A Mal Functional Variant is Associated with Protection Against Invasive Pneumococcal Disease, Bacteremia, Malaria and Tuberculosis

Overview

Journal Nat Genet

Specialty Genetics

Date 2007 Feb 27

PMID 17322885

Citations 186

Authors

Chiea C Khor

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 ONeill

Adrian V S Hill

Affiliations

Soon will be listed here.

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.

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