Browsing by Author "Clegg, J.B."
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Item The Global distribution of length polymorphisms of the promoters of the gucuronosyltransferase I gene(UGTIAI): hematologic and evolutionary implications(Academic Press, 2003) Premawardhena, A.P.; Fisher, C.A.; Liu, Y.T.; Verma, I.C.; de Silva, S.; Arambepola, M.; Clegg, J.B.; Weatherall, D.J.The promoter region of the UDP glucuronosyltransferase 1 gene (UGT1A1) contains a run of thymine-adenine (TA) repeats, usually six (TA)(6). As well as its relationship to Gilbert's syndrome, homozygosity for the extended sequence, (TA)(7) (TA)(7), has been found to be an important risk factor for hyperbilirubinemia and gallstones in patients with hemoglobin E-beta-thalassemia and other intermediate forms of beta thalassemia. To assess the importance of this polymorphism in these common disorders a wide-scale population study of the relative frequency of the size alleles of the UGT1A1 promoter has been carried out. Homozygosity for the (TA)(7) allele occurs in 10-25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurs at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations show a much greater diversity of length alleles than other populations. These findings define those populations with a high frequency of hemoglobin E-beta-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gall bladder disease and provide evolutionary insights into how these polymorphisms have arisen and are so unequally distributed among human populations.Item Thalassaemia in Sri Lanka: implications for the future health burden of asian populations(Lancet Publishing Group, 2000) de Silva, S.; Fisher, C.A.; Premawardhena, A.P.; Lamabadusuriya, S.P.; Peto, T.E.; Perera, G.; Old, J.M.; Clegg, J.B.; Olivieri, N.F.; Weatherall, D.J.; Sri Lanka Thalassaemia Study GroupBACKGROUND: Thalassaemias pose an increasing problem for the Indian subcontinent and many Asian countries. We analysed the different types of thalassaemia in the Sri Lankan population, surveyed gene frequencies in schoolchildren, and estimated the burden of disease and requirements for its control. METHODS: We analysed blood samples from patients attending clinics in nine hospitals and defined the different types of beta thalassaemia by high-performance liquid chromatography (HPLC) and DNA analysis. The range of mutations was obtained by analysis of beta-globin genes. Capillary blood was obtained from schoolchildren from different parts of the island and analysed by HPLC to provide an approximate assessment of the carrier frequency of beta thalassaemia and haemoglobin E (HbE). To estimate the frequency of alpha thalassaemia the alpha-globin genotypes were also analysed when it was possible. FINDINGS: Blood samples were obtained from 703 patients with beta thalassaemia and from 1600 schoolchildren. The thalassaemia mutations were unevenly spread. Although 23 different beta-thalassaemia mutations were found, three accounted for the thalassaemia phenotype in about 70% of the patients, most whom are homozygotes or compound heterozygotes for IVS1-5 (G-->C) or IVS1-1 (G-->A). The third common mutation, codon 26 (G-->A), which produces HbE, interacts with one or other of these mutations to produce HbE/beta thalassaemia; this comprises 13.0-30.9% of cases in the main centres. Samples from 472 patients were analysed to determine the alpha-globin genotype. Overall, 15.5% patients were carriers for deletion forms of alpha+ thalassaemia. Average gene frequencies showed that there will be more than 2000 patients requiring treatment at any one time, in thefuture, of whom those with HbE/beta thalassaemia will account for about 40%. INTERPRETATION: In Sri Lanka, interactions of the two common beta-thalassaemia alleles will nearly always result in a transfusion-dependent disorder. However, about 40% of patients will have HbE/beta thalassaemia, which has a variable course. The management of these disorders could require about 5% of the total health budget. We need to learn more about the natural history and appropriate management of HbE/beta thalassaemia if resources are to be used effectively.Item The worldwide prevalence of the UGT-1A1 promoter polymorphism as a contributor for phenotypic variability in thalassaemia(Sri Lanka Medical Association, 2003) Premawardhena, A.P.; Lilt, Y.T.; Fisher, C.A.; Clegg, J.B.; Weatherall, D.J.INTRODUCTION: The number of TA repeats in the promoter region of the UGTIA1 gene is involved in fine-tuning of the serum bilirubin level. People who inherit more TA repeats than in the wild type (6), tend to have higher than normal Serum bilirubin levels. When homozygosity for 7 repeats is co-inherited with hereditary anaemias the patients have an elevated serum bilirubin level and an increased incidence of gallstone formation. OBJECTIVES: To investigate the pattern of UGTIAI promoter genotype in several diverse populations across the world. METHODS: A fluorescent labeled PCR method was designed which would amplify the region of interest of the UGTIAI gene. The PCR products were separated using (PAGE) polyacrelymide gel electrophoresis. DNA samples for the study were collected from people from 15 countries, from 5 continents. RESULTS: We found remarkable diversity of the UGTIAI polymorphism amongst people of African origin. The haplotype 7/7 was found in very high frequencies in India. Sri Lanka and Bangladesh, and was extremely rare amongst people of Southeast Asian origin. The Europeans and the Africans had intermediate frequencies. DISCUSSION: These results suggest that in people of Southeast Asian origin, a group that has a high prevalence of thalassaemia and other heamoglobinopathies, the UGTIAI polymorphisms are unlikely to be important genetic modifiers of the phenotype. However, Sri Lankans and other South Asians are very likely to be influenced by this polymorphism. These results also support the theory of African origins of Homo sapiens.