A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis.
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.
Khor
Chiea C
CC
The Wellcome Trust Centre for Human Genetics, University of Oxford, UK.
Chapman
Stephen J
SJ
Vannberg
Fredrik O
FO
Dunne
Aisling
A
Murphy
Caroline
C
Ling
Edmund Y
EY
Frodsham
Angela J
AJ
Walley
Andrew J
AJ
Kyrieleis
Otto
O
Khan
Amir
A
Aucan
Christophe
C
Segal
Shelley
S
Moore
Catrin E
CE
Knox
Kyle
K
Campbell
Sarah J
SJ
Lienhardt
Christian
C
Scott
Anthony
A
Aaby
Peter
P
Sow
Oumou Y
OY
Grignani
Robert T
RT
Sillah
Jackson
J
Sirugo
Giorgio
G
Peshu
Nobert
N
Williams
Thomas N
TN
Maitland
Kathryn
K
Davies
Robert J O
RJ
Kwiatkowski
Dominic P
DP
Day
Nicholas P
NP
Yala
Djamel
D
Crook
Derrick W
DW
Marsh
Kevin
K
Berkley
James A
JA
O'Neill
Luke A J
LA
Hill
Adrian V S
AV
D000349:Africa; D016470:Bacteremia / Q000235:genetics*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008288:Malaria / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000502:physiology; D008958:Models, Molecular; D009185:Myelin Proteins / Q000235:genetics* / Q000502:physiology; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D011008:Pneumococcal Infections / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011510:Proteolipids / Q000235:genetics* / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014376:Tuberculosis / Q000235:genetics*; D006113:United Kingdom; D014744:Vietnam
C569026:MAL protein, human; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D011510:Proteolipids; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4