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

Nat Genet. 2007 Apr;39(4):523-8. doi: 10.1038/ng1976.

Chiea C Khor ¹, Stephen J Chapman, Fredrik O Vannberg, Aisling Dunne, Caroline Murphy, Edmund Y Ling, Angela J Frodsham, Andrew J Walley, Otto Kyrieleis, Amir Khan, Christophe Aucan, Shelley Segal, Catrin E Moore, Kyle Knox, Sarah J Campbell, Christian Lienhardt, Anthony Scott, Peter Aaby, Oumou Y Sow, Robert T Grignani, Jackson Sillah, Giorgio Sirugo, Nobert Peshu, Thomas N Williams, Kathryn Maitland, Robert J O Davies, Dominic P Kwiatkowski, Nicholas P Day, Djamel Yala, Derrick W Crook, Kevin Marsh, James A Berkley, Luke A J O'Neill, Adrian V S Hill

Affiliations

Affiliation

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

PMID: 17322885 DOI: 10.1038/ng1976

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.