Coinheritance of sickle cell anemia and α‐thalassemia delays disease onset and could improve survival in cameroonian's patients (Sub‐Saharan Africa)
Authors: Ambroise Wonkam, Maryam Bibi Rumaney, Valentina Josiane Ngo Bitoungui, Anna Alvera Vorster, Raj Ramesar, Jeanne Ngogang
Journal: American Journal of Hematology (2014)

To the editor: Although Sickle Cell Anemia (SCA) is genetically characterized by a single point mutation, the coinheritance of α-thalassemia has been associated with lower stroke rate and higher vaso-occlusive painful episodes 1. There is a scarcity of data on the coinheritance of α-thalassemia and SCA in Africa; this study aimed to explore the prevalence of α-thalassemia among a group of Cameroonian SCA patients and unaffected controls and the correlation with the age of diagnosis among patients. Ethical approval was given by the National Ethical Committee Ministry of Public Health, Republic of Cameroon (No 033/CNE/DNM/07); and the University of Cape Town, Faculty of Health Sciences Human Research Ethics Committee (HREC REF. 132/2010). The study was conducted at the Yaoundé Central Hospital and Douala Laquintinie Hospital in Cameroon. Socio-demographic data were collected by means of a structured questionnaire and the review of patients' medical records. The control group consisted of randomly selected individuals (HbAS and HbAA) who were apparently healthy blood donors. Hemoglobin electrophoresis and complete routine blood count were conducted on arrival at the hospital. Only patients with SCA (HbSS type) who had not received a blood transfusion or hospitalization in the past 6 weeks were included, with no patient receiving hydroxyurea treatment. Using multiplex gap-PCR following a reported method 2 with a few modifications (Supporting Information 1), 3.7 and 4.2 kb α-globin gene deletions were screened. Using SPSS (IBM, version 21.0), nonparametric tests compared groups of participants; additive model per copy of the α-globin gene deletions were performed, as well as multinomial logistic regression analysis incorporating SCA genotype, α-thalassemia genotype, age, and gender. Significance was set at the 0.05 level. All 161 SCA patients and 93 controls (59.1% HbAA; n = 55) lived in urban areas; 51% (n = 76) of patients and 67.8% (n = 59) of controls were female (P = 0.043). Patients were relatively younger than controls (P < 0.001); the median ages of SCA patients, HbAS, and HbAA controls were 17.5, 24, and 26.5 years. Only 3.7 kb α-globin gene deletion was identified. Among patients, the median RBC count increased with the number of 3.7 kb deletions [2.6, 3.0, and 3.4 million/dl, with no, one, and two deletions (P = 0.01)] and the median WBC counts decreased with the number of 3.7 kb deletion [13.2, 10.5, and 9.8 × 109/L (P < 0.0001)]. Among controls, 20.4 % (n = 19) had at least one 3.7 kb α-globin gene deletion, compared to 37.3% (n = 60) among patients (P = 0.007; Fig. 1A). Multinomial logistic regressions analysis indicated that, HbAA individuals were about 4–5 times less likely to have a single or a double 3.7 kb α-globin gene deletion than patients (Supporting Information Table SI). In addition, being male increased the likelihood of having the 3.7 kb α-globin gene deletion (Likelihood Ratio P = 0.013). The median age of SCA diagnosis increased with the number of α-globin gene deletions (P = 0.026; Fig. 1B,C). In a seminal work in the USA, authors reported that, in the first 10 years of life among HbSS individuals, the prevalence of 3.7 kb α-globin gene deletions was 17%, which was comparable to that in the general Black population, whereas in the group over 20 years of age, the prevalence increased to 49% 3. Equally, the prevalence of the 3.7 kb α-globin gene deletion has also been shown to increase with age in Cuban SCA patients 4, implying that α-thalassemia could be associated with longer survival. To support this hypothesis, the high prevalence of 3.7 kb α-globin gene deletions was also reported in Tanzanian SCA patients (58%) 5. Interestingly, the increasing age of diagnosis of SCA with number of 3.7 kb α-globin gene deletion, reported in the present study, is novel finding that was only possible to be described, in a context where neonatal screening for SCA is nonexistent. Thus, in Cameroon, the SCA diagnosis is often made when the onset of clinical manifestations brings the patient to medical attention 6. Taken together with the higher proportion of 3.7 kb α-globin gene deletions among patients, this finding consolidates the hypothesis that the coinheritance α-thalassemia and SCA could ultimately improve survival of SCA patients. In future, data from a larger ethnically, age and sex matched patients and controls sample or ideally, data from a prospective SCA birth cohort, could definitively confirm or affirm the contribution of α-thalassemia in survival of SCA patients. The molecular experiments of the study were funded by the National Health Laboratory Services, South Africa; the University Research Committee and Carnegie Research Development Grant, University of Cape Town, South Africa. The students' bursaries were provided by the National Research Foundation-DAAD scholarship, South Africa, and the Third World Academy of Sciences. AW designed the study, raised funding, provided general supervision of the research group, drafted the manuscript and compiled the revisions. MBR performed the molecular experiments and drafted the manuscript. VJN acquired clinical data and performed DNA extraction and molecular confirmation of SCA. RR and AAV performed and supervised the molecular analysis. JG performed all the hematological indices and supervised the samples collection. All the authors revised and approved the final version of the manuscript. The authors are grateful to Ms. Famidah Essop and Prof. Amanda Krause, from the National Health Laboratory Services, Division of Human Genetics, University of the Witwatersrand, Johannesburg, South Africa, and Prof. Samuel Chong from NUS, Singapore, for the kind donation of controls DNA, for the 3.7 kb and 4.2 kb α-globin gene deletion experiments. They also thank Prof. Andre Pascal Kengne from the Medical Research Council, South Africa, for his assistance with statistical analysis. Ambroise Wonkam1Maryam Bibi Rumaney1Valentina Josiane Ngo Bitoungui2Anna Alvera Vorster1,3Raj Ramesar1,3Jeanne Ngogang2 1Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town (UCT), Cape Town, Republic of South Africa; 2Department of Microbiology, Parasitology and Haematology, Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé, Cameroon; 3Division of Human Genetics, MRC Human Genetics Research Unit, Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town (UCT), Cape Town, Republic of South Africa Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.