A functional variant in TIRAP, also known as MAL, and protection against invasive pneumococcal disease, bacteraemia, malaria and tuberculosis

• Published in: Nature genetics Vol. 39; no. 4; pp. 523 - 528
• Main Authors: Khor, Chiea C., Chapman, Stephen J., Vannberg, Fredrik O, Dunne, Aisling, Murphy, Caroline, Ling, Edmund Y, Frodsham, Angela J., Walley, Andrew J, Kyrieleis, Otto, Khan, Amir, Aucan, Christophe, Segal, Shelley, Moore, Catrin E., Knox, Kyle, Campbell, Sarah J., Lienhardt, Christian, Scott, Anthony, Aaby, Peter, Sow, Oumou Y., Grignani, Robert T., Sillah, Jackson, Sirugo, Girogio, Peshu, Nobert, Williams, Thomas N., Maitland, Kathryn, Davies, Robert J. O., Kwiatkowski, Dominic P., Day, Nicholas P., Yala, Djamel, Crook, Derrick W., Marsh, Kevin, Berkley, James A, O’Neill, Luke A.J., Hill, Adrian V. S.
• Format: Journal Article
• Language: English
• Published: 25.02.2007
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1976

Toll-like receptors (TLRs) and members of their signalling pathway play an important role in the initiation of the innate immune response to a wide variety of pathogens 1 , 2 , 3 . The adaptor protein TIRAP mediates downstream signalling of TLR-2 and -4 4 , 5 , 6 . We report a case-control genetic association study of 6106 individuals from Gambia, Kenya, United Kingdom, and Vietnam, with invasive pneumococcal disease, bacteraemia, malaria and tuberculosis. Thirty-three SNPs were genotyped, including TIRAP S180L. Heterozygous carriage of this variant was found to associate independently with all four infectious diseases in the different study populations ( P =0.003, OR=0.59, 95%CI 0.42-0.83 for IPD; P =0.003, OR=0.40, 95%CI 0.21-0.77 for bacteraemia; P =0.002, OR=0.47, 95%CI 0.28-0.76 for malaria; P =0.008, OR=0.23 95%CI 0.07-0.73 for tuberculosis). Substantial support for a protective effect of S180L heterozygosity against infectious diseases was observed when the study groups were combined (N=6106, Overall P ≤9.6×10 -8 ). Tirap S180L was also shown to be functionally impaired in TLR2 signal transduction.