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Hepcidin gene polymorphisms and iron overload in ?-thalassemia major patients refractory to iron chelating therapy.

ABSTRACT: BACKGROUND:? Thalassemia is one of the most common groups of hereditary haemoglobinopathies. Affected people with thalassemia major are dependent on regular blood transfusion which on the long term leads to iron overload. Hepcidin is a peptide hormone and an important regulator of iron homeostasis, especially in thalassemia. Expression of this hormone is influenced by polymorphisms within the hepcidin gene, HAMP. Several studies emphasized the role of single nucleotide polymorphisms (SNPs) located in the promoter region of the gene. This study aimed to analyze the association between three SNPs in promoter of HAMP, c.-582A?>?G, c.-443C?>?T, and c.-153C?>?T, with iron overload in ?-thalassemia major patients. METHODS:A total of 102 samples from ? thalassemia major patients were collected. Genomic DNA was extracted and segments of DNA encompassing rs10421768 and rs142126068 were sequenced. Statistical analysis was performed by SPSS Statistics 23 using independent t test and Fisher's exact test. RESULTS:A total of 102 adult ?-thalassemia major patients were genotyped for three SNPs in the promoter region of HAMP gene by PCR and direct sequencing. Most of the patients (71.3%) were iron overloaded (based on plasma ferritin >?1000?ng/ml) in spite of receiving regular iron-chelating therapy. Our analysis revealed a statistically significant difference between the level of cardiac iron accumulation and c.-582A?>?G variant (p?=?0.02). For c.-443C?>?T statistical analysis was on the edge of the significant relationship between the minor allele and serum ferritin (p?=?0.058). All samples were homozygous for allele C of c.-153C?>?T. CONCLUSIONS:Despite chelating therapy, iron overload is still one of the main complications of thalassemia. Our findings and others emphasize the role of hepcidin -582A?>?G polymorphism as a key component of iron homeostasis in these patients.

SUBMITTER: Zarghamian P

PROVIDER: S-EPMC7140315 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Hepcidin gene polymorphisms and iron overload in β-thalassemia major patients refractory to iron chelating therapy.

Zarghamian Parinaz P Azarkeivan Azita A Arabkhazaeli Ali A Mardani Ahmad A Shahabi Majid M

BMC medical genetics 20200408 1

<h4>Background</h4>β Thalassemia is one of the most common groups of hereditary haemoglobinopathies. Affected people with thalassemia major are dependent on regular blood transfusion which on the long term leads to iron overload. Hepcidin is a peptide hormone and an important regulator of iron homeostasis, especially in thalassemia. Expression of this hormone is influenced by polymorphisms within the hepcidin gene, HAMP. Several studies emphasized the role of single nucleotide polymorphisms (SNP ...[more]

PMID: 32268883

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Project description:Iron homeostasis is regulated by hepcidin (HEPC) that controls the dietary iron absorption and iron recycling. HEPC deficiency contributes to iron overload in β-thalassemia patients. The present study aimed to investigate the correlation between HEPC concentration and serum iron status among hemoglobin E (HbE)/β-thalassemia patients and their parents (HbE trait and β-thalassemia trait) compared with healthy controls. This study is a comparative cross-sectional study in which iron profile and HEPC level were examined in 65 HbE/β-thalassemia patients (pretransfusion) and 65 parents at the Hospital Sultanah Nur Zahirah and in 130 students as healthy controls from Univesiti Sultan Zainal Abidin, Terengganu, Malaysia. Furthermore, six samples from each group (HbE/β-thalassemia patients, parents and healthy controls) were randomly selected for gene expression analysis of HEPC and ferroportin1 (FPN1) using reverse transcription quantitative PCR. The results demonstrated that serum HEPC level were significantly decreased in HbE/β-thalassemia patients and their parents (P<0.001) compared with healthy controls. In addition, the gene expression analysis showed a dramatically downregulated HEPC in HbE/β-thalassemia patients and their parents (P=0.001) compared with healthy controls. However, there was a marked upregulation of FPN1 in HbE/β-thalassemia patients and their parents (P=0.001) compared with healthy controls. Iron profiling results revealed a significantly increased serum ferritin in HbE/β-thalassemia patients and their parents compared with healthy controls (P<0.001). In summary, the present study demonstrated that HEPC expression level and serum level were significantly decreased in HbE/β-thalassemia patients and their parents, which was combined with a marked increased FPN1 expression level and serum ferritin level compared with healthy volunteers. These findings supported the hypothesis that downregulated HEPC could lose its function as a negative regulator of FPN1, resulting in iron overload in HbE/β-thalassemia patients. Subsequently, assessing HEPC and FPN1 gene expression may be a useful tool to determine the risk of iron toxicity in patients with HbE/β-thalassemia and their parents, and could therefore be considered as a therapeutic target in the management of iron burden in these patients.

Project description:In iron overload, almost all the excess iron is stored intracellularly as rapidly mobilizable ferritin iron and slowly exchangeable hemosiderin iron. Increases in cytosolic iron may produce oxidative damage that ultimately results in cardiomyocyte dysfunction. Because intracellular ferritin iron is evidently in equilibrium with the low-molecular-weight cytosolic iron pool, measurements of ferritin iron potentially provide a clinically useful indicator of changes in cytosolic iron. The cardiovascular magnetic resonance (CMR) index of cardiac iron used clinically, the effective transverse relaxation rate (R(2)*), is principally influenced by hemosiderin iron and changes only slowly over several months, even with intensive iron-chelating therapy. Another conventional CMR index of cardiac iron, the transverse relaxation rate (R(2)), is sensitive to both hemosiderin iron and ferritin iron. We have developed a new MRI measure, the 'reduced transverse relaxation rate' (RR(2)), and have proposed in previous studies that this measure is primarily sensitive to ferritin iron and largely independent of hemosiderin iron in phantoms mimicking ferritin iron and human liver explants. We hypothesized that RR(2) could detect changes produced by 1 week of iron-chelating therapy in patients with transfusion-dependent thalassemia. We imaged 10 patients with thalassemia major at 1.5 T in mid-ventricular short-axis planes of the heart, initially after suspending iron-chelating therapy for 1 week and subsequently after resuming oral deferasirox. After resuming iron-chelating therapy, significant decreases were observed in the mean myocardial RR(2) (7.8%, p < 0.01) and R(2) (5.5%, p < 0.05), but not in R(2)* (1.7%, p > 0.90). Although the difference between changes in RR(2) and R(2) was not significant (p > 0.3), RR(2) was consistently more sensitive than R(2) (and R(2)*) to the resumption of iron-chelating therapy, as judged by the effect sizes of relaxation rate differences detected. Although further studies are needed, myocardial RR(2) may be a promising investigational method for the rapid assessment of the effects of iron-chelating therapy in the heart.

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Hepcidin gene polymorphisms and iron overload in ?-thalassemia major patients refractory to iron chelating therapy.

Publications

Hepcidin gene polymorphisms and iron overload in β-thalassemia major patients refractory to iron chelating therapy.

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