The online version of this article (doi:10.1186/1475-2875-11-409) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
VAS designed the research project, carried out the laboratory assays, and wrote the manuscript; MGC participated in the study design, planning and data collection, revised the manuscript for important intellectual content and approved the version to be published; MDOO participated in the study design, planning and data collection, performed the malaria diagnosis and revised the manuscript for important intellectual content and approved the version to be published; JMS participated in the study design, planning and data collection, performed the malaria diagnosis and revised the manuscript for important intellectual content and approved the version to be published; NPCS participated in the study design, planning and data collection, performed the malaria diagnosis and revised the manuscript for important intellectual content and approved the version to be published; AKCR participated in the study design, planning and data collection, revised the manuscript for important intellectual content and approved the version to be published; SMC-J participated in the study design, planning and performed the statistical analysis and approved the version to be published; SEBS genotyped the ancestry informative markers, revised the manuscript for important intellectual content, and approved the version to be published; MHH conceived the study, and participated in its design and coordination, analysed the data, and wrote the final version of the article. All authors read and approved the final manuscript.
Malaria is among the most prevalent parasitic diseases worldwide. In Brazil, malaria is concentrated in the northern region, where Plasmodium vivax accounts for 85% disease incidence. The role of genetic factors in host immune system conferring resistance/susceptibility against P. vivax infections is still poorly understood.
The present study investigates the influence of polymorphisms in 18 genes related to the immune system in patients with malaria caused by P. vivax. A total of 263 healthy individuals (control group) and 216 individuals infected by P. vivax (malaria group) were genotyped for 33 single nucleotide polymorphisms (SNPs) in IL1B, IL2, IL4, IL4R, IL6, IL8, IL10, IL12A, IL12B, IL12RB1, SP110, TNF, TNFRSF1A, IFNG, IFNGR1, VDR, PTPN22 and P2X7 genes. All subjects were genotyped with 48 ancestry informative insertion-deletion polymorphisms to determine the proportion of African, European and Amerindian ancestry. Only 13 SNPs in 10 genes with differences lower than 20% between cases and controls in a Poisson Regression model with age as covariate were further investigated with a structured population association test.
The IL1B gene -5839C > T and IL4R 1902A > G polymorphisms and IL12RB1 -1094A/-641C and TNF -1031 T/-863A/-857 T/-308 G/-238 G haplotypes were associated with malaria susceptibility after population structure correction (p = 0.04, p = 0.02, p = 0.01 and p = 0.01, respectively).
Plasmodium vivax malaria pathophysiology is still poorly understood. The present findings reinforce and increase our understanding about the role of the immune system in malaria susceptibility.
Additional file 1: Table S1. List of SNPs investigated in the present study. List of SNPs investigated, their location in the gene, pubmed database SNP identification, manufacturer’s assay identification and allele frequencies in case and control groups. (PDF 134 KB)12936_2012_2568_MOESM1_ESM.pdf
Additional file 2: Table S2. Control and malaria group genotypic frequencies. Genotypic frequencies of all SNPs in case and control groups. (PDF 183 KB)12936_2012_2568_MOESM2_ESM.pdf
Additional file 3: Table S3. Poisson Regression for association between malaria and control samples controlling for age. Poisson Regression results for association between malaria and control samples controlling for age. (PDF 114 KB)12936_2012_2568_MOESM3_ESM.pdf
WHO: World malaria report. 2011, http://www.who.int/malaria/world_malaria_report_2011/9789241564403_eng.pdf,
Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM: Vivax malaria: neglected and not benign. AmJTrop Med Hyg. 2007, 77: 79-87.
Hotez PJ, Bottazzi ME, Franco-Paredes C, Ault SK, Periago MR: The neglected tropical diseases of Latin America and the Caribbean: a review of disease burden and distribution and a roadmap for control and elimination. PLoS Negl Trop Dis. 2008, 2: e300-10.1371/journal.pntd.0000300. PubMedCentralCrossRefPubMed
Park JW, Jun G, Yeom JS: Plasmodium vivax malaria: status in the republic of Korea following reemergence. Korean J Parasitol. 2009, 47 (Suppl): 39-50. 10.3347/kjp.2009.47.S.S39. CrossRef
Lacerda MV, Mourão MP, Alexandre MA, Siqueira AM, Magalhães BM, Martinez-Espinosa FE, Filho FS, Brasil P, Ventura AM, Tada MS, Couto VS, Silva AR, Silva RS, Alecrim MG: Understanding the clinical spectrum of complicated Plasmodium vivax malaria: a systematic review on the contributions of the Brazilian literature. Malar J. 2012, 11: 12-10.1186/1475-2875-11-12. PubMedCentralCrossRefPubMed
Sohail M, Kaul A, Bali P, Raziuddin M, Singh MP, Singh OP, Dash AP, Adak T: Alleles -308A and -1031C in the TNF-alpha gene promoter do not increase the risk but associated with circulating levels of TNF-alpha and clinical features of vivax malaria in Indian patients. Mol Immunol. 2008, 45: 1682-1692. 10.1016/j.molimm.2007.10.002. CrossRefPubMed
Medina TS, Costa SP, Oliveira MD, Ventura AM, Souza JM, Gomes TF, Vallinoto AC, Póvoa MM, Silva JS, Cunha MG: Increased interleukin-10 and interferon-γ levels in plasmodium vivax malaria suggest a reciprocal regulation which is not altered by IL-10 gene promoter polymorphism. Malar J. 2011, 10: 264-10.1186/1475-2875-10-264. PubMedCentralCrossRefPubMed
Manual de diagnóstico laboratorial da malária. 2005, http://portal.saude.gov.br/portal/arquivos/pdf/manual_diagnostico_malaria.pdf,
Sambrook J, Fritsch EF, Maniatis T: Molecular cloning. A laboratory manual. 1989, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press, 2
Santos NP, Ribeiro-Rodrigues EM, Ribeiro-Dos-Santos AK, Pereira R, Gusmão L, Amorim A, Guerreiro JF, Zago MA, Matte C, Hutz MH, Santos SE: Assessing individual interethnic admixture and population substructure using a 48-insertion-deletion (INSEL) ancestry-informative marker (AIM) panel. Hum Mutat. 2010, 31: 184-190. 10.1002/humu.21159. CrossRefPubMed
Pena SD, Di Pietro G, Fuchshuber-Moraes M, Genro JP, Hutz MH, KehdyFde S, Kohlrausch F, Magno LA, Montenegro RC, Moraes MO, de Moraes ME, de Moraes MR, Ojopi EB, Perini JA, Racciopi C, Ribeiro-Dos-Santos AK, Rios-Santos F, Romano-Silva MA, Sortica VA, Suarez-Kurtz G: The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS One. 2011, 6: e17063-10.1371/journal.pone.0017063. PubMedCentralCrossRefPubMed
Dinarello CA: Biologic basis for interleukin-1 in disease. Blood. 1996, 87: 2095-2147. PubMed
de Jong R, Altare F, Haagen IA, Elferink DG, Boer T, van Breda Vriesman PJ, Kabel PJ, Draaisma JM, van Dissel JT, Kroon FP, Casanova JL, Ottenhoff TH: Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science. 1998, 280: 1435-1438. 10.1126/science.280.5368.1435. CrossRefPubMed
Trinchieri G: Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood. 1994, 84: 4008-4027. PubMed
Ouma C, Davenport GC, Awandare GA, Keller CC, Were T, Otieno MF, Vulule JM, Martinson J, Ong’echa JM, Ferrell RE, Perkins DJ: Polymorphic variability in the interleukin (IL)-1beta promoter conditions susceptibility to severe malarial anemia and functional changes in IL-1beta production. J Infect Dis. 2008, 198: 1219-1226. 10.1086/592055. PubMedCentralCrossRefPubMed
Zhang L, Prather D, VandenEng J, Crawford S, Kariuki S, TerKuile F, Terlouw D, Nahlen B, Lal AA, Slutsker L, Udhayakumar V, Shi YP: Polymorphisms in genes of interleukin 12 and its receptors and their association with protection against severe malarial anaemia in children in western Kenya. Malar J. 2010, 9: 87-10.1186/1475-2875-9-87. PubMedCentralCrossRefPubMed
Sinha S, Mishra SK, Sharma S, Patibandla PK, Mallick PK, Sharma SK, Mohanty S, Pati SS, Mishra SK, Ramteke BK, Bhatt R, Joshi H, Dash AP, Ahuja RC, Awasthi S, Venkatesh V, Habib S, Indian Genome Variation Consortium: Polymorphisms of TNF-enhancer and gene for FcgammaRIIa correlate with the severity of falciparum malaria in the ethnically diverse Indian population. Malar J. 2008, 7: 13-10.1186/1475-2875-7-13. PubMedCentralCrossRefPubMed
Clark TG, Diakite M, Auburn S, Campino S, Fry AE, Green A, Richardson A, Small K, Teo YY, Wilson J, Jallow M, Sisay-Joof F, Pinder M, Griffiths MJ, Peshu N, Williams TN, Marsh K, Molyneux ME, Taylor TE, Rockett KA, Kwiatkowski DP: Tumor necrosis factor and lymphotoxin-alpha polymorphisms and severe malaria in African populations. J Infect Dis. 2009, 199: 569-575. 10.1086/596320. PubMedCentralCrossRefPubMed
Saeftel M, Krueger A, Arriens S, Heussler V, Racz P, Fleischer B, Brombacher F, Hoerauf A: Mice deficient in interleukin-4 (IL-4) or IL-4 receptor alpha have higher resistance to sporozoite infection with plasmodium berghei (ANKA) than do naive wild-type mice. Infect Immun. 2004, 72: 322-331. 10.1128/IAI.72.1.322-331.2004. PubMedCentralCrossRefPubMed
Lyke KE, Burges R, Cissoko Y, Sangare L, Dao M, Diarra I, Kone A, Harley R, Plowe CV, Doumbo OK, Sztein MB: Serum levels of the pro inflammatory cytokines interleukin-1 beta (IL-1beta), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in Malian children with severe plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls. Infect Immun. 2004, 72: 5630-5637. 10.1128/IAI.72.10.5630-5637.2004. PubMedCentralCrossRefPubMed
- IL1B, IL4R, IL12RB1 and TNF gene polymorphisms are associated with Plasmodium vivax malaria in Brazil
Vinicius A Sortica
Maristela G Cunha
Maria Deise O Ohnishi
Jose M Souza
Ândrea KC Ribeiro-dos-Santos
Ney PC Santos
Sídia M Callegari-Jacques
Sidney EB Santos
Mara H Hutz
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II