This mutation is a cause of beta-plus-thalassemia (613985). See Hunt and Ingram (1961), Shibata et al. (1962), Blackwell et al. (1970), Fairbanks et al. (1980), Benz et al. (1981), and Kazazian et al. (1984).
Orkin et al. (1982) reported the complete nucleotide sequence of a beta-E-globin gene. They found a GAG-to-AAG change in codon 26 as the only abnormality. Expression of the beta-E gene was tested by introducing it into HeLa cells. Two abnormalities of RNA processing were shown: slow excision of intervening sequence-1 and alternative splicing into exon 1 at a cryptic donor sequence within which the codon 26 nucleotide substitution resides.
Antonarakis et al. (1982) used the Kazazian haplotype approach of analyzing DNA polymorphisms in the beta-globin cluster to present evidence that the beta-E mutation occurred at least twice in Southeast Asia. Thein et al. (1987) demonstrated that the GAG-to-AAG change could be recognized by the restriction enzyme MnlI which cleaves DNA at the sequence 3-prime-GGAG-5-prime.
Rey et al. (1991) described SE disease in 3 black American children of Haitian origin. They pointed out that the disorder is probably more benign than SC disease, SO(Arab) disease, and SC(Harlem) disease, all of which have increased risk of the complications of sickling including pneumococcal sepsis.
Rees et al. (1996) reported a girl homozygous for Hb E with severe anemia and anisopoikilocytosis, who was also homozygous for pyrimidine 5-prime nucleotidase deficiency (P5N; 266120). In erythrocytes deficient for P5N, the stability of the Hb E was decreased.
Hemoglobin E is very common in parts of Southeast Asia. Chotivanich et al. (2002) examined the possible protective role of Hb E and other prevalent inherited hemoglobin abnormalities against malaria (611162) in Thailand. They assessed the effect of Hb E by means of a mixed erythrocyte invasion assay. In vitro, starting at 1% parasitemia, Plasmodium falciparum preferentially invaded normal (HbAA) compared to abnormal hemoglobin red blood cells, including those heterozygous and homozygous for Hb E. The heterozygote HbAE cells differed markedly from all the other cells tested, with invasion restricted to approximately 25% of the red blood cells. Despite their microcytosis, AE heterozygous cells were functionally relatively normal in contrast to the red blood cells from the other hemoglobinopathies studied. Chotivanich et al. (2002) interpreted these findings as suggesting that HbAE erythrocytes have an unidentified membrane abnormality that renders most of the red blood cell population relatively resistant to invasion by P. falciparum. This would not protect from uncomplicated malaria infections but would prevent the development of heavy parasite burdens and was considered consistent with the 'Haldane hypothesis' of heterozygote protection against severe malaria for Hb E.
The Hb E variant is concentrated in parts of Southeast Asia where malaria is endemic, and Hb E carrier status confers some protection against Plasmodium falciparum malaria. To examine the effect of natural selection on the pattern of linkage disequilibrium (LD) and to infer the evolutionary history of the Hb E variant, Ohashi et al. (2004) analyzed biallelic markers surrounding the Hb E variant in a Thai population. Pairwise LD analysis of Hb E and 43 surrounding biallelic markers revealed LD of Hb E extending beyond 100 kb, whereas no LD was observed between non-Hb E variants and the same markers. The inferred haplotype network suggested a single origin of the Hb E variant in the Thai population. Forward-in-time computer simulations under a variety of selection models indicated that the Hb E variant arose 1,240 to 4,440 years ago. Thus, the Hb E mutation occurred recently and allele frequency increased rapidly. The study demonstrated that a high resolution LD map across the human genome can detect recent variants that have been subjected to positive selection.
The highest frequencies of the Hb E gene in large population samples, approximately 0.3, had been observed in the southern part of northeastern Thailand. Even higher frequencies were observed by Flatz et al. (2004) in Austroasiatic populations in southern Laos. One frequency was as high as 0.433 in a population of Sekong Province.
As in other areas of Southeast Asia, hemoglobin E is a very common hemoglobin variant in India, where the highest prevalence of hemoglobin E has been observed in the northeastern regions. In West Bengal, carrier frequency varies from 5 to 35% in different subpopulations, whereas in Assam and Meghalaya, the heterozygous frequency ranges from 27 to 51%. Individuals heterozygous for hemoglobin E have normal or near-normal mean corpuscular volume (MCV) with 27 to 31% of the abnormal Hb in peripheral blood. Homozygosity for hemoglobin E is commonly benign, characterized by mild hypochromic microcytic anemia with the presence of target cells. Edison et al. (2005) observed hyperbilirubinemia among patients with homozygosity for the hemoglobin E gene in the Indian population, with jaundice being the major complaint at presentation. A study of UGT1A1 gene polymorphism showed that the variant TA(7) in the promoter region of the UGT1A1 gene (191740.0011) was associated with hyperbilirubinemia in homozygous HbE patients.
The role of the TA(7) polymorphism of UGT1A1 in the determination of jaundice and gallstones in hemoglobin E beta-thalassemia had been pointed out by Premawardhena et al. (2001) in studies from Sri Lanka. The same group (Premawardhena et al., 2003) studied the global distribution of length polymorphisms of the promoters of the UGT1A1 gene. They found that homozygosity for the TA(7) allele occurred in 10 to 25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurred at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations showed a much greater diversity of length alleles than other populations. These findings defined those populations with a high frequency of hemoglobin E beta-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gallbladder disease. Beutler et al. (1998) had suggested that the wide diversity in the frequency of the UGT1A1 promoter alleles might reflect a balanced polymorphism mediated through the protective effect of bilirubin against oxidative damage.
O'Donnell et al. (2009) studied Sri Lankan patients with HbE beta-thalassemia for exposure to malaria caused by P. falciparum or P. vivax. They found that there were high frequencies of antibodies to both malaria parasites, as well as DNA-based evidence of current infection with P. vivax. Comparisons with age-matched controls showed that there was a higher frequency of antibodies in thalassemic patients, particularly against P. vivax and in young children, that was unlikely to be related to transfusion. A higher frequency was also found in patients who had undergone splenectomy. O'Donnell et al. (2009) proposed that patients with HbE beta-thalassemia may be more prone to malaria, particularly P. vivax malaria.
The estimated number of worldwide annual births of patients with HbE beta-thalassemia is 19,128 (Modell and Darlison, 2008 and Weatherall, 2010).
