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      Fetal‐haemoglobin enhancing genotype at BCL11A reduces HbA 2 levels in patients with sickle cell anaemia

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          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 HbA 2. We conclude that in general, interventions boosting HbF are likely to reduce HbA 2 in patients’ erythroid cells and that such therapeutic strategies might benefit from a parallel stimulation of HbA 2 through independent mechanisms.

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          The interaction of alpha-thalassemia and homozygous sickle-cell disease.

          Edmund Lamb, D Weatherall, Keith R. Hayes … (1982)
          Patients with homozygous sickle-cell disease may be homozygous for alpha-thalassemia 2 (alpha-/alpha-), may be heterozygous for alpha-thalassemia 2 (alpha-/alpha alpha), or may have a normal alpha-globin-gene complement (alpha alpha/alpha alpha). We compared the clinical and hematologic features of 44 patients who had sickle-cell disease and homozygous alpha-thalassemia 2 with those of controls with the two hematologic conditions. The patients with homozygous alpha-thalassemia 2 had significantly higher red-cell counts and levels of hemoglobin and hemoglobin A2, as well as significantly lower hemoglobin F, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, reticulocyte counts, irreversibly-sickled cell counts, and serum total bilirubin levels, than those with a normal alpha-globin-gene complement. Heterozygotes (alpha-/alpha alpha) had intermediate values. In the group with homozygous alpha-thalassemia 2, fewer patients had episodes of acute chest syndrome and chronic leg ulceration and more patients had splenomegaly, as compared with patients in other two subgroups. These data confirm previous suggestions that alpha-thalassemia inhibits in vivo sickling in homozygous sickle-cell disease and may be an important genetic determinant of its hematologic severity.
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            Genome Wide Association Study of Fetal Hemoglobin in Sickle Cell Anemia in Tanzania

            Siana Mtatiro, Tarjinder Singh, Helen Rooks … (2014)
            Background Fetal hemoglobin (HbF) is an important modulator of sickle cell disease (SCD). HbF has previously been shown to be affected by variants at three loci on chromosomes 2, 6 and 11, but it is likely that additional loci remain to be discovered. Methods and Findings We conducted a genome-wide association study (GWAS) in 1,213 SCA (HbSS/HbSβ0) patients in Tanzania. Genotyping was done with Illumina Omni2.5 array and imputation using 1000 Genomes Phase I release data. Association with HbF was analysed using a linear mixed model to control for complex population structure within our study. We successfully replicated known associations for HbF near BCL11A and the HBS1L-MYB intergenic polymorphisms (HMIP), including multiple independent effects near BCL11A, consistent with previous reports. We observed eight additional associations with P<10−6. These associations could not be replicated in a SCA population in the UK. Conclusions This is the largest GWAS study in SCA in Africa. We have confirmed known associations and identified new genetic associations with HbF that require further replication in SCA populations in Africa.
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              Concurrent sickle-cell anemia and alpha-thalassemia: effect on severity of anemia.

              B Lubin, J. Davis, A M Dozy … (1982)
              We studied 47 patients with sickle-cell anemia to determine the effect of alpha-thalassemia on the severity of their hemolytic anemia. We diagnosed alpha-thalassemia objectively by using alpha-globin-gene mapping to detect alpha-globin-gene deletions, studying 25 subjects with the normal four alpha-globin-genes, 18 with three, and four with two. The mean hemoglobin, hematocrit, and absolute reticulocyte levels (+/- S.D.) were 7.9 +/- 0.9 g per deciliter (4.9 +/- 0.6 mmol per liter), 22.9 +/- 2.9 per cent, and 501,000 +/- 126,000 per cubic millimeter, respectively, in the non-thalassemic group; 9.8 +/- 1.6 g per deciliter (6.1 +/- 1.0 mmol per liter), 29.0 +/- 5.0 per cent, and 361,000 +/- 51,000 per cubic millimeter in the group with three alpha-globin genes; and 9.2 +/- 1.0 g per deciliter (5.7 +/- 0.6 mmol per liter), 27.5 +/- 3.0 per cent, and 100,000 +/- 15,000 per cubic millimeter in the group with two alpha-globin genes. Deletion of alpha-globin genes was also accompanied by a decreased mean corpuscular hemoglobin concentration (MCHC) in post-reticulocyte erythrocytes and by increased hemoglobin F levels. The decreased intraerythrocytic hemoglobin S concentration and elevated hemoglobin F levels associated with alpha-thalassemia appear to diminish the degree of hemolytic anemia found in sickle-cell disease.
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                Author and article information

                Contributors
                Stephan Menzel:
                ORCID: https://orcid.org/0000-0002-1590-9108
                Stephan.menzel@kcl.ac.uk
                Journal
                Journal ID (nlm-ta): EJHaem
                Journal ID (iso-abbrev): EJHaem
                Journal ID (doi): 10.1002/(ISSN)2688-6146
                Journal ID (publisher-id): JHA2
                Title: EJHaem
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2688-6146
                Publication date (Electronic): 04 May 2021
                Publication date Collection: August 2021
                Volume: 2
                Issue: 3 ( doiID: 10.1002/jha2.v2.3 )
                Pages: 459-461
                Affiliations
                [ 1 ] Department of Haematology and Blood Transfusion, College of Medicine University of Lagos Idi‐Araba Lagos Nigeria
                [ 2 ] Sickle Cell Foundation Nigeria Idi‐Araba Lagos Nigeria
                [ 3 ] Haematology/Oncology Unit, Department of Medicine, College of Medicine University of Lagos Idi‐Araba Lagos Nigeria
                [ 4 ] School of Cancer and Pharmaceutical Sciences King's College London London UK
                Author notes
                [*] [* ] Correspondenc e

                S. Menzel, School of Cancer and Pharmaceutical Sciences, King's College London, London, UK.

                Email: Stephan.menzel@ 123456kcl.ac.uk

                Author information
                https://orcid.org/0000-0003-2097-469X
                https://orcid.org/0000-0002-1590-9108
                Article
                Publisher ID: JHA2186
                DOI: 10.1002/jha2.186
                PMC ID: 9175773
                SO-VID: c07b2311-3d78-465d-ade0-72d57300f50c
                Copyright © © 2021 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date revision received : 28 February 2021
                Date received : 29 January 2021
                Date accepted : 02 March 2021
                Page count
                Figures: 0, Tables: 1, Pages: 3, Words: 2399
                Categories
                Subject: Short Report
                Subject: Short Reports
                Custom metadata
                source-schema-version-number 2.0
                cover-date August 2021
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.6 mode:remove_FC converted:23.05.2022

                Keywords: african patient population,bcl11a,genetic analysis,hba,sickle cell disease
                Data availability:
                Keywords: african patient population, bcl11a, genetic analysis, hba, sickle cell disease

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