A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Masters of Science, Johannesburg, 2013 / At the University of Witwatersrand academic hospitals, unexplained microcytosis is a commonly encountered clinical problem. The differential diagnosis of microcytosis includes iron deficiency, anaemia of chronic disorder, sideroblastic anaemia (both congenital and acquired e.g. lead poisoning) and thalassaemia trait. α thalassaemia trait is most often not detected through conventional laboratory methods and molecular analysis becomes necessary in this setting.

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The AIMS of this study are to: (1) To explore how South Asian women (those who have ethnic origins in India, Pakistan or Bangladesh) make sense of the beta-thalassaemia trait in the context of their everyday experiences and, in turn, how these experiences impact their identities. (2) To ascertain the extent of the assimilation and management of genetic information by women of South Asian origin. (3) To contribute towards the debate on the provision of culturally sensitive screening policies and the dissemination of genetic information and to analyse ways in which such policies can be improved. STUDY DESIGN: A qualitative modified grounded theory study comprising of semi-structured interviews conducted in English, Urdu, Punjabi, Sylheti and Hindi. Five geographical sites were selected for the study: three in London, one in the West Midlands and a further site in Northern England based on their high density of South Asian populations as indicated by the 1991 UK Census data. Purposive sampling ensured diversity in participant backgrounds (e.g. socio-economic, religion, marital, child’s health and age). Interviews were translated and transcribed by the researcher and the computer software NVivo was used to analyse the data. SAMPLE: Forty-one South Asian women who had been diagnosed with the beta-thalassaemia trait and two haemoglobinopathy nurse specialists who undertook the role of counselling. FINDINGS: The empirical findings revealed the importance of identity, faith, culture and diversity in how women managed the knowledge of the beta thalassaemia trait. Common perceptions held by health service staff of South Asian women being homogenous in attitudes to prenatal diagnosis and termination; as subjugated to their husbands in decision-making; and as fatalistic because of their religious convictions were shown by this study to be misconceived. South Asian women actively managed their trait within the context of their everyday socio-cultural and religious experiences. For example, liberal notions of ‘informed choice’ were found not to take account of the institutional importance of motherhood for South Asian women living in the UK. Their experience of beta-thalassaemia trait was also mediated through relations of power, both within kinship networks and between family and health professionals. In making sense of the genetic identities accorded to them by health professionals, they also re-interpreted, negotiated and contested the ethos of the screening and prenatal testing processes. The participants used power and positionality to relocate their sense of genetic responsibility away from the self onto others, employing geographical and cultural explanations to justify their apparent inaction in the face of biomedical expectations and assumptions. CONCLUSION: Women acted according to their perceptions of how others would perceive them if their trait were to be disclosed and as a result they presented and constructed the trait in order to preserve the ‘self’ within the context of their everyday life experiences which has implications for the delivery of appropriately targeted screening and health services.

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Haemoglobinopathies, which include sickle-cell anaemia (SCA) and α- and β-thalassaemia, represent some of our few unequivocal examples of human evolution. The underlying genetic mutations reflect a recurring adaptation against one of the biggest infectious disease killers of humans, Plasmodium falciparum malaria. Inheritance of one copy of a sickle-cell or thalassaemic allele leads to protection against death from malaria, while two copies can result in a severe blood disorder. As a result, haemoglobinopathies have risen in frequency through balancing selection and pose a significant public health problem in parts of the world with a history of malaria transmission. Their study therefore lies at the interface between evolutionary biology and public health. In this thesis, I explore different aspects of the epidemiology and population genetics of haemoglobinopathies around the world. Using pre-existing epidemiological data, statistical and geostatistical methods and Geographic Information System tools, I develop detailed evidence-based maps of the α-thalassaemia allele frequency distribution and genetic diversity in Southeast Asia and sickle-cell allele frequency in India. Pairing these with birth data, I generate sub-national estimates of the number of newborns born with severe forms of α-thalassaemia and SCA in Thailand and India, respectively, together with uncertainty estimates. In addition, I use a flexible population genetic simulation model to explore evolutionary explanations for the contrasting spatial haplotype patterns observed for SCA and the severe form of β-thalassaemia (β0-thalassaemia) in sub-Saharan Africa and the Middle East, and resurrect a 20-year old question surrounding the genetic origin of sickle-cell. Understanding the fine-scale geographical heterogeneities in the distributions of malaria-protective haemoglobinopathies is critical for addressing basic science questions and applied public health queries. Working at the interface between evolutionary biology and public health has provided me with the opportunity to build a more complete overview of the neglected increasing public health burden that this group of human disorders represents.

Thalassaemia and sickle cell disease (SCD) are the most widely distributed blood genetic disorders that occur at a high frequency in some populations including the Mediterranean region, parts of the Middle East, South East Asia and the Indian subcontinent. It is estimated that thalassaemia major affects 100,000 newborn every year world-wide. The high incidence of these chronic haemolytic diseases in developing countries poses a high load on the national economy because of the expensive treatment protocols and the considerably high morbidity rates of these patients. Repeated blood transfusion to keep haemoglobin above an acceptable level requires well-equipped blood banks with expensive facilities to screen, store and manipulate blood and blood products. Iron chelation therapy is an essential part of treatment to avoid or delay the deleterious effects of iron overload on different organs including the liver, heart, pancreas and endocrine glands. This inquires injecting deferoxamine subcutaneously for 12 hours daily with a special pump. Both deferoxamine and pumps are expensive and therefore not accessible for all patients. In developing countries, the majority of transfusion-dependent patients with chronic haemolytic anaemia (thalassaemia and SCD) suffer from the consequences of sub-optimal treatment. The mortality rate is still high and usually patients die before the age of 30 years. They also suffer from chronic multi-organ damage including cardiac failure, liver cirrhosis, insulin-dependent diabetes mellitus, growth and pubertal failure and many skeletal abnormalities and fractures. In developed countries the introduction of high transfusion regimes and efficient chelation therapy improved survival rates and prevented cardiac and hepatic damage. However, a majority of thalassaemic patients still have significant growth and pubertal abnormalities, bone disease and multiple endocrine disorders. In Egypt the incidence of thalassaemia major ranges between 0.1 - 0.2% which gives very high patient load on the medical services. In our University of Alexandria Children's Hospital, Alexandria, Egypt. The Haematology clinic has an average of 150 thalassaemic children registered. The same problem is encountered by me in the Royal Hospital, Muscat, Oman, with high prevalence of SCD and thalassaemia and suboptimal treatment. Because of the restricted economic resources, both hospitals adopt a low transfusion therapy (to keep haemoglobin above 9 g/dl) with IM chelation 3 times per week. With this form of sub-optimal treatment we observed that a large number of our thalassaemic children have severe growth and pubertal failure/delay, beside other hepatic, cardiac and skeletal abnormalities. In fact they constitute 40% of patients attending our Endocrinology clinic. This stimulated me to perform an extensive study to survey growth and pubertal development in theses patients (study-1) and investigate the different factors that might affect their growth and pubertal development (studies 4 through 10) a \veU as bone mass density (studies > 1,12). The frequent involvement of the liver in these patients led us to study some hepatic functions and the prevalence of transfusion-associated hepatitis B surface antigenaemia and hepatitis-C virus antibody scropositivity in relation to their linear growth (studies 2,3). We studied the nutritional intake of these patients, their intestinal absorption of D-Xylosc and 48-h stool fat content in relation to their body mass index, subcutaneous 'at thickness and mid-arm circumference (studies 4,5,9). Their defective linear growth urged us to investigate their growth hormone (GH) secretion (spontaneous nocturnal as well as after provocation) and insulin-like growth factor-I (IGF-I) and IGK-binding protein-3 (IGKBl'3) concentrations. Our findings demonstrated high prevalence of defective GH secretion in these children that necessitated imaging of their hypothalamic pituitary area. Imaging studies revealed original data about structural abnormalities in the anterior pituitary gland, different degrees of pituitary atrophy and empty sella and infiltration the gland as well as the mid-brain by hacniosidrin in thalassaemic children, the mechanism of these findings was explained (studies 4-6,10). Because of their slow growth, the presence of abnormal GH/IGF-I/BP3 axis, and structural abnormalities of the pituitary gland, the next step dealt with the response of IGF-I to exogenous GH and the clinical response of their linear growth to GH therapy for a year or more (studies 4,9). Based on the fact that these patients have high prevalence of bone pains and osteoporosis during late childhood and have high risk of spontaneous fracture thereafter, we measured their bone mass density to investigate the relation between the former and the degree of iron load, growth parameters, and different anabolic hormone concentrations in these patients (studies 11,12).

Thalassaemia is a blood disorder prevalent amongst the Cypriot population because of genetic, ecological, and social reasons. Although a successful prevention system has been in place since the early 1980s, approximately 650 thalassaemia patients still live on the island whose births preceded the given system. For my fieldwork I spent a year in Cyprus with the PanCyprian Thalassaemia Association (PTA) – a patients group which acts as the main channel of politicisation for thalassaemia patients in Cyprus. By organising events such as conferences, fundraisers and workshops, the PTA strives to maintain the awareness of thalassaemia in the Cypriot public sphere. The association also maintains an agonistic yet healthy relationship with the Cypriot state. Thalassaemia treatment in Cy-prus is provided by public healthcare and, since its foundation in 1973, the PTA has won several skirmishes against the state on issues such as a more reliable blood supply, better provision of medicines, and more hospital space for patients. In addition, the PTA has forged numerous alliances with national and international organisations, patient associa-tions and scientific research bodies which have a decisive say in how thalassaemia comes to be enacted on a Cypriot and global level. Throughout the thesis I focus on the tactics the PTA uses to politically activate thalassaemia. As I argue, activating illness entails mak-ing discernible political dimensions of illness which previously evaded, or were left unac-counted, by public and governmental perceptions. In addition, through the anthropologi-cal analysis of PTA case studies, I develop tactics of my own by which patient associa-tions can activate illness. Through an ethnography and at the same time conceptual de-velopment of tactics, the thesis aims to fruitfully reconcile the ontology and politics of illness.