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Fetal-haemoglobin enhancing genotype at BCL11A reduces HbA₂ levels in patients with sickle cell anaemia.

ABSTRACT: Understanding the interplay of genetic factors with haemoglobin expression and pathological processes in sickle cell disease is important for pharmacological and gene-therapeutic interventions. In our nascent study cohort of Nigerian patients, we found that three major disease-modifying factors, HbF levels, α-thalassaemia deletion and BCL11A genotype, had expected beneficial haematological effects. A key BCL11A variant, while improving HbF levels (5.7%-9.0%), also led to a small, but significant decrease in HbA₂. We conclude that in general, interventions boosting HbF are likely to reduce HbA₂ in patients' erythroid cells and that such therapeutic strategies might benefit from a parallel stimulation of HbA₂ through independent mechanisms.

SUBMITTER: Adeyemo TA

PROVIDER: S-EPMC9175773 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Fetal-haemoglobin enhancing genotype at BCL11A reduces HbA2 levels in patients with sickle cell anaemia.

Adeyemo Titilope A TA Ojewunmi Oyesola O OO Oyetunji Idayat Ajoke IA Kalejaiye Olufunto Olufela OO Menzel Stephan S

EJHaem 20210504 3

Understanding the interplay of genetic factors with haemoglobin expression and pathological processes in sickle cell disease is important for pharmacological and gene-therapeutic interventions. In our nascent study cohort of Nigerian patients, we found that three major disease-modifying factors, HbF levels, α-thalassaemia deletion and BCL11A genotype, had expected beneficial haematological effects. A key BCL11A variant, while improving HbF levels (5.7%-9.0%), also led to a small, b ...[more]

PMID: 35844678

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Project description:Background & objectivesThe amount of foetal haemoglobin that persists in adulthood affects the clinical severity of haemoglobinopathies including β-thalassaemia major and sickle cell anaemia (SCA). The present study was undertaken to analyse β-thalassaemia as well as SCA patients for the single nucleotide polymorphism (SNP), rs11886868 (T/C) in BCL11A gene and to evaluate the association between this polymorphism and severity of β-thalassaemia major and SCA.Methodsa total of 620 samples (420 β-thalassaemia major and 200 SCA cases) were analysed before blood transfusion using basic screening tests like complete blood analysis and osmotic fragility and further confirmed by high performance liquid chromatography (HPLC), amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and reverse dot blot techniques. All patients were transfusion dependent. Patients with β-thalassaemia and SCA were classified into mild, moderate, severe according to the severity score based on Hb levels, age of onset, age at which patients received their first blood transfusion, the degree of growth retardation and splenectomy. β-thalassaemia as well as SCA patients were analysed for the SNP, rs11886868 (T/C) in BCL11A gene and association between this polymorphism and severity of β-thalassaemia major as well as SCA was evaluated.ResultsThere was a significant difference in genotypic and allelic frequencies of BCL11A gene polymorphism between mild and moderate and mild and severe cases in both the groups. A significant (P<0.001) difference was observed in the mean HbF levels between the three genotypes in different severity groups. HbF levels were found to be high in CC genotype bearing individuals followed by TC and TT in β-thalassaemia major as well as SCA.Interpretation & conclusionsThis study confirms that the T/C variant (rs11886868) of the BCL11A gene causing downregulation of BCL11A gene expression in adult erythroid precursors results in the induction of HbF and ameliorates the severity of β-thalassaemia as well as SCA.

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Fetal-haemoglobin enhancing genotype at BCL11A reduces HbA₂ levels in patients with sickle cell anaemia.

Publications

Fetal-haemoglobin enhancing genotype at <i>BCL11A</i> reduces HbA<sub>2</sub> levels in patients with sickle cell anaemia.

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Fetal-haemoglobin enhancing genotype at BCL11A reduces HbA2 levels in patients with sickle cell anaemia.

Publications

Fetal-haemoglobin enhancing genotype at &lt;i&gt;BCL11A&lt;/i&gt; reduces HbA&lt;sub&gt;2&lt;/sub&gt; levels in patients with sickle cell anaemia.

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OmicsDI is part of the ELIXIR infrastructure

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Fetal-haemoglobin enhancing genotype at BCL11A reduces HbA₂ levels in patients with sickle cell anaemia.

Fetal-haemoglobin enhancing genotype at <i>BCL11A</i> reduces HbA<sub>2</sub> levels in patients with sickle cell anaemia.