uncharted in clinical studies.
PubMed: 38752170
DOI: 10.1002/hem3.78 -
BMC Pediatrics May 2024Thalassemias represent some of the most common monogenic diseases worldwide and are caused by variations in human hemoglobin genes which disrupt the balance of synthesis...
BACKGROUND
Thalassemias represent some of the most common monogenic diseases worldwide and are caused by variations in human hemoglobin genes which disrupt the balance of synthesis between the alpha and beta globin chains. Thalassemia gene detection technology is the gold standard to achieve accurate detection of thalassemia, but in clinical practice, most of the tests are only for common genotypes, which can easily lead to missing or misdiagnosis of rare thalassemia genotypes.
CASE PRESENTATION
We present the case of an 18-year-old Chinese female with abnormal values of routine hematological indices who was admitted for genetic screening for thalassemia. Genomic DNA was extracted and used for the genetic assays. Gap polymerase chain reaction and agarose gel electrophoresis were performed to detect HBA gene deletions, while PCR-reverse dot blot hybridization was used to detect point mutations in the HBA and HBB genes. Next-generation sequencing and third-generation sequencing (TGS) were used to identify known and potentially novel genotypes of thalassemia. We identified a novel complex variant ααα/-α in a patient with rare alpha-thalassemia.
CONCLUSIONS
Our study identified a novel complex variant that expands the thalassemia gene variants spectrum. Meanwhile, the study suggests that TGS could effectively improve the specificity of thalassemia gene detection, and has promising potential for the discovery of novel thalassemia genotypes, which could also improve the accuracy of genetic counseling. Couples who are thalassemia carriers have the opportunity to reduce their risk of having a child with thalassemia.
Topics: Humans; alpha-Thalassemia; Female; Adolescent; High-Throughput Nucleotide Sequencing; Genotype; Genetic Testing; Point Mutation; Hemoglobins, Abnormal
PubMed: 38741052
DOI: 10.1186/s12887-024-04811-1 -
BMC Veterinary Research May 2024Hydrops fetalis (HF) is fluid accumulation in fetus body cavities and subcutaneous tissue. The condition has been described in various farm and companion animal species,...
BACKGROUND
Hydrops fetalis (HF) is fluid accumulation in fetus body cavities and subcutaneous tissue. The condition has been described in various farm and companion animal species, including dogs. Most of cases result from a heart defect. Exact nature of this defect is rarely clarified.
CASE PRESENTATION
A newborn, male French bulldog puppy with severe HF underwent a full anatomopathological examination to diagnose the primary cause of HF. Based on the anatomopathological examination, fetal ultrasound, and micro-computed tomography, transposition of the great arteries with hypoplasia of the ascending aorta, aortic arch interruption, ostium secundum atrial septal defect, severe tricuspid valve dysplasia, as well as hypoplasia of pulmonary vessels and lungs were diagnosed.
CONCLUSIONS
This is the first report of HF caused by severe, complex congenital heart defects with concurrent pulmonary vessel and lung hypoplasia.
Topics: Animals; Hydrops Fetalis; Male; Lung; Dog Diseases; Dogs; Heart Defects, Congenital; X-Ray Microtomography; Animals, Newborn
PubMed: 38734649
DOI: 10.1186/s12917-024-04060-5 -
Journal of Clinical Medicine Apr 2024: in β-thalassemia, important clinical complications are caused by the presence of free α-globin chains in the erythroid cells of β-thalassemia patients. These free...
Increased Expression of α-Hemoglobin Stabilizing Protein (AHSP) mRNA in Erythroid Precursor Cells Isolated from β-Thalassemia Patients Treated with Sirolimus (Rapamycin).
: in β-thalassemia, important clinical complications are caused by the presence of free α-globin chains in the erythroid cells of β-thalassemia patients. These free α-globin chains are present in excess as a result of the lack of β-globin chains to bind with; they tend to aggregate and precipitate, causing deleterious effects and overall cytotoxicity, maturation arrest of the erythroid cells and, ultimately, ineffective erythropoiesis. The chaperone protein α-hemoglobin-stabilizing protein (AHSP) reversibly binds with free α-globin; the resulting AHSP-αHb complex prevents aggregation and precipitation. Sirolimus (rapamycin) has been previously demonstrated to induce expression of fetal hemoglobin and decrease the excess of free α-globin chain in the erythroid cells of β-thalassemia patients. The objective of this study was to verify whether sirolimus is also able to upregulate AHSP expression in erythroid precursor cells (ErPCs) isolated from β-thalassemia patients. the expression of AHSP genes was analyzed by measuring the AHSP mRNA content by real-time quantitative PCR (RT-qPCR) and the AHSP protein production by Western blotting. AHSP gene expression was found to be higher in ErPCs of β-thalassemia patients in comparison to ErPCs isolated from healthy subjects. In addition, AHSP expression was further induced by treatment of β-thalassemia ErPCs with sirolimus. Finally, AHSP mRNA was expressed at an increased level in ErPCs of sirolimus-treated β-thalassemia patients participating in the NCT03877809 Sirthalaclin clinical trial. this exploratory study suggests that AHSP expression should be considered as an endpoint in clinical trials based on sirolimus.
PubMed: 38731008
DOI: 10.3390/jcm13092479 -
The American Journal of Case Reports May 2024BACKGROUND Thalassemia and hemoglobin (Hb) variants are the most common hereditary red blood cell disorders worldwide. Alpha-thalassemia and alpha-globin variants are...
BACKGROUND Thalassemia and hemoglobin (Hb) variants are the most common hereditary red blood cell disorders worldwide. Alpha-thalassemia and alpha-globin variants are caused by mutations of the alpha-globin genes (HBA2 and HBA1), resulting in impaired alpha-globin production and structurally abnormal globin, respectively. Clinical severity of alpha-thalassemia correlates with the number of affected alpha-globin genes, yielding a spectrum of clinical manifestations from mild to severe anemia. Routine diagnosis involves Hb analysis and PCR-based methods, yet identifying rare variants necessitates comprehensive clinical and hematologic laboratory data. The knowledge of phenotype and genotype correlation is useful for genetic counseling and treatment planning. CASE REPORT A 59-year-old Thai woman presented with chronic anemia. Her baseline Hb level ranged between 8.0 and 9.0 g/dL, with no history of transfusion. Physical examination showed mild pallor, without enlarged liver and spleen. Laboratory investigations showed microcytic, hypochromic anemia and abnormal Hb peak by Hb analysis (retention time 4.58 min by HPLC method). Common alpha-globin gene deletions, including the Southeast-Asian/Thai 3.7 kb and 4.2 kb deletions were tested using gap-PCR, with none of these deletions detected. Direct DNA sequencing revealed a compound heterozygosity of Hb Jax (HBA2: c.44G>C) and Hb Constant Spring (HBA2: c.427T>C). CONCLUSIONS Compound heterozygosity of Hb Jax and Hb Constant Spring results in microcytic anemia. Hb Jax can be identified by Hb analysis, and diagnosis can be confirmed by direct DNA sequencing method. Coinheritance of Hb Jax and alpha-globin variants should be considered in cases with microcytic anemia and a specific Hb peak seen in Hb chromatogram.
Topics: Humans; Female; Hemoglobins, Abnormal; Middle Aged; Anemia, Hypochromic; alpha-Thalassemia; alpha-Globins
PubMed: 38725231
DOI: 10.12659/AJCR.943560 -
Anemia 2024Anemia, a global health concern, affects one-fourth of the global population, particularly women. In Indonesia, its prevalence is 23.7%, with 32.0% among 15-24...
BACKGROUND
Anemia, a global health concern, affects one-fourth of the global population, particularly women. In Indonesia, its prevalence is 23.7%, with 32.0% among 15-24 year-olds. Factors include poor nutrition, infectious diseases, chronic diseases, inherited disorders, and inadequate healthcare access. This study aimed to investigate anemia prevalence and its etiology among medical students from Jakarta.
METHODS
This study was a descriptive research with a cross-sectional approach. Undergraduate students aged 18-23 years old were selected and consented to participate by a consecutive nonrandom sampling methods. Laboratory blood data were evaluated (including Hb, MCV, MCH, HbA, and ferritin levels) and DNA was isolated to confirm the type of thalassemia carrier.
RESULTS
In total, 140 medical students, mainly female, were recruited. Anemia was found in 13.6% (11.4% had low MCV and/or MCH), and 16.5% had low MCV and/or MCH without anemia. Hb electrophoresis revealed high HbA values, suggesting the HbE variant (2.1%), and -thalassemia carrier (0.7%). DNA analysis confirmed the cd26 mutation and heterozygous IVS1nt5. Among those without anemia, 5% had , while in the group with anemia, 1.4% had (with coexistent IDA), 3.6% had , and 0.7% had .
CONCLUSION
DNA analysis can identify specific mutations associated with alpha-thalassemia, distinguishing between iron deficiency anemia and the alpha-thalassemia trait. Thalassemia screening should involve low MCV and/or MCH values as the first step (stage 1), followed by Hb analysis (stage 2) and DNA analysis (stage 3). In common areas, a combination of Hb and DNA testing is best. However, healthcare professionals must diagnose and treat thalassemia, as proper management relies on accurately identifying the underlying condition.
PubMed: 38716362
DOI: 10.1155/2024/4215439