CISH and susceptibility to infectious diseases.
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.
Khor
Chiea C
CC
The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. khorcc@gis.a-star.edu.sg
Vannberg
Fredrik O
FO
Chapman
Stephen J
SJ
Guo
Haiyan
H
Wong
Sunny H
SH
Walley
Andrew J
AJ
Vukcevic
Damjan
D
Rautanen
Anna
A
Mills
Tara C
TC
Chang
Kwok-Chiu
KC
Kam
Kai-Man
KM
Crampin
Amelia C
AC
Ngwira
Bagrey
B
Leung
Chi-Chiu
CC
Tam
Cheuk-Ming
CM
Chan
Chiu-Yeung
CY
Sung
Joseph J Y
JJ
Yew
Wing-Wai
WW
Toh
Kai-Yee
KY
Tay
Stacey K H
SK
Kwiatkowski
Dominic
D
Lienhardt
Christian
C
Hien
Tran-Tinh
TT
Day
Nicholas P
NP
Peshu
Nobert
N
Marsh
Kevin
K
Maitland
Kathryn
K
Scott
J Anthony
JA
Williams
Thomas N
TN
Berkley
James A
JA
Floyd
Sian
S
Tang
Nelson L S
NL
Fine
Paul E M
PE
Goh
Denise L M
DL
Hill
Adrian V S
AV
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*
D007376:Interleukin-2; D050826:Suppressor of Cytokine Signaling Proteins