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PMID:17322885

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Citation

Khor, CC, Chapman, SJ, Vannberg, FO, Dunne, A, Murphy, C, Ling, EY, Frodsham, AJ, Walley, AJ, Kyrieleis, O, Khan, A, Aucan, C, Segal, S, Moore, CE, Knox, K, Campbell, SJ, Lienhardt, C, Scott, A, Aaby, P, Sow, OY, Grignani, RT, Sillah, J, Sirugo, G, Peshu, N, Williams, TN, Maitland, K, Davies, RJ, Kwiatkowski, DP, Day, NP, Yala, D, Crook, DW, Marsh, K, Berkley, JA, O'Neill, LA and Hill, AV (2007) A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat. Genet. 39:523-8

Abstract

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction.

Links

PubMed PMC2660299 Online version:10.1038/ng1976

Keywords

Africa; Bacteremia/genetics; Case-Control Studies; Genetic Predisposition to Disease; Great Britain; Humans; Linkage Disequilibrium; Malaria/genetics; Membrane Glycoproteins/genetics; Membrane Transport Proteins/genetics; Membrane Transport Proteins/physiology; Models, Molecular; Myelin Proteins/genetics; Myelin Proteins/physiology; Pneumococcal Infections/genetics; Polymorphism, Single Nucleotide/physiology; Proteolipids/genetics; Proteolipids/physiology; Receptors, Interleukin-1/genetics; Toll-Like Receptor 2/metabolism; Toll-Like Receptor 4/metabolism; Tuberculosis/genetics; Vietnam

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:TIRAP

enables

GO:0035663: Toll-like receptor 2 binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9QUN7

F

Seeded From UniProt

complete

MOUSE:TIRAP

involved_in

GO:0034141: positive regulation of toll-like receptor 3 signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TIRAP

involved_in

GO:0032755: positive regulation of interleukin-6 production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TLR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99JY1

F

Seeded From UniProt

complete


See also

References

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