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Toll-like receptor 9 (TLR9) polymorphism associated with symptomatic malaria: a cohort study.

ABSTRACT: BACKGROUND: In areas mesoendemic for malaria transmission, symptomatic individuals play a significant role as reservoirs for malaria infection. Understanding the pathogenesis of symptomatic malaria is important in devising tools for augmenting malaria control. In this study, the effect of TLR9 polymorphisms on susceptibility to symptomatic malaria was investigated among Ghanaian children. METHODS: Four hundred and twenty nine (429) healthy Ghanaian children, aged three to eleven years (3-11?years), were enrolled into a cohort study and actively followed up for symptomatic malaria for one year. Four TLR9 single nucleotide polymorphisms (SNPs) namely: rs187084 (C-1486?T), rs5743836(C-1237?T), rs352139 (G?+?1174A) and rs352140 (G?+?2848A) were genotyped by direct sequencing, and their attributable and relative risks for symptomatic malaria determined. TLR9 haplotypes were inferred using the PHASE software and analysed for the risk of symptomatic malaria. A luciferase assay was performed to investigate whether the TLR9 haplotypes influence TLR9 promoter activity. RESULTS: The rs352139 GG genotype showed a significantly increased relative risk of 4.8 for symptomatic malaria (P?=?0.0024) and a higher mean parasitaemia (P?=?0.04). Conversely, the rs352140 GG genotype showed a significantly reduced relative risk of 0.34 (P?=?0.048). TLR9 haplotypes analyses showed that TTAG haplotype was significantly associated with reduced relative risk of 0.2 for symptomatic malaria (P?=?4×10??) and a lower mean parasitaemia (0.007), while CTGA haplotype had an increased relative risk of 3.3 (P?=?0.005). Functional luciferase reporter gene expression assay revealed that the TTA haplotype had a significantly higher promoter activity than the CCG, CTG and TCG haplotypes. CONCLUSIONS: Taken together, these findings indicate a significant association of TLR9 gene polymorphisms with symptomatic malaria among Ghanaian children in Dangme-West district.

SUBMITTER: Omar AH

PROVIDER: S-EPMC3426469 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Toll-like receptor 9 (TLR9) polymorphism associated with symptomatic malaria: a cohort study.

Omar Ahmeddin H AH Yasunami Michio M Yamazaki Akiko A Shibata Hiroki H Ofori Michael F MF Akanmori Bartholomew D BD Shuaibu Mohammed Nasir MN Kikuchi Mihoko M Hirayama Kenji K

Malaria journal 20120517

<h4>Background</h4>In areas mesoendemic for malaria transmission, symptomatic individuals play a significant role as reservoirs for malaria infection. Understanding the pathogenesis of symptomatic malaria is important in devising tools for augmenting malaria control. In this study, the effect of TLR9 polymorphisms on susceptibility to symptomatic malaria was investigated among Ghanaian children.<h4>Methods</h4>Four hundred and twenty nine (429) healthy Ghanaian children, aged three to eleven yea ...[more]

PMID: 22594374

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Project description:BACKGROUND: Malaria caused by Plasmodium falciparum is one of the leading causes of human morbidity and mortality from infectious diseases, predominantly in tropical and sub-tropical countries. As genetic variations in the toll-like receptors (TLRs)-signalling pathway have been associated with either susceptibility or resistance to several infectious and inflammatory diseases, the supposition is that single nucleotide polymorphisms (SNPs) of TLR2, TLR4, TLR9, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and FCGR2A could modulate malaria susceptibility and severity. METHODS: This study was planned to make a further contribution to solving the problem of the real role of the most common polymorphisms of TLR4, TLR9, TIRAP and FCGR2A genes in modulating the risk of malaria and disease severity in children from Burundi, Central Africa. All the paediatric patients aged six months to 10 years admitted to the hospital of Kiremba, Burundi, between February 2011 and September 2011, for fever and suspicion of acute malaria were screened for malaria parasitaemia by light microscopy of thick and thin blood smears. In children with malaria and in uninfected controls enrolled during the study period in the same hospital, blood samples were obtained on filter paper and TLR4 Asp299Gly rs4986790, TLR9 G1174A rs352139, T-1486?C rs187084 TLR9 T-1237?C rs5743836, TIRAP Ser180Leu rs8177374 and the FCGR2A His131Arg rs1801274 polymorphisms were studied using an ABI PRISM 7900 HT Fast Real-time instrument. RESULTS: A total of 602 patients and 337 controls were enrolled. Among the malaria cases, 553 (91.9%) were considered as suffering from uncomplicated and 49 (8.1%) from severe malaria. TLR9 T1237C rs5743836CC was associated with an increased risk of developing malaria (p=0.03), although it was found with the same frequency in uncomplicated and severe malaria cases. No other differences were found in all alleles studied and in genotype frequencies between malaria cases and uninfected controls as well as between uncomplicated and severe malaria cases. CONCLUSIONS: TLR9 T1237C seems to condition susceptibility to malaria in Burundian children but not its severity, whereas none of the assessed SNPs of TLR4, TIRAP and FCGR2A seem to influence susceptibility to malaria and disease severity in this population.

Project description:BackgroundToll-like receptors (TLR) and related downstream signaling pathways of innate immunity have been implicated in the pathogenesis of Plasmodium falciparum malaria. Because of their potential role in malaria pathogenesis, polymorphisms in these genes may be under selective pressure in populations where this infectious disease is endemic.MethodsA post-PCR Ligation Detection Reaction-Fluorescent Microsphere Assay (LDR-FMA) was developed to determine the frequencies of TLR2, TLR4, TLR9, MyD88-Adaptor Like Protein (MAL) single nucleotide polymorphisms (SNPs), and TLR2 length polymorphisms in 170 residents of two regions of Kenya where malaria transmission is stable and high (holoendemic) or episodic and low, 346 residents of a malaria holoendemic region of Papua New Guinea, and 261 residents of North America of self-identified ethnicity.ResultsThe difference in historical malaria exposure between the two Kenyan sites has significantly increased the frequency of malaria protective alleles glucose-6-phoshpate dehydrogenase (G6PD) and Hemoglobin S (HbS) in the holoendemic site compared to the episodic transmission site. However, this study detected no such difference in the TLR2, TLR4, TLR9, and MAL allele frequencies between the two study sites. All polymorphisms were in Hardy Weinberg Equilibrium in the Kenyan and Papua New Guinean populations. TLR9 SNPs and length polymorphisms within the TLR2 5' untranslated region were the only mutant alleles present at a frequency greater than 10% in all populations.ConclusionSimilar frequencies of TLR2, TLR4, TLR9, and MAL genetic polymorphisms in populations with different histories of malaria exposure suggest that these innate immune pathways have not been under strong selective pressure by malaria. Genotype frequencies are consistent with Hardy-Weinberg Equilibrium and the Neutral Theory, suggesting that genetic drift has influenced allele frequencies to a greater extent than selective pressure from malaria or any other infectious agents in these populations.

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Toll-like receptor 9 (TLR9) polymorphism associated with symptomatic malaria: a cohort study.

Publications

Toll-like receptor 9 (TLR9) polymorphism associated with symptomatic malaria: a cohort study.

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