A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis.

Authors:
Chiea C Khor
Chiea C Khor
University of Oxford
United Kingdom
Stephen J Chapman
Stephen J Chapman
University of Oxford
United Kingdom
Fredrik O Vannberg
Fredrik O Vannberg
University of Oxford
United Kingdom
Aisling Dunne
Aisling Dunne
School of Biochemistry and Immunology
Ireland
Caroline Murphy
Caroline Murphy
King's College London
United Kingdom
Edmund Y Ling
Edmund Y Ling
The Wellcome Trust Sanger Institute
United Kingdom
Angela J Frodsham
Angela J Frodsham
University of Oxford
United Kingdom
Andrew J Walley
Andrew J Walley
Hammersmith Hospital
United Kingdom

Nat Genet 2007 Apr 25;39(4):523-8. Epub 2007 Feb 25.

The Wellcome Trust Centre for Human Genetics, University of Oxford, UK.

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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2660299PMC
April 2007
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