title: A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis.
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.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, UK.
authors.forename: Chiea C
authors.initials: CC
authors.lastname: Khor
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chapman
authors.forename: Fredrik O
authors.initials: FO
authors.lastname: Vannberg
authors.forename: Aisling
authors.initials: A
authors.lastname: Dunne
authors.forename: Caroline
authors.initials: C
authors.lastname: Murphy
authors.forename: Edmund Y
authors.initials: EY
authors.lastname: Ling
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Frodsham
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Walley
authors.forename: Otto
authors.initials: O
authors.lastname: Kyrieleis
authors.forename: Amir
authors.initials: A
authors.lastname: Khan
authors.forename: Christophe
authors.initials: C
authors.lastname: Aucan
authors.forename: Shelley
authors.initials: S
authors.lastname: Segal
authors.forename: Catrin E
authors.initials: CE
authors.lastname: Moore
authors.forename: Kyle
authors.initials: K
authors.lastname: Knox
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Campbell
authors.forename: Christian
authors.initials: C
authors.lastname: Lienhardt
authors.forename: Anthony
authors.initials: A
authors.lastname: Scott
authors.forename: Peter
authors.initials: P
authors.lastname: Aaby
authors.forename: Oumou Y
authors.initials: OY
authors.lastname: Sow
authors.forename: Robert T
authors.initials: RT
authors.lastname: Grignani
authors.forename: Jackson
authors.initials: J
authors.lastname: Sillah
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sirugo
authors.forename: Nobert
authors.initials: N
authors.lastname: Peshu
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Williams
authors.forename: Kathryn
authors.initials: K
authors.lastname: Maitland
authors.forename: Robert J O
authors.initials: RJ
authors.lastname: Davies
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Day
authors.forename: Djamel
authors.initials: D
authors.lastname: Yala
authors.forename: Derrick W
authors.initials: DW
authors.lastname: Crook
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.forename: James A
authors.initials: JA
authors.lastname: Berkley
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
mesh_terms: 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
chemical_list: 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