Regulatory Single Nucleotide Polymorphism rs368698783 (G>A): a Genetic Modifier of Hb F Production Only under Erythropoietic Stress Characteristic for β-Globin Chain Deficiency?
TL;DR: A regulatory single nucleotide polymorphism (rSNP) located in the HBG1 proximal promoter, the Aγ (+25 G>A) is a significant predictor of clinical severity by elevating Hb F levels in β-thalassemia (β-thal).
Abstract: A regulatory single nucleotide polymorphism (rSNP), the Aγ (+25 G>A) (rs368698783) (NG_000007.3: g47783G>A) located in the HBG1 proximal promoter, is a significant predictor of clinical sev...
Citations
More filters
TL;DR: In this article , the effects of different types of β-globin gene mutations, coinheritance with αglobin genes mutations, XmnI-Gγ, and rs368698783 polymorphisms on the β-thalassemia phenotypes in Sabahan patients were investigated.
Abstract: Abstract β-thalassemia is a serious public health problem in Sabah due to its high prevalence. This study aimed to investigate the effects of different types of β-globin gene mutations, coinheritance with α-globin gene mutations, XmnI-Gγ, and rs368698783 polymorphisms on the β-thalassemia phenotypes in Sabahan patients. A total of 111 patients were included in this study. The sociodemographic profile of the patients was collected using a semi-structured questionnaire, while clinical data were obtained from their medical records. Gap-PCR, ARMS-PCR, RFLP-PCR, and multiplex PCR were performed to detect β- and α-globin gene mutations, as well as XmnI-Gγ and rs368698783 polymorphisms. Our data show that the high prevalence of β-thalassemia in Sabah is not due to consanguineous marriages (5.4%). A total of six different β-globin gene mutations were detected, with Filipino β°-deletion being the most dominant (87.4%). There were 77.5% homozygous β-thalassemia patients, 16.2% compound heterozygous β-thalassemia patients, and 6.3% β-thalassemia/Hb E patients. Further evaluation on compound heterozygous β-thalassemia and β-thalassemia/Hb E patients found no concomitant α-globin gene mutations and the rs368698783 polymorphism. Furthermore, the XmnI-Gγ (−/+) genotype did not demonstrate a strong impact on the disease phenotype, as only two of five patients in the compound heterozygous β-thalassemia group and two of three patients in the β-thalassemia/Hb E group had a moderate phenotype. Our findings indicate that the severity of the β-thalassemia phenotypes is closely related to the type of β-globin gene mutations but not to the XmnI-Gγ and rs368698783 polymorphisms.
References
More filters
TL;DR: A broad range of hitherto unrelated human red cell disorders are caused by variants in KLF1, a master regulator of erythropoiesis, which were previously considered to be extremely rare causes of human genetic disease.
124 citations
"Regulatory Single Nucleotide Polymo..." refers background in this paper
...Hb F-accociated mediators, the Kr€ uppel-like factor 1 (KLF1) variant and the c –196 (C>T) polymorphism, were excluded in all four subgroups [5,6]....
[...]
TL;DR: The 7.2 kilobase (kb) Corfu δβ thalassemia mutation is the smallest known deletion encompassing a region upstream of the human δ gene that has been suggested to account for the vastly different phenotypes in hereditary persistence of fetal hemoglobin (HPFH) versus β thalasemia.
77 citations
TL;DR: Tailoring combinations of therapeutics to patient subsets characterized for quantitative trait loci which modulate basal fetal hemoglobin and erythroid cell survival should provide effective amelioration of clinical symptoms in β-thalassemia and sickle cell disease.
Abstract: Fetal globin (gamma globin; HBG) is normally expressed during fetal life and prevents the clinical manifestations of beta hemoglobinopathies before birth. HBG genes are normally integrated in hematopoietic stem cells in all humans, and are at least partially amenable to reactivation. Inducing expression of fetal globin (HBG) gene expression to 60% to 70% of alpha globin synthesis produces a β-thalassemia trait phenotype, and reduces anemia. Tailoring combinations of therapeutics to patient subsets characterized for quantitative trait loci which modulate basal fetal hemoglobin and erythroid cell survival should provide effective amelioration of clinical symptoms in β-thalassemia and sickle cell disease.
37 citations
"Regulatory Single Nucleotide Polymo..." refers background in this paper
...The severity of disease can be ameliorated when fetal hemoglobin (Hb F) levels are elevated [1]....
[...]
TL;DR: Beta haplotypes are determined, testing for the presence of the Xmn I site is tested, and Hb F and G gamma expression levels are measured in 143 American Black patients with sickle cell anemia to indicate that the X Mn I site maintains a G gamma /A gamma ratio typical of fetal life but does not necessarily cause elevation of HbF.
Abstract: There are three major African haplotypes associated with the sickle mutation: Benin (#19), Senegalese (#3), and Central African Repblic (#20). Previous studies have suggested that the Xmn I site (-158 bp 5′ to the Gγ gene) is associated with elevated levels of Gγ andwiththe Senegalesehaplotype, while other investigators questioned this association. In order to clarify theissue.we have determined βhalotypes, tested fortlie presenceof theXninI site, and measured HbF and Gγ expressionlevels in 143 AmericanBlackpatients with sickle cell anemia. Haplotypes were determined using eight polvmorphic sites in the β-like globin gene cluster: Hinc II 5′ to ϵ, Hind III in IVS-II Gγ and Aγ, Hinc II within and 3′ to φ β, Ava II in IVS-II of β, and Hpa I and Bani HI 3′ to β. The Gγ/Aγ ratio was analyzed by high performance liquid chromatography using a C18 column. The Xmn I site was present in all 31chromosomes with the Sengalese haplotype. Of the remaining 255 chromosomes with other haplotypes, only 2 (0.8%) had the Xmn...
33 citations
"Regulatory Single Nucleotide Polymo..." refers background in this paper
...[9] reported that the c XmnI polymorphism maintains a c:c ratio typical of fetal life, but does not necessarily cause elevation of Hb F levels....
[...]
TL;DR: Identification of the genetic variants modifying HbF production in combination with α-globin genotype provide some prediction of disease severity for β-thalassemia and SCD but generation of a personalized genetic risk score to inform prognosis and guide management requires a larger panel of genetic modifiers yet to be discovered.
Abstract: β-thalassemia and sickle cell disease (SCD) are prototypical Mendelian single gene disorders, both caused by mutations affecting the adult β-globin gene. Despite the apparent genetic simplicity, both disorders display a remarkable spectrum of phenotypic severity and share two major genetic modifiers—α-globin genotype and innate ability to produce fetal hemoglobin (HbF, α2γ2).
32 citations