Main Article Content
Background: The protective effect of α-thalassemia, a common hematological disorder in Southeast Asia, against Plasmodium falciparum malaria has been well established. However, there are much less well understood the effect of α-thalassemia against P.vivax. Here, we aimed to investigate the proportion of α-thalassemia including the effect of α-thalassemia and HbE on the parasitemia of P.vivax in Southeast Asian malaria patients in Thailand.
Methods: A total of 210 malaria patients, admitted to the Hospital for Tropical Diseases, Thailand during 2011-2012, consist of 159 Myanmeses, 13 Karens, 26 Thais, 3 Mons, 3 Laotians, and 6 Cambodians were recruited. Plasmodium spp. and parasite densities were determined. Group of deletion mutation (--SEA, -α3.7, -α4.2deletion) and substitution mutation (HbCS and HbE) were genotyped using multiplex gap-PCR and PCR-RFLP, respectively.
Results: In our malaria patients, 17/210 homozygous and 74/210 heterozygous -α3.7 deletion were found. Only 3/210 heterozygous -α4.2 deletion and 2/210 heterozygous--SEA deletion were detected. HbE is frequently found with 6/210 homozygote and 35/210 heterozygote. The most common thalassemia allele frequencies in Myanmar population were -α3.7 deletion (0.282), followed by HbE (0.101), HbCS (0.016), -α4.2 deletion (0.009), and --SEA deletion (0.003). Only density of P.vivax in α-thalassemia trait patients (-α3.7/-α3.7, --SEA/αα, -α3.7/-α4.2) but not in silent α-thalassemia (-α3.7/αα, -α4.2/αα, ααCS/αα) were significantly higher compared with non α-thalassemia patients (p=0.027). Density of P.falciparum significantly increased in heterozygous HbE patients (p=0.046).
Conclusions: Alpha-thalassemia trait is associated with high level of P.vivax parasitemia in malaria patients in Southeast Asia.
Downloads month by month
2. Thailand malaria report 2016. Bangkok: Bureau of Vector Borne Diseases Department of Disease Control, Ministry of Public Health. http://www.thaivbd.org. Accessed 26 Oct 2016.
3. Haldane JB. Disease and evolution. La Ricerca Sci 1949; 19: 68-76.
4. Flint J, Hill AV, Bowden DK, Oppenheimer SJ, Sill PR, Serjeantson SW, Bana-Koiri J, Bhatia K, Alpers MP, Boyce AJ, Weatherall DJ, Clegg JB. High frequencies of alpha-thalassaemia are the result of natural selection by malaria. Nature 1986; 321: 744-750.
5. Kwiatkowski DP. How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet 2005; 77: 171-192.
6. Verra F, Mangano VD, Modiano D. Genetics of susceptibility to Plasmodium falciparum: from classical malaria resistance genes towards genome-wide association studies. Parasite Immunol 2009; 31: 234-253.
7. Louicharoen C, Patin E, Paul R, Nuchprayoon I, Witoonpanich B, Peerapittayamongkol C, Casademont I, Sura T, Laird M. N, Singhasivanon P, Quintana-murci L, Sakuntabhai A. Positively selected G6PD-Mahidol mutation reduces Plasmodium vivax density in Southeast Asians. Science 2009; 326: 1546-1549.
8. Williams TN, Wambua S, Uyoga S, Macharia A, Mwacharo JK, Newton CR, Maitland K. Both heterozygous and homozygous alpha+ thalassemias protect against severe and fatal Plasmodium falciparum malaria on the coast of Kenya. Blood 2005; 106: 368–371.
9. Wambua S, Mwangi TW, Kortok M, Uyoga SM, Macharia AW, Mwacharo JK, Weatherall DJ, Snow RW, Marsh K, Williams TN. The effect of α+-thalassaemia on the incidence of malaria and other diseases in children living on the coast of Kenya. PLoS Med 2006; 3: 158.
10. Agarwal A, Guindo A, Cissoko Y, Taylor JG, Coulibaly D, Koné A, Kayentao K, Djimde A, Plowe CV, Doumbo O, Wellems TE, Diallo D. Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S. Blood 2000; 96: 2358–2363.
11. Modiano D, Luoni G, Sirima BS, Simporé J, Verra F, Konaté A, Rastrelli E, Olivieri A, Calissano C, Paganotti GM, D'Urbano L, Sanou I, Sawadogo A, Modiano G, Coluzzi M. Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 2001; 414: 305–308.
12. Cabrera G, Cot M, Migot-Nabias F, Kremsner PG, Deloron P, Luty AJ. The sickle cell trait is associated with enhanced immunoglobulin G antibody responses to Plasmodium falciparum variant surface antigens. J Infect Dis 2005; 191: 1631–1638.
13. Chotivanich K, Udomsangpetch R, Pattanapanyasat K, Chierakul W, Simpson J, Looareesuwan S, White N. Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P. falciparum malaria. Blood 2002; 100: 1172–1176.
14. Taylor SM, Parobek CM, Pairhurst RM. Haemoglobinopathiesand the clinical epidemiology of malaria: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12: 457-468.
15. Chen YL, Shih CJ, Ferrance J, Chang YS, Chang JG, Wu SM. Genotyping of alpha-thalassemia deletions using multiplex polymerase chain reactions and gold nanoparticle-filled capillary electrophoresis. J Chromatogr A 2009; 1216: 1206-1212.
16. Fucharoen S, Winichagoon P. Haemoglobinopathies in Southeast Asia. Indian J Med Res 2011; 134: 498-506.
17. Rosanas-Urgell A, Senn N, Rarau P, Aponte JJ, Reeder JC, Siba PM, Michon P, Mueller I. Lack of association of α+-thalassemia with the risk of Plasmodium falciparum and Plasmodium vivax infection and disease in a cohort of children aged 3-21 months from Papua New Guinea. Int J Parasitol 2012; 1: 1107-1113.
18. Mockenhaupt FP, Ehrhardt S, Gellert S, Otchwemah RN, Dietz E, Anemana SD, Bienzie U. Alpha(+)-thalassemia protects African children from severe malaria. Blood 2004; 104: 2003-2006.
19. Allen SJ, O'Donnell A, Alexander ND, Alpers MP, Peto TE, Clegg JB, Weatherall DJ. alpha+-Thalassemia protects children against disease caused by other infections as well as malaria. ProcNatlAcadSci U S A 1997; 94: 14736-14741.
20. May J, Evans JA, Timmann C, Ehmen C, Busch W, Thye T, Agbenyega T, Horstmann RD. Hemoglobin variants and disease manifestations in severe falciparum malaria. JAMA 2007; 297: 2220-2226.
21. Opoku-Okrah C, Gordge M, KwekuNakua E, Agbenyega T, Parry M, Robertson C, Smith CL. An investigation of the protective effect of alpha+-thalassemia against severe Plasmodium falciparum amongst children in Kumasi, Ghana. Int J Lab Hematol 2014; 36: 62-70.
22. Qiu Q, Wu D, Yu L, Yan T, Zhang W, Li ZT, Liu YH, Zhang YP, Xu XM. Evidence of recent natural selection on the Southeast Asian deletion (--SEA) causing α-thalassemia in South China. BMC Evol Biol 2013; 13: 63.
23. Williams TN, Maitland K, Bennett S, Ganczakowski M, Peto TEA, Newbold CI, Bowden DK, Weatherall DJ, Clegg JB. High incidence of malaria in α-thalassaemic children. Nature 1996; 383: 522-525.
24. O’Donnell A, Premawardhena A, Arambepola M, Samaranyake R, Allen SJ, Peto TE, Fisher CA, Cook J, Corran PH, Olivieri NF, Weatherall DJ. Interaction of malaria with a common form of severe thalassemia in an Asian population. ProcNatlAcadSci USA 2009; 106: 18716-18721.
25. Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: A Laboratory Manual. Second ed. NewYork. Cold Spring Harbour 1989.
26. Chong SS, Boehm CD, Higgs DR, Cutting GR. Single-tube multiple-PCR screen for common deletional determinants of alpha-thalassemia. Blood 2000; 95: 360-362.
27. Makonkawkeyoon L, Sanguansermsri T, Asato T, Nakashima Y, Takei H. Rapid detection of chain termination mutations in the alpha 2 globin gene. Blood 1993; 82: 3503-3504.
28. Tachavanich K, Viprakasit V, Chinchang W, Glomglao W, Pung-Amritt P, Tanphaichitr VS. Clinical and hematological phenotype of homozygous hemoglobin E: revisit of a benign condition with hidden reproductive risk. Southeast Asian J Trop Med Public Health 2009; 40: 306-316.
29. Kuesap J, Chaijaroenkul W, Rungsihirunrat K, Pongjantharasatien K, Na-Bangchang K. Coexistence of Malaria and Thalassemia in Malaria Endemic Areas of Thailand. Korean J Parasitol 2015; 53: 265-270.
30. Than AM, Harano T, Harano K, Myint AA, Ogino T, Okada S. High incidence of α-thalassemia, Hemoglobin E, and glucose-6-phosphate dehydrogenase deficiency in population of malaria-endemic southern Shan state, Myanmar. Int J Hematol 2005; 82: 119-123.
31. Krügner F, Zaccariotto TR, Rosim ET, Costa FF, Grotto HZ, Sonati MF. Reticulocyte evaluation in alpha(+)-thalassemia. Am J Hematol 2006; 81: 68-70.
32. Maitland K, William TN, Newbold CI. Plasmodium vivax and P.falicparum: biological interactions and the possibility of cross-species immunity. Parasitol Today 1997; 13: 227-231.
33. Oo M, Shwe T, Than M, O’Sullivan WJ. Genetic red cell disorders and severity of falciparum malaria in Myanmar. B World Health Organ 1995; 73: 659-665.
34. Nagel RL, Raventos-Suarez C, Fabry ME, Tanowitz H, Sicard D, Labie D. Impairment of the growth of Plasmodium falciparum in HbEE erythrocytes. J Clin Invest 1981; 68: 303-305.