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TLR9 polymorphisms in African populations: no association with severe malaria, but evidence of cis-variants acting on gene expression

Campino, Susana, Forton, Julian, Auburn, Sarah, Fry, Andrew, Diakite, Mahamadou, Richardson, Anna, Hull, Jeremy, Jallow, Muminatou, Sisay-Joof, Fatou, Pinder, Margaret, Molyneux, Malcolm E., Taylor, Terrie E., Rockett, Kirk, Clark, Taane G. and Kwiatkowski, Dominic P. (2009). TLR9 polymorphisms in African populations: no association with severe malaria, but evidence of cis-variants acting on gene expression. Malaria Journal,8(1):44-51.

Document type: Journal Article
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Title TLR9 polymorphisms in African populations: no association with severe malaria, but evidence of cis-variants acting on gene expression
Author Campino, Susana
Forton, Julian
Auburn, Sarah
Fry, Andrew
Diakite, Mahamadou
Richardson, Anna
Hull, Jeremy
Jallow, Muminatou
Sisay-Joof, Fatou
Pinder, Margaret
Molyneux, Malcolm E.
Taylor, Terrie E.
Rockett, Kirk
Clark, Taane G.
Kwiatkowski, Dominic P.
Journal Name Malaria Journal
Publication Date 2009
Volume Number 8
Issue Number 1
ISSN 1475-2875   (check CDU catalogue open catalogue search in new window)
Start Page 44
End Page 51
Total Pages 8
Place of Publication United Kingdom
Publisher BioMed Central Ltd.
Abstract Background: During malaria infection the Toll-like receptor 9 (TLR9) is activated through induction with plasmodium DNA or another malaria motif not yet identified. Although TLR9 activation by malaria parasites is well reported, the implication to the susceptibility to severe malaria is not clear. The aim of this study was to assess the contribution of genetic variation at TLR9 to severe malaria.

Methods: This study explores the contribution of TLR9 genetic variants to severe malaria using two approaches. First, an association study of four common single nucleotide polymorphisms was performed on both family- and population-based studies from Malawian and Gambian populations (n>6000 individual). Subsequently, it was assessed whether TLR9 expression is affected by cis-acting variants and if these variants could be mapped. For this work, an allele specific expression (ASE) assay on a panel of HapMap cell lines was carried out.

Results: No convincing association was found with polymorphisms in TLR9 for malaria severity, in either Gambian or Malawian populations, using both case-control and family based study designs. Using an allele specific expression assay it was observed that TLR9 expression is affected by cis-acting variants, these results were replicated in a second experiment using biological replicates.

Conclusion: By using the largest cohorts analysed to date, as well as a standardized phenotype definition and study design, no association of TLR9 genetic variants with severe malaria was found. This analysis considered all common variants in the region, but it is remains possible that there are rare variants with association signals. This report also shows that TLR9 expression is potentially modulated through cis-regulatory variants, which may lead to differential inflammatory responses to infection between individuals.
Keywords TLR9 polymorphisms
Toll-like receptor 9 (TLR9)
severe malaria
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