CISH and susceptibility to infectious diseases

Khor, C. C. et al. (2010) CISH and susceptibility to infectious diseases. New England Journal of Medicine, 362(22), pp. 2092-2101. (doi: 10.1056/nejmoa0905606) (PMID:20484391) (PMCID:PMC3646238)

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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=3.8×10−11 for all comparisons), with −292 accounting for most of the association signal (P=4.58×10−7). 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.

Item Type:Articles
Additional Information:Supported by grants (to Drs. Khor, Goh, and Hill) and clinical research fellowships (to Drs. Chapman, Williams, Scott, and Berkley) from the Wellcome Trust and the Agency for Science, Technology and Research, Singapore, by the Wellcome Trust Kenya Major Overseas Programme, and by funding from the NIHR Oxford Biomedical Research Centre Programme.
Glasgow Author(s) Enlighten ID:Crampin, Professor Mia
Authors: Khor, C. C., Vannberg, F. O., Chapman, S. J., Guo, H., Wong, S. H., Walley, A. J., Vukcevic, D., Rautanen, A., Mills, T. C., Chang, K.-C., Kam, K.-M., Crampin, A. C., Ngwira, B., Leung, C.-C., Tam, C.-M., Chan, C.-Y., Sung, J. J.Y., Yew, W.-W., Toh, K.-Y., Tay, S. K.H., Kwiatkowski, D., Lienhardt, C., Hien, T.-T., Day, N. P., Peshu, N., Marsh, K., Maitland, K., Scott, J. A., Williams, T. N., Berkley, J. A., Floyd, S., Tang, N. L.S., Fine, P. E.M., Goh, D. L.M., and Hill, A. V.S.
College/School:College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health
Journal Name:New England Journal of Medicine
Publisher:Massachusetts Medical Society
ISSN (Online):1533-4406
Published Online:19 May 2010

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