Global Study of Thalassaemia

Lead Research Organisation: University of Oxford
Department Name: UNLISTED

Abstract

The inherited disorders of haemoglobin are by far the commonest genetic diseases and will cause an increasing global health problem in the future. This programme is directed at trying to develop better ways of estimating the true global burden of these diseases, and, in particular, better to understand the reasons for why some of them are so remarkably diverse despite being due to the same genetic defect. A better understanding of these mechanisms are absolutely critical to improving the future management of many of these diseases in the developing countries.

Technical Summary

The inherited disorders of haemoglobin are by far the commonest monogenic diseases. Over 300,000 babies are born each year with either sickle cell anaemia or a form of thalassaemia; 80% of these births occur in low or middle-income countries. The commonest forms of severe thalassaemia are the ? thalassaemias, which are divided into ? thalassaemia major and the co-inheritance of ? thalassaemia and haemoglobin (Hb) E, HbE ? thalassaemia. Globally, HbE ? thalassaemia comprises about 50% of severe cases of ? thalassaemia and occurs at its highest incidence in parts of India, Bangladesh and throughout Southeast Asia. The management of HbE ? thalassaemia is in many ways more difficult than that of other severe forms of ? thalassaemia because it has such an extraordinarily diverse clinical phenotype, ranging from a transfusion-dependent disorder similar to ? thalassaemia major to a condition which is compatible with survival into adult life with little or no transfusion. As well as this phenotypic diversity the management of HbE ? thalassaemia is further complicated by the instability of its clinical manifestations over the first few years of life. Another difficult aspect of the phenotype associated with its clinical management is the fact that the steady-state haemoglobin levels in the mild and severe phenotypes often only vary between 1-2 g/dl. Surprisingly however, there are very few data on the natural history of this disease and its overall mortality, either in the developed or developing countries. Over the last 15 years we have developed partnerships with a variety of countries in Asia, notably Sri Lanka, to study HbE ? thalassaemia. This work has two major objectives. First, to try to understand some of the reasons for the remarkable phenotypic variability of the disease. Second, to describe its natural history and, in particular, to follow the course of older patients with this condition who have not received regular transfusion to determine whether a lifelong course of a low haemoglobin level is associated with complications as these patients age. By raising money from several different sources it has been possible to build a new treatment centre for these patients in Kurunegala, Sri Lanka, which now cares for over 600 patients with ? thalassaemia, 200 of which have HbE ? thalassaemia. We have also raised money for the building of a major diagnostic centre at the University of Kelaniya in Colombo, to which is attached an adult thalassaemia centre and full facilities for diagnosis at the protein and DNA level. The third aspect of this programme is directed at micromapping the frequency of the thalassaemias in Asian countries. Little work has been done on the population frequency of these diseases since the 1980s and there are very limited data, a major deficiency in trying to determine their true public health problems. Most of the published data is based on one or two centres and it is already clear that the distribution of the thalassaemias is extremely heterogeneous within different countries. Therefore extensive mapping of their frequency is required from numerous different regions in high-frequency populations. Towards this end we have carried out several micromapping studies and are also trying to develop an Asian Network between countries which have already developed this type of technology and those where facilities for the diagnosis and management of the thalassaemias are non-existent.

Publications

10 25 50

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Allen A (2019) The p.H63D allele of the HFE gene protects against low iron stores in Sri Lanka. in Blood cells, molecules & diseases

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Blobel GA (2021) Testing the super-enhancer concept. in Nature reviews. Genetics

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Hay D (2017) The future of academic haematology. in British journal of haematology

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Hentges LD (2022) LanceOtron: a deep learning peak caller for genome sequencing experiments. in Bioinformatics (Oxford, England)

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Higgs DR (2020) Enhancer-promoter interactions and transcription. in Nature genetics

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Kato GJ (2018) Sickle cell disease. in Nature reviews. Disease primers

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Oudelaar AM (2021) The mouse alpha-globin cluster: a paradigm for studying genome regulation and organization. in Current opinion in genetics & development

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Premawardhena A (2019) Headache: an important symptom possibly linked to white matter lesions in thalassaemia. in British journal of haematology

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Taher AT (2018) Thalassaemia. in Lancet (London, England)

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Weatherall DJ (2018) The Evolving Spectrum of the Epidemiology of Thalassemia. in Hematology/oncology clinics of North America

Related Projects

Project Reference Relationship Related To Start End Award Value
MC_UU_00016/1 31/03/2017 30/03/2022 £3,035,000
MC_UU_00016/2 Transfer MC_UU_00016/1 31/03/2017 30/03/2022 £3,411,000
MC_UU_00016/3 Transfer MC_UU_00016/2 31/03/2017 30/03/2022 £1,366,000
MC_UU_00016/4 Transfer MC_UU_00016/3 31/03/2017 30/03/2020 £3,017,000
MC_UU_00016/5 Transfer MC_UU_00016/4 31/03/2017 30/03/2020 £497,000
MC_UU_00016/6 Transfer MC_UU_00016/5 31/03/2017 30/03/2022 £2,530,000
MC_UU_00016/7 Transfer MC_UU_00016/6 31/03/2017 30/03/2022 £2,018,000
MC_UU_00016/8 Transfer MC_UU_00016/7 31/03/2017 30/03/2018 £1,131,000
MC_UU_00016/9 Transfer MC_UU_00016/8 31/03/2017 30/03/2022 £2,500,000
MC_UU_00016/10 Transfer MC_UU_00016/9 31/03/2017 30/03/2018 £1,171,000
MC_UU_00016/11 Transfer MC_UU_00016/10 31/03/2017 30/03/2022 £1,387,000
MC_UU_00016/12 Transfer MC_UU_00016/11 31/03/2017 30/03/2022 £446,000
 
Description Anthony Cerami and Ann Dunne Foundation for World Health
Amount £112,750 (GBP)
Organisation Anthony Cerami and Anne Dunne Foundation for World Health 
Sector Charity/Non Profit
Country United States
Start 03/2017 
End 02/2019
 
Description Gift from American Charity
Amount $100,000 (USD)
Organisation Anthony Cerami and Anne Dunne Foundation for World Health 
Sector Charity/Non Profit
Country United States
Start 01/2012 
End 01/2020
 
Description Enhancing tumour specific immune responses for the treatment of ovarian cancer 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Access to ovarian cancer biology and computational work
Collaborator Contribution Immunology expertise and cancer antigene prediction.
Impact The Ovarian Cancer Action (OCA) international grand challenge award Publication by Cancer Cell in Feb 2020: " The Repertoire of Serous Ovarian Cancer Non-genetic Heterogeneity Revealed by Single-Cell Sequencing of Normal Fallopian Tube Epithelial Cells"
Start Year 2016
 
Description Long term collaboration with the Hemoglobal Program in Toronto 
Organisation University of Toronto
Country Canada 
Sector Academic/University 
PI Contribution The Toronto group have taken part in our collaboration with Sri Lanka and helped it to develop in every level
Collaborator Contribution They have played a particularly strong role in the analysis of the clinical features of thalassaemia in Sri Lanka and also parts of India where we also work
Impact Capacity building (new treatment and diagnostic centre built in Sri Lanka) and many publications - 22631040, 21879898, 21726207, 20712787, 22885163, 23138098, 23834321, 25519750, 25572187
Start Year 2006
 
Description Long-term collaborative programme with Department of Medicine, University of Kelaniya, Sri Lanka 
Organisation University of Kelaniya
Country Sri Lanka 
Sector Academic/University 
PI Contribution This programme has been going on for 15 years and has entailed us carrying out wide range research on the different forms of thalassaemia in Sri Lanka
Collaborator Contribution We have trained Professor Premawardhena and his staff in the diagnosis and care of the thalassaemias and helped them develop some local research programmes. We have also carried out a lot of capacity building - having built them a new treatment centre and diagnostic centre and helped the government to develop a thalassaemia control programme. Our partners have taken part in every aspect of this programme over the last 15 years
Impact Capacity building (new treatment and diagnostic centre built in Sri Lanka) and many publications - 22631040, 21879898, 21726207, 20712787, 22885163, 23138098, 23834321,25519750, 25572187
Start Year 2006
 
Description Research partnership with the Department of Evolutionary Ecology of Infectious Diseases 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution My team carries out all the diagnostic and molecular analysis together with the population genetics of the inherited haemoglobin disorders while Professor Gupta's group provide invaluable aid with the statistical analysis of every aspect of our work.
Collaborator Contribution The essential statistical analyses of every aspect of our thalassaemia work
Impact Many publications - 24748392, 23874164, 23591685, 23568771, 23103089, 21045822, 23874164, 24748392, 25521998
Start Year 2009
 
Description 11th Cooley's Anemia Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists.
Year(s) Of Engagement Activity 2022
 
Description David & Jean Nathan Inaugural Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists.
Year(s) Of Engagement Activity 2022
 
Description EBMT Haemoglobinopathy Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists.
Year(s) Of Engagement Activity 2022
 
Description European School of Haematology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists.
Year(s) Of Engagement Activity 2023
 
Description MPI Berlin 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists.
Year(s) Of Engagement Activity 2023
 
Description Oxford TEE meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists.
Year(s) Of Engagement Activity 2022
 
Description Spetses Summer School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists.
Year(s) Of Engagement Activity 2022
 
Description Switching Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists.
Year(s) Of Engagement Activity 2022
 
Description Symposium on Chromatin Changes 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists.
Year(s) Of Engagement Activity 2022