Cardiovascular Journal of Africa: Vol 26 No 2 Supplement (March/April 2015)

S50

AFRICA

CVJAFRICA • Volume 26, No 2, H3Africa Supplement, March/April 2015

Sickle cell disease and H3Africa: enhancing genomic

research on cardiovascular diseases in African patients

Ambroise Wonkam, Julie Makani, Solomon Ofori-Aquah, Obiageli E Nnodu, Marsha Treadwell,

Charmaine Royal, Kwaku Ohene-Frempong, as members of the H3Africa Consortium

Abstract

Background:

Sickle cell disease (SCD) has a high prevalence in

sub-Saharan Africa. There are several cardiovascular pheno-

types in SCD that contribute to its morbidity and mortality.

Discussion:

SCD is characterised by marked clinical vari-

ability, with genetic factors playing key modulating roles.

Studies in Tanzania and Cameroon have reported that single-

nucleotide 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 cardio-

vascular diseases and present major opportunities to build

genome-based research on existing SCD platforms in Africa

to transform the health outcomes of patients.

Keywords:

sickle cell disease, stroke, kidney diseases, pulmonary

hypertension, genetics, Africa

Cardiovasc J Afr

2015;

: S50–S55

www.cvja.co.za

DOI:

10.5830/CVJA

-2015-040

Sickle cell disease (SCD) is a genetic disorder of public health

significance with high prevalence, high mortality rate and limited

interventions. An estimated 305 800 births are affected annually

worldwide by homozygous SCD (SCD-SS), nearly two-thirds of

this incidence occurs in Africa.

This estimate does not include

SCD-SC, which is more prevalent than SCD-SS in some West

African countries.

Although the first clinical description of SCD occurred over

100 years ago and this condition was described in 1949 as the

first molecular disease, to date only one drug, hydroxyurea, is

available for its specific treatment.

Furthermore, despite the

evidence from high-income countries that new-born screening

(NBS) and comprehensive care are associated with a 70%

reduction in early childhood deaths,

and can have a significant

impact on reducing morbidity,

4,5

few African countries have

programmes dedicated to NBS, follow-up care, family and

patient education and counselling, and prevention and treatment

of disease complications. As a consequence, in sub-Saharan

Africa, mortality rates are high before the age of five years

and estimates suggest that without intervention, up to 90% of

affected infants may die in childhood.

6,7

The role of genomic research to improve

health of SCD patients: preliminary data from

Cameroon and Tanzania

Genomics of foetal haemoglobin-promoting loci

Advancement in genomic research offers an unprecedented

opportunity to address the health challenges of SCD in an

integrated manner. As a Mendelian disorder caused by a single

gene mutation on the

-globin gene (

Glu6Val

) on chromosome 11,

there is considerable phenotypic diversity in SCD, due largely to

the influence of genetic and environmental factors.

8-10

Although there are several key phenotypes (anaemia, stroke,

infections), foetal haemoglobin (HbF) has emerged as a central

disease modifier; importantly, the expression of this modifier

is amenable to therapeutic manipulation.

11,12

Genetic variants

at three principal loci,

BCL11A

HBS1L-MYB

and the

HBB

cluster account for 10–20% of HbF variation among SCD

patients in the USA, Brazil and the UK.

8,9

Initial studies in Tanzania

and recently in Cameroon

14,15

have shown that single-nucleotide polymorphisms (SNPs) in the

BCL11A

loci are prevalent in both Tanzanian and Cameroonian

patients [minor allele frequency (MAF) of rs4671393

0.30],

with significant association of these SNPs with HbF (Table

1). These studies have also shown that rs9399137, which acts

as a tagging SNP for the

HMIP-2

sub-locus in European

Division of Human Genetics, Faculty of Health Sciences,

University of Cape Town, South Africa

Ambroise Wonkam, MD,

ambroise.wonkam@uct.ac.za

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

Salaam, Tanzania

Julie Makani, PhD

Center for Translational and International Hematology,

University of Pittsburgh, Pittsburgh, USA

Solomon Ofori-Aquah, PhD

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

Obiageli E Nnodu, MD

Hematology/Oncology Department, UCSF Benioff

Children’s Hospital, Oakland, USA

Marsha Treadwell, PhD

Department of African and African American Studies, Duke

University, Durham, USA

Charmaine Royal, PhD

Children’s Hospital of Philadelphia, Comprehensive Sickle

Cell Centre, Philadelphia, USA

Kwaku Ohene-Frempong, MD