title: CISH and susceptibility to infectious diseases.
abstract: 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.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. khorcc@gis.a-star.edu.sg
authors.forename: Chiea C
authors.initials: CC
authors.lastname: Khor
authors.forename: Fredrik O
authors.initials: FO
authors.lastname: Vannberg
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chapman
authors.forename: Haiyan
authors.initials: H
authors.lastname: Guo
authors.forename: Sunny H
authors.initials: SH
authors.lastname: Wong
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Walley
authors.forename: Damjan
authors.initials: D
authors.lastname: Vukcevic
authors.forename: Anna
authors.initials: A
authors.lastname: Rautanen
authors.forename: Tara C
authors.initials: TC
authors.lastname: Mills
authors.forename: Kwok-Chiu
authors.initials: KC
authors.lastname: Chang
authors.forename: Kai-Man
authors.initials: KM
authors.lastname: Kam
authors.forename: Amelia C
authors.initials: AC
authors.lastname: Crampin
authors.forename: Bagrey
authors.initials: B
authors.lastname: Ngwira
authors.forename: Chi-Chiu
authors.initials: CC
authors.lastname: Leung
authors.forename: Cheuk-Ming
authors.initials: CM
authors.lastname: Tam
authors.forename: Chiu-Yeung
authors.initials: CY
authors.lastname: Chan
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
authors.forename: Wing-Wai
authors.initials: WW
authors.lastname: Yew
authors.forename: Kai-Yee
authors.initials: KY
authors.lastname: Toh
authors.forename: Stacey K H
authors.initials: SK
authors.lastname: Tay
authors.forename: Dominic
authors.initials: D
authors.lastname: Kwiatkowski
authors.forename: Christian
authors.initials: C
authors.lastname: Lienhardt
authors.forename: Tran-Tinh
authors.initials: TT
authors.lastname: Hien
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Day
authors.forename: Nobert
authors.initials: N
authors.lastname: Peshu
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.forename: Kathryn
authors.initials: K
authors.lastname: Maitland
authors.forename: J Anthony
authors.initials: JA
authors.lastname: Scott
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Williams
authors.forename: James A
authors.initials: JA
authors.lastname: Berkley
authors.forename: Sian
authors.initials: S
authors.lastname: Floyd
authors.forename: Nelson L S
authors.initials: NL
authors.lastname: Tang
authors.forename: Paul E M
authors.initials: PE
authors.lastname: Fine
authors.forename: Denise L M
authors.initials: DL
authors.lastname: Goh
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
mesh_terms: D000328:Adult; D016470:Bacteremia / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology; D015810:Linkage Disequilibrium; D008288:Malaria / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D014376:Tuberculosis / Q000235:genetics*
chemical_list: D007376:Interleukin-2; D050826:Suppressor of Cytokine Signaling Proteins