CISH and Susceptibility to Infectious Diseases

被引：94

作者：

Khor, Chiea C. ^{[1
,3
]}

Vannberg, Fredrik O. ^{[1
]}

Chapman, Stephen J. ^{[1
]}

Guo, Haiyan ^{[3
]}

Wong, Sunny H. ^{[1
]}

Walley, Andrew J. ^{[6
]}

Vukcevic, Damjan ^{[1
]}

Rautanen, Anna ^{[1
]}

Mills, Tara C. ^{[1
]}

Chang, Kwok-Chiu ^{[10
]}

Kam, Kai-Man ^{[11
]}

Crampin, Amelia C. ^{[17
]}

Ngwira, Bagrey ^{[17
]}

Leung, Chi-Chiu ^{[10
]}

Tam, Cheuk-Ming ^{[10
]}

Chan, Chiu-Yeung ^{[12
]}

Sung, Joseph J. Y. ^{[13
]}

Yew, Wing-Wai ^{[16
]}

Toh, Kai-Yee ^{[3
]}

Tay, Stacey K. H. ^{[4
,5
]}

Kwiatkowski, Dominic ^{[1
]}

Lienhardt, Christian ^{[18
]}

Hien, Tran-Tinh ^{[19
,20
]}

Day, Nicholas P. ^{[19
,20
]}

Peshu, Nobert ^{[21
,22
]}

Marsh, Kevin ^{[7
,8
,21
,22
]}

Maitland, Kathryn ^{[7
,8
,21
,22
]}

Scott, J. Anthony ^{[2
,21
,22
]}

Williams, Thomas N. ^{[2
,21
,22
]}

Berkley, James A. ^{[2
,21
,22
]}

Floyd, Sian ^{[9
]}

Tang, Nelson L. S. ^{[14
,15
]}

Fine, Paul E. M. ^{[9
]}

Goh, Denise L. M. ^{[3
,4
,5
]}

Hill, Adrian V. S. ^{[1
]}

机构：

[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[2] Univ Oxford, Ctr Clin Vaccinol & Trop Med, Oxford, England

[3] Agcy Sci Technol & Res, Host Susceptibil Infect Program, Singapore Inst Clin Sci, Singapore, Singapore

[4] Natl Univ Hlth Syst, Univ Childrens Med Inst, Dept Paediat, Singapore, Singapore

[5] Natl Univ Singapore, Singapore 117548, Singapore

[6] Hammersmith Hosp, Imperial Coll, Sect Genom Med, London, England

[7] Univ London Imperial Coll Sci Technol & Med, Fac Med, Wellcome Trust Ctr, Clin Trop Med, London SW7 2AZ, England

[8] Univ London Imperial Coll Sci Technol & Med, Dept Paediat, London SW7 2AZ, England

[9] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, Infect Dis Epidemiol Unit, London, England

[10] Chinese Univ Hong Kong, TB & Chest Serv, Dept Hlth, Hong Kong, Hong Kong, Peoples R China

[11] Chinese Univ Hong Kong, Publ Hlth Lab, Dept Hlth, Hong Kong, Hong Kong, Peoples R China

[12] Chinese Univ Hong Kong, Dept Microbiol, Hong Kong, Hong Kong, Peoples R China

[13] Chinese Univ Hong Kong, Stanley Ho Ctr Emerging Infect Dis, Hong Kong, Hong Kong, Peoples R China

[14] Chinese Univ Hong Kong, Dept Chem Pathol, Fac Med, Hong Kong, Hong Kong, Peoples R China

[15] Chinese Univ Hong Kong, Lab Genet Dis Susceptibil, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China

[16] Grantham Hosp, Hosp Author, TB & Chest Unit, Hong Kong, Hong Kong, Peoples R China

[17] Karonga Prevent Study, Chilumba, Malawi

[18] Inst Rech Dev, Dakar, Senegal

[19] Cho Quan Hosp, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam

[20] Hosp Trop Dis, Ho Chi Minh City, Vietnam

[21] Kilifi Dist Hosp, Ctr Geog Med Res, Wellcome Trust Programme, Kilifi, Kenya

[22] Kenya Govt Med Res Ctr, Kilifi, Kenya

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2010年 / 362卷 / 22期

基金：

英国惠康基金;

关键词：

HUMAN-IMMUNODEFICIENCY-VIRUS; SIGNALING PATHWAYS; T-CELLS; INTERLEUKIN-2; TUBERCULOSIS; PROTEIN; RECEPTOR; MALARIA; CHILDREN; STAT5;

D O I：

10.1056/NEJMoa0905606

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND The interleukin-2-mediated immune response is critical for host defense against infectious pathogens. Cytokine-inducible SRC homology 2 (SH2) domain protein (CISH), a suppressor of cytokine signaling, controls interleukin-2 signaling. METHODS Using a case-control design, we tested for an association between CISH polymorphisms and susceptibility to major infectious diseases (bacteremia, tuberculosis, and severe malaria) in blood samples from 8402 persons in Gambia, Hong Kong, Kenya, Malawi, and Vietnam. We had previously tested 20 other immune-related genes in one or more of these sample collections. RESULTS We observed associations between variant alleles of multiple CISH polymorphisms and increased susceptibility to each infectious disease in each of the study populations. When all five single-nucleotide polymorphisms (SNPs) (at positions -639, -292, -163, +1320, and +3415 [all relative to CISH]) within the CISH-associated locus were considered together in a multiple-SNP score, we found an association between CISH genetic variants and susceptibility to bacteremia, malaria, and tuberculosis (P = 3.8x10(-11) for all comparisons), with -292 accounting for most of the association signal (P = 4.58x10(-7)). Peripheral-blood mononuclear cells obtained from adult subjects carrying the -292 variant, as compared with wild-type cells, showed a muted response to the stimulation of interleukin-2 production-that is, 25 to 40% less CISH expression. CONCLUSIONS Variants of CISH are associated with susceptibility to diseases caused by diverse infectious pathogens, suggesting that negative regulators of cytokine signaling have a role in immunity against various infectious diseases. The overall risk of one of these infectious diseases was increased by at least 18% among persons carrying the variant CISH alleles.

引用

页码：2092 / 2101

页数：10

共 41 条

[1] CIS associates with the interleukin-2 receptor β chain and inhibits interleukin-2-dependent signaling [J].