Polymorphic variations influencing fetal hemoglobin levels: Association study in beta-thalassemia carriers and in normal individuals of Portuguese origin

Pereira, Clara; Relvas, Luís; Bento, Celeste; Abade, Augusto; Ribeiro, M. Letícia; Manco, Licínio

doi:10.1016/j.bcmd.2015.02.001

Cited by 24 publications

(15 citation statements)

References 33 publications

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“…In respect to this point, our last conclusion is that the Aγ(+25 G->A) and Gγ-globin-XmnI polymorphisms might be associated with high HbF in erythroid precursor cells isolated from the β 0 39/β 0 39 thalassemia patients (Fig. 4 ), in agreement with several studies suggesting the association between XmnI polymorphism and high HbF production [ 18 , 24 , 34 , 35 ].…”

Section: Discussionsupporting

confidence: 89%

An Aγ-globin G->A gene polymorphism associated with β039 thalassemia globin gene and high fetal hemoglobin production

et al. 2017

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BackgroundIncrease of the expression of γ-globin gene and high production of fetal hemoglobin (HbF) in β-thalassemia patients is widely accepted as associated with a milder or even asymptomatic disease. The search for HbF-associated polymorphisms (such as the XmnI, BCL11A and MYB polymorphisms) has recently gained great attention, in order to stratify β-thalassemia patients with respect to expectancy of the first transfusion, need for annual intake of blood, response to HbF inducers (the most studied of which is hydroxyurea).MethodsAγ-globin gene sequencing was performed on genomic DNA isolated from a total of 75 β-thalassemia patients, including 31 β039/β039, 33 β039/β+IVSI-110, 9 β+IVSI-110/β+IVSI-110, one β0IVSI-1/β+IVSI-6 and one β039/β+IVSI-6.ResultsThe results show that the rs368698783 polymorphism is present in β-thalassemia patients in the 5’UTR sequence (+25) of the Aγ-globin gene, known to affect the LYAR (human homologue of mouse Ly-1 antibody reactive clone) binding site 5′-GGTTAT-3′. This Aγ(+25 G->A) polymorphism is associated with the Gγ-globin-XmnI polymorphism and both are linked with the β039-globin gene, but not with the β+IVSI-110-globin gene. In agreement with the expectation that this mutation alters the LYAR binding activity, we found that the Aγ(+25 G->A) and Gγ-globin-XmnI polymorphisms are associated with high HbF in erythroid precursor cells isolated from β039/β039 thalassemia patients.ConclusionsAs a potential explanation of our findings, we hypothesize that in β-thalassemia the Gγ-globin-XmnI/Aγ-globin-(G->A) genotype is frequently under genetic linkage with β0-thalassemia mutations, but not with the β+-thalassemia mutation here studied (i.e. β+IVSI-110) and that this genetic combination has been selected within the population of β0-thalassemia patients, due to functional association with high HbF. Here we describe the characterization of the rs368698783 (+25 G->A) polymorphism of the Aγ-globin gene associated in β039 thalassemia patients with high HbF in erythroid precursor cells.

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Section: Discussionsupporting

confidence: 89%

An Aγ-globin G->A gene polymorphism associated with β039 thalassemia globin gene and high fetal hemoglobin production

et al. 2017

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“…In the developing fetus, HBG1 and HBG2 code for two gamma chain proteins, which along with corresponding alpha chains, make up fetal hemoglobin (HbF). At birth, HbF undergoes replacement by mature adult hemoglobin (HbA), in a process that continues over the first 6 months of age (19). As shown in Table I, the mean expression levels of HBG2 decreased significantly with age as HbA replaced HbF.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Age-specific Variability of Plasma Proteins in Healthy Neonates, Children and Adults

Bjelosevic

Pascovici

Peng

et al. 2017

Molecular & Cellular Proteomics

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Human blood plasma is a complex biological fluid containing soluble proteins, sugars, hormones, electrolytes, and dissolved gasses. As plasma interacts with a wide array of bodily systems, changes in protein expression, or the presence or absence of specific proteins are regularly used in the clinic as a molecular biomarker tool. A large body of literature exists detailing proteomic changes in pathologic contexts, however little research has been conducted on the quantitation of the plasma proteome in age-specific, healthy subjects, especially in pediatrics. In this study, we utilized SWATH-MS to identify and quantify proteins in the blood plasma of healthy neonates, infants under 1 year of age, children between 1-5 years, and adults. We identified more than 100 proteins that showed significant differential expression levels across these age groups, and we analyzed variation in protein expression across the age spectrum. The plasma proteomic profiles of neonates were strikingly dissimilar to the older children and adults. By extracting the SWATH data against a large human spectral library we increased protein identification more than 6-fold (940 proteins) and confirmed the concentrations of several of these using ELISA. The results of this study map the variation in expression of proteins and pathways often implicated in disease, and so have significant clinical implication.

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“…Similarly, several authors found a significant associated between Xmn I polymorphism and HbF levels in Chinese, Brazilian, and Portuguese β-thal carriers. [ 12 22 25 29 30 ] On the other hand, an association could only be documented with the combination of Xmn I and (AT) x (T) Y polymorphisms in Italian carriers. [ 15 ] Conversely, other investigators failed to demonstrate an association between this polymorphism and HbF in carriers.…”

Section: Discussionmentioning

confidence: 99%

“…The latter has been found to contribute to variability in HbF among β-thal carriers in other populations. [ 12 29 ] Other culprits that may have played a role in this variability as documented by other studies in other populations and need scrutiny are the β-genotype and alpha gene triplication. [ 13 14 32 ]…”

Section: Discussionmentioning

confidence: 99%

“…While earlier studies have focused and documented the contribution of Xmn I polymorphism to phenotype and HbF levels in homozygous and compound heterozygous β-thal in various populations including Iraq,[ 6 8 9 10 11 ] such contribution particularly to HbF has been subject to controversy in heterozygous β-thal (thal minor)[ 12 13 14 15 ] and was not addressed in Iraqi patients, and that is why this study was initiated.…”

Section: Introductionmentioning

confidence: 99%

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HBG2 -158 (C>T) polymorphism and its contribution to fetal hemoglobin variability in Iraqi Kurds with beta-thalassemia minor

2018

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PURPOSE: Hemoglobin (Hb) F% is increased in up to half of beta-thalassemia (β-thal) carriers. Several polymorphisms have been linked to such variability in different populations, including HBG2 - 158(C>T) (Xmn I polymorphism) on chromosome 11. To determine the role of this polymorphism in such variability among Iraqi Kurds, the current study was initiated. MATERIALS AND METHODS: A total of 102 consecutive patients diagnosed as β-thal minor were enrolled. The enrollees had their diagnosis based on peripheral blood counts and high-performance liquid chromatography to determine HbA2 and HbF. All enrollees had their DNA extracted by phenol-chloroform method and Xmn I polymorphism detected by restriction fragment length polymorphism-polymerase chain reaction. RESULTS: The mean age (standard deviation [SD]) of the 102 enrollees was 25.4 (14.0) years, and the enrollees included 48 males and 54 females. Xmn I polymorphism was identified in heterozygous state in 46 (45.1%) patients and in homozygous state in one patient (0.98%). Thus, the minor allele frequency of this polymorphism was 0.235 in the studied group. There were no significant differences in red cell indices and HbA2% in carriers of the minor allele compared to noncarriers, while HbF% and absolute HbF concentrations were significantly higher in the former subgroup (P = 0.032 and 0.014, respectively). This polymorphism's contribution to HbF variability was found to be 5.8% in the studied sample. Furthermore, those with HbF ≥2% were 3.2 folds more likely to carry the minor allele. CONCLUSIONS: Xmn I polymorphism is frequently encountered in Iraqi Kurds with β-thal minor, and it is significantly associated with higher fetal hemoglobin in these patients.

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Polymorphic variations influencing fetal hemoglobin levels: Association study in beta-thalassemia carriers and in normal individuals of Portuguese origin

Cited by 24 publications

References 33 publications

An Aγ-globin G->A gene polymorphism associated with β039 thalassemia globin gene and high fetal hemoglobin production

An Aγ-globin G->A gene polymorphism associated with β039 thalassemia globin gene and high fetal hemoglobin production

Quantitative Age-specific Variability of Plasma Proteins in Healthy Neonates, Children and Adults

HBG2 -158 (C>T) polymorphism and its contribution to fetal hemoglobin variability in Iraqi Kurds with beta-thalassemia minor

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