Prevalence of polymorphisms in glucose-6-phosphate dehydrogenase, sickle haemoglobin and nitric oxide synthase genes and their relationship with incidence of uncomplicated malaria in Iganga, Uganda
Tóm tắt
Host genetics play an important role in Plasmodium falciparum malaria susceptibility. However, information on host genetic factors and their relationships with malaria in the vaccine trial site of Iganga, Uganda is limited. The main objective of this study was to determine the prevalence of selected host genetic markers and their relationship to malaria incidence in the vaccine trial site of Iganga, Uganda. In a 1-year longitudinal cohort study, 423 children aged below 9 years were recruited and their malaria episodes were investigated. Host genetic polymorphisms were assessed by PCR–RFLP, haemoglobin electrophoresis and DNA sequencing. Using a multivariate negative binomial regression model, estimates of the impact of human genetic polymorphisms on malaria incidence were performed. In all statistical tests, a P value of <0.05 was considered as significant. The prevalences of sickle cell haemoglobin trait, G6PD c.202 G>A (rs 1050828) and NOS2 −954 G>C (rs 1800482) variants were 26.6, 22.7 and 17.3%, respectively. Inducible nitric oxide synthase 2 (NOS2 −954 G>C; rs 1800482) heterozygosity was associated with lower incidence of malaria in all age groups {Adjusted incident rates ratio (aIRR) 0.59; 95% CI [0.386–0.887]; P = 0.012)}. About 4% of study subjects had co-existence of sickle cell Hb trait and G6PD deficiency. Sickle cell Hb heterozygotes (Hb AS) aged less than 1 year experienced significantly more malaria episodes annually than children with normal haemoglobin (Hb AA) {aIRR = 1.98; 95% CI [1.240–3.175]; P = 0.004}. There was no significant influence of the sickle cell trait on malaria incidence among older children of 1–9 years. Mutation (NOS2 −954 G>C; rs 1800482) of nitric oxide synthase 2 gene promoter was associated with a lower incidence of acute malaria. The normal haemoglobin (wild genotype; HbAA) was associated with reduced malaria incidence rates during the first year of life. More understanding of the interplay between host genetics and malaria susceptibility is required.
Tài liệu tham khảo
Jallow M, Teo YY, Small KS, Rockett KA, Deloukas P, Clark TG, et al. Genome-wide and fine-resolution association analysis of malaria in West Africa. Nat Genet. 2009;41:657–65.
Timmann C, Thye T, Vens M, Evans J, May J, Ehmen C, et al. Genome-wide association study indicates two novel resistance loci for severe malaria. Nature. 2012;489:443–6.
Malaria Genomic Epidemiology Network, Rockett KA, Clarke GM, Fitzpatrick K, Hubbart C, Jeffreys AE, et al. Reappraisal of known malaria resistance loci in a large multicenter study. Nat Genet. 2014;46:1197–204.
May J, Evans JA, Timmann C, Ehmen C, Busch W, Thye T, et al. Hemoglobin variants and disease manifestations in severe falciparum malaria. JAMA. 2007;297:2220–6.
Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S, et al. Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet. 2002;359:1311–2.
Williams TN, Mwangi TW, Wambua S, Peto TE, Weatherall DJ, Gupta S, et al. Negative epistasis between the malaria-protective effects of alpha+-thalassemia and the sickle cell trait. Nat Genet. 2005;37:1253–7.
Williams TN, Mwangi TW, Wambua S, Alexander ND, Kortok M, Snow RW, et al. Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases. J Infect Dis. 2005;192:178–86.
Clark TD, Greenhouse B, Njama-Meya D, Nzarubara B, Maiteki-Sebuguzi C, Staedke SG, et al. Factors determining the heterogeneity of malaria incidence in children in Kampala, Uganda. J Infect Dis. 2008;198:393–400.
Kreuels B, Kreuzberg C, Kobbe R, Ayim-Akonor M, Apiah-Thompson P, Thompson B, et al. Differing effects of HbS and HbC traits on uncomplicated falciparum malaria, anemia, and child growth. Blood. 2010;115:4551–8.
Crompton PD, Traore B, Kayentao K, Doumbo S, Ongoiba A, Diakite SA, et al. Sickle cell trait is associated with a delayed onset of malaria: implications for time-to-event analysis in clinical studies of malaria. J Infect Dis. 2008;198:1265–75.
Taylor SM, Parobek CM, Fairhurst RM. Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12:457–68.
Carter N, Pamba A, Duparc S, Waitumbi JN. Frequency of glucose-6-phosphate dehydrogenase deficiency in malaria patients from six African countries enrolled in two randomized anti-malarial clinical trials. Malar J. 2011;10:241.
Clarke GM, Rockett K, Kivinen K, Hubbart C, Jeffreys AE, Rowlands K, et al. Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia. Elife. 2017;6:15085.
Uyoga S, Ndila CM, Macharia AW, Nyutu G, Shah S, Peshu N, et al. Glucose-6-phosphate dehydrogenase deficiency and the risk of malaria and other diseases in children in Kenya: a case–control and a cohort study. Lancet Haematol. 2015;2:437–44.
Manjurano A, Sepulveda N, Nadjm B, Mtove G, Wangai H, Maxwell C, et al. African glucose-6-phosphate dehydrogenase alleles associated with protection from severe malaria in heterozygous females in Tanzania. PLoS Genet. 2015;11:1004960.
Guindo A, Fairhurst RM, Doumbo OK, Wellems TE, Diallo DA. X-linked G6PD deficiency protects hemizygous males but not heterozygous females against severe malaria. PLoS Med. 2007;4:66.
Ruwende C, Khoo SC, Snow RW, Yates SN, Kwiatkowski D, Gupta S, et al. Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature. 1995;376:246–9.
Clark TG, Fry AE, Auburn S, Campino S, Diakite M, Green A, et al. Allelic heterogeneity of G6PD deficiency in West Africa and severe malaria susceptibility. Eur J Hum Genet. 2009;17:1080–5.
Toure O, Konate S, Sissoko S, Niangaly A, Barry A, Sall AH, et al. Candidate polymorphisms and severe malaria in a Malian population. PLoS ONE. 2012;7:43987.
Parikh S, Dorsey G, Rosenthal PJ. Host polymorphisms and the incidence of malaria in Ugandan children. Am J Trop Med Hyg. 2004;71:750–3.
Migot-Nabias F, Mombo LE, Luty AJ, Dubois B, Nabias R, Bisseye C, et al. Human genetic factors related to susceptibility to mild malaria in Gabon. Genes Immun. 2000;1:435–41.
Kun JF, Mordmuller B, Perkins DJ, May J, Mercereau-Puijalon O, Alpers M, et al. Nitric oxide synthase 2 (Lambarene) (G−954C), increased nitric oxide production, and protection against malaria. J Infect Dis. 2001;184:330–6.
Cramer JP, Nussler AK, Ehrhardt S, Burkhardt J, Otchwemah RN, Zanger P, et al. Age-dependent effect of plasma nitric oxide on parasite density in Ghanaian children with severe malaria. Trop Med Int Health. 2005;10:672–80.
Gramaglia I, Sobolewski P, Meays D, Contreras R, Nolan JP, Frangos JA, et al. Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria. Nat Med. 2006;12:1417–22.
Serirom S, Raharjo WH, Chotivanich K, Loareesuwan S, Kubes P, Ho M. Anti-adhesive effect of nitric oxide on Plasmodium falciparum cytoadherence under flow. Am J Pathol. 2003;162:1651–60.
Weinberg JB, Lopansri BK, Mwaikambo E, Granger DL. Arginine, nitric oxide, carbon monoxide, and endothelial function in severe malaria. Curr Opin Infect Dis. 2008;21:468–75.
Levesque MC, Hobbs MR, O’Loughlin CW, Chancellor JA, Chen Y, Tkachuk AN, et al. Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes. Hum Genet. 2010;127:163–82.
Mombo LE, Ntoumi F, Bisseye C, Ossari S, Lu CY, Nagel RL, et al. Human genetic polymorphisms and asymptomatic Plasmodium falciparum malaria in Gabonese schoolchildren. Am J Trop Med Hyg. 2003;68:186–90.
Kamugisha E, Bujila I, Lahdo M, Pello-Esso S, Minde M, Kongola G, et al. Large differences in prevalence of Pfcrt and Pfmdr1 mutations between Mwanza, Tanzania and Iganga, Uganda—a reflection of differences in policies regarding withdrawal of chloroquine? Acta Trop. 2012;121:148–51.
Kaddumukasa M, Buwembo W, Sekikubo M, Naiwumbwe H, Namusoke F, Kiwuwa S, et al. Malariometric indices from Iganga, Uganda: baseline characterization in preparation of GMZ2 vaccine trial. BMC Res Notes. 2014;7:793.
Lwanira CN, Kaddumukasa M, Swedberg G, Kironde F. Frequency of RANTES gene polymorphisms and their association with incidence of malaria: a longitudinal study on children in Iganga district, Uganda. Malar J. 2015;14:341.
Republic of Uganda. Uganda Clinical Guidelines: National guidelines on management of common conditions. Ministry of Health. 2010.
World Health Organization. World malaria report. Basic malaria microscopy part I learner’s guide. 2nd ed. 1998. p. 74–5.
de Onis M, Onyango AW, Borghi E, Garza C, Yang H, WHO Multicentre Growth Reference Study Group. Comparison of the World Health Organization (WHO) child growth standards and the National Center for Health Statistics/WHO international growth reference: implications for child health programmes. Public Health Nutr. 2006;9:942–7.
Zhang Y, Li C, Li K, Liu L, Jian Z, Gao T. Analysis of inducible nitric oxide synthase gene polymorphisms in vitiligo in Han Chinese people. PLoS ONE. 2011;6:27077.
Rowe JA, Handel IG, Thera MA, Deans AM, Lyke KE, Kone A, et al. Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting. Proc Natl Acad Sci USA. 2007;104:17471–6.
Balamurari V. Generalisation of the Hardy–Weinberg equation in the case of polygenic inheritance in population genetics and an estimation of the number of genes controlling human height. Nugegoda: University of Sri Jayewardenepura; 2016.
Lugada ES, Mermin J, Kaharuza F, Ulvestad E, Were W, Langeland N, et al. Population-based hematologic and immunologic reference values for a healthy Ugandan population. Clin Diagn Lab Immunol. 2004;11:29–34.
Lopera-Mesa TM, Doumbia S, Konate D, Anderson JM, Doumbouya M, Keita AS, et al. Impact of red blood cell variants on childhood malaria in Mali: a prospective cohort study. Lancet Haematol. 2015;2:140–9.
Billig EM, McQueen PG, McKenzie FE. Foetal haemoglobin and the dynamics of paediatric malaria. Malar J. 2012;11:396.
Kangoye DT, Nebie I, Yaro JB, Debe S, Traore S, Ouedraogo O, et al. Plasmodium falciparum malaria in children aged 0–2 years: the role of foetal haemoglobin and maternal antibodies to two asexual malaria vaccine candidates (MSP3 and GLURP). PLoS ONE. 2014;9:107965.
Mmbando BP, Mgaya J, Cox SE, Mtatiro SN, Soka D, Rwezaula S, et al. Negative epistasis between sickle and foetal haemoglobin suggests a reduction in protection against malaria. PLoS ONE. 2015;10:0125929.