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

被引：353

作者：

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, Giorgio

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.

机构：

[1] Churchill Hosp, Osler Chest Unit, Oxford, England

[2] Trinity Coll Dublin, Sch Biochem & Immunol, Dublin, Ireland

[3] John Radcliffe Hosp, Dept Paediat, Oxford OX3 9DU, England

[4] John Radcliffe Hosp, Dept Microbiol, Oxford OX3 9DU, England

[5] Inst Rech Dev, Dakar, Senegal

[6] Kilifi District Hosp, Ctr Geog Med Res, Kenya Med Res Inst, Wellcome Trust Programme, Kilifi, Kenya

[7] Bandim Hlth Project, Bissau, Guinea Bissau

[8] Univ Ignace Deen, Serv Pneumophtisol, Conarky 634, Guinea

[9] MRC Labs, Fajara, Gambia

[10] Cho Quan Hosp, Ctr Trop Dis, Ho Chi Minh City, Vietnam

[11] Inst Pasteur, Serv TB, Algiers, Algeria

[12] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England

来源：

NATURE GENETICS | 2007年 / 39卷 / 04期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

D O I：

10.1038/ng1976

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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(1-3). 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.

引用

页码：523 / 528

页数：6

共 28 条

[1] Population genetics -: Malaria susceptibility and CD36 mutation [J].