Sickle cell disease and H3Africa: enhancing genomic research on cardiovascular diseases in African patients

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Summary

Background

Sickle cell disease (SCD) has a high prevalence in sub-Saharan Africa. There are several cardiovascular phenotypes in SCD that contribute to its morbidity and mortality.

Discussion

SCD is characterised by marked clinical variability, with genetic factors playing key modulating roles. Studies in Tanzania and Cameroon have reported that singlenucleotide polymorphisms in BCL11A and HBS1L-MYB loci and co-inheritance of alpha-thalassaemia impact on foetal haemoglobin levels and clinical severity. The prevalence of overt stroke among SCD patients in Cameroon (6.7%) and Nigeria (8.7%) suggests a higher burden than in high-income countries. There is also some evidence of high burden of kidney disease and pulmonary hypertension in SCD; however, the burden and genetics of these cardiovascular conditions have seldom been investigated in Africa.

Conclusions

Several H3Africa projects are focused on cardiovascular diseases and present major opportunities to build genome-based research on existing SCD platforms in Africa to transform the health outcomes of patients.

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Most cited references 48

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An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level.

Daniel E Bauer, Sophia C Kamran, Samuel Lessard … (2013)

Genome-wide association studies (GWASs) have ascertained numerous trait-associated common genetic variants, frequently localized to regulatory DNA. We found that common genetic variation at BCL11A associated with fetal hemoglobin (HbF) level lies in noncoding sequences decorated by an erythroid enhancer chromatin signature. Fine-mapping uncovers a motif-disrupting common variant associated with reduced transcription factor (TF) binding, modestly diminished BCL11A expression, and elevated HbF. The surrounding sequences function in vivo as a developmental stage-specific, lineage-restricted enhancer. Genome engineering reveals the enhancer is required in erythroid but not B-lymphoid cells for BCL11A expression. These findings illustrate how GWASs may expose functional variants of modest impact within causal elements essential for appropriate gene expression. We propose the GWAS-marked BCL11A enhancer represents an attractive target for therapeutic genome engineering for the β-hemoglobinopathies.

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Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.

Mark Gladwin, Vandana Sachdev, Maria Jison … (2004)

The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated. Copyright 2004 Massachusetts Medical Society

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Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing.

Jian Xu, Cong Peng, Vijay G. Sankaran … (2011)

Persistence of human fetal hemoglobin (HbF, α(2)γ(2)) in adults lessens the severity of sickle cell disease (SCD) and the β-thalassemias. Here, we show that the repressor BCL11A is required in vivo for silencing of γ-globin expression in adult animals, yet dispensable for red cell production. BCL11A serves as a barrier to HbF reactivation by known HbF inducing agents. In a proof-of-principle test of BCL11A as a potential therapeutic target, we demonstrate that inactivation of BCL11A in SCD transgenic mice corrects the hematologic and pathologic defects associated with SCD through high-level pancellular HbF induction. Thus, interference with HbF silencing by manipulation of a single target protein is sufficient to reverse SCD.

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Author and article information

Contributors

Ambroise Wonkam

Julie Makani

Solomon Ofori-Aquah

Obiageli E Nnodu

Marsha Treadwell

Charmaine Royal

Kwaku Ohene-Frempong

Journal

Journal ID (nlm-ta): Cardiovasc J Afr

Journal ID (iso-abbrev): Cardiovasc J Afr

Journal ID (publisher-id): TBC

Title: Cardiovascular Journal of Africa

Publisher: Clinics Cardive Publishing

ISSN (Print): 1995-1892

ISSN (Electronic): 1680-0745

Publication date (Print): Mar-Apr 2015

Volume: 26

Issue: 2 H3Africa Suppl

Pages: S50-S55

Affiliations

Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, South Africa

Muhimbili University of Health and Allied Sciences, Dar-Es-Salaam, Tanzania

Center for Translational and International Hematology, University of Pittsburgh, Pittsburgh, USA

Department of Haematology and Blood Transfusion, College of Health Sciences, University of Abuja, Abuja, Nigeria/Department of Haematology and Blood Transfusion, University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria

Hematology/Oncology Department, UCSF Benioff Children’s Hospital, Oakland, USA

Department of African and African American Studies, Duke University, Durham, USA

Children’s Hospital of Philadelphia, Comprehensive Sickle Cell Centre, Philadelphia, USA

Article

DOI: 10.5830/CVJA-2015-040

PMC ID: 4547555

SO-VID: 88a26729-7c37-4035-8394-fd7d0b1fdff6

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Sickle cell disease and H3Africa: enhancing genomic research on cardiovascular diseases in African patients

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Summary

Background

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Conclusions

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Most cited references 48

An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level.

Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.

Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing.

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