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Despite major advances in our understanding of the molecular pathology, pathophysiology, and control and management of the inherited disorders of haemoglobin, thousands of infants and children with these diseases are dying through lack of appropriate medical care. This problem will undoubtedly increase over the next 20 years because, as the result of a reduction in childhood mortality due to infection and malnutrition, more babies with haemoglobin disorders will survive to present for treatment. Although WHO and various voluntary agencies have tried to disseminate information about these diseases, they are rarely mentioned as being sufficiently important to be included in setting health care priorities for the future. It takes considerable time to establish expertise in developing programmes for the control and management of these conditions, and the lessons learned in developed countries will need to be transmitted to those countries in which they occur at a high frequency.

In many Asian populations, the commonest form of severe thalassemia results from the coinheritance of HbE and/3 thalassemia. The management of this disease is particularly difficult because of its extreme clinical diversity; although some genetic and adaptive factors have been identified as phenotypic modifiers, the reasons remain unclear. Because the role of the environment in the course of severe thalassemia has been neglected completely and because malaria due to both Plasmodium falciparum and Plasrnodium vivax has been prevalent in Sri Lanka, we carried out a pilot study of patients with HbE [beta] thalassemia that showed high frequencies of antibodies to both parasite species and that 28.6% of the children had DNA-based evidence of current infection with P. vivax. Malarial antibodies then were assessed in patients with HbE [beta] thalassemia compared with those in age-matched controls. There was a significant increase in the frequency of antibodies in the thalassemic patients, particularly against P. vivax and in young children. There was also a higher frequency in those who had been splenectomized compared with those with intact spleens, although in the latter it was still higher than that in the controls. The thalassemic patients showed significant correlations between malaria antibody status and phenotype. Patients with HbE [beta] thalassemia may be more prone to malaria, particularly P. vivax, which is reflected in their clinical severity. Because Po vivax malaria is widespread in Asia, further studies of its interaction with HbE [beta] thalassemia and related diseases are required urgently as a part of ongoing thalassemia control programs. www.pnas.org/cgi/doi/10.1073/pnas.0910142106

Severe forms of anemia in children in the developing countries may be characterized by different clinical manifestations at particular stages of development. Whether this reflects developmental changes in adaptation to anemia or other mechanisms is not clear. The pattern of adaptation to anemia has been assessed in 110 individuals with hemoglobin (Hb) E [beta]-thalassemia, one of the commonest forms of inherited anemia in Asia. It has been found that age and Hb levels are independent variables with respect to erythropoietin response and that there is a decline in the latter at a similar degree of anemia during development. To determine whether this finding is applicable to anemia due to other causes, a similar study has been carried out on 279 children with severe anemia due to Plasmodium falciparum malaria; the results were similar to those in the patients with thalassemia. These observations may have important implications both for the better understanding of the pathophysiology of profound anemia in early life and for its more logical and cost-effective management. erythropoietin | malaria | thalassemia | hemoglobin

Studies show that the hemochromatosis gene has been impacted by selection pressure. In research comparing data from the Middle East and Sri Lanka, three new haplotypes were discovered in the Sri Lanka independent from known forms in the Middle East, indicating that mutations arose separately from other origins. This implies that causation of hemochromatosis is multicentric.

In the South West Pacific region, the striking geographical correlation between the frequency of [[Alpha].sup.+]-thalassemia and the endemicity of Plasmodium falciparum suggests that this hemoglobinopathy provides a selective advantage against malaria. In Vanuatu, paradoxically, [[Alpha].sup.+]-thalassemia increases the incidence of contracting mild malaria in the first 2 years of life, but severe disease was too uncommon to assess adequately. Therefore, we undertook a prospective case-control study of children with severe malaria on the north coast of Papua New Guinea, where malaria transmission is intense and [[Alpha].sup.+]-thalassemia affects more than 90% of the population. Compared with normal children, the risk of having severe malaria was 0.40 (95% confidence interval 0.22-0.74) in [[Alpha].sup.+]-thalassemia homozygotes and 0.66 (0.37-1.20) in heterozygotes. Unexpectedly, the risk of hospital admission with infections other than malaria also was reduced to a similar degree in homozygous (0.36; 95% confidence interval 0.22-0.60) and heterozygous (0.63; 0.38-1.07) children. This clinical study demonstrates that a malaria resistance gene protects against disease caused by infections other than malaria. The mechanism of the remarkable protective effect of [[Alpha].sup.+]-thalassemia against severe childhood disease remains unclear but must encompass the clear interaction between this hemoglobinopathy and both malarial and nonmalarial infections.

An epidemiological study of children on the island of Espiritu Santo in Vanuatu revealed a higher incidence of malaria in alpha-thalassaemic children, an effect most pronounced in the youngest children and for the less virulent malarial parasite Plasmodium vivax. The increased malaria incidence among alpha-thalassaemic children may be due to their beneficial ability to increase susceptibility to P. vivax, which acts as a natural vaccine and generates increased immunity, thus reducing the likelihood of a fatal or life-threatening attack.

Almost 25 years have passed since the advent of human recombinant DNA technology yet it has brought only small benefits for medical practice. Molecular geneticists studying common conditions such as heart disease and diabetes have merely identified one of a number of genes that may, in certain circumstances, affect an individual's susceptibility to the action of different environmental agents, some of which are known to be implicated in those diseases. 'Gene therapy' is another somewhat disappointing area of human genetics since replacing genes that cause disease with good ones has so far proved too difficult.