Genetic Contribution of CISH Promoter Polymorphisms to Susceptibility to Tuberculosis in Chinese Children

Abstract

Tuberculosis (TB) is the leading cause of death due to an infectious disease worldwide, particularly in developing countries. A series of candidate genes have been suggested to be associated with development of TB disease. Among them, the human Cytokine-inducible Src homology 2(SH2) domain protein (CISH) gene has been very recently reported to be involved in T cell activation and differentiation in response to Mycobacterium tuberculosis infection. Here, we studied the association between CISH promoter polymorphisms and pediatric TB. A case-control study enrolled 352 TB patients and 527 healthy controls, who were of Han Chinese ethnicity and aged from 0.2 to 18 years. CISH gene promoter SNPs rs414171, rs622502 and rs809451 were genotyped in all subjects and transcriptional activity, mRNA level, and plasma cytokine level of subjects with different genotypes were further examined. Carriers with rs414171TT homozygotes and rs809451GC heterozygotes had a 1.78-fold (95% CI,1.16–2.74) and 1.86-fold (95% CI, 1.26–2.74) excess risk of developing TB compared to those with wild-type genotypes. A greater risk of TB disease was observed in population carrying C−809451-T−414171-C−622502 haplotype (OR 3.66, 95% CI:2.12–6.32). The G−809451-A−414171-C−622502-containing CISH promoter drove a 5.43-fold increased reporter expression compared to the C−809451-T−414171-C−622502-containing counterpart in Hela cell lines (P = 0.0009). PBMCs carrying rs414171TT homozygotes and rs809451GC heterozygotes showed a reduced CISH mRNA level compared to cells carrying wild type genotypes. Individuals with the rs414171TT genotype had significantly increased IL-12p40 and IL-10 production. In conclusion, CISH promoter rs414171 and rs809451 polymorphisms may play a vital role in mediating individual susceptibility to tuberculosis.

Negative Regulation of Cytokine Signaling in Immunity

“…Human genetic linkage studies of CISH have shown an association between CISH genetic variants and susceptibility to bacteremia, malaria, and tuberculosis (Khor et al 2010;Sun et al 2014), as well as persistent hepatitis B virus (HBV) infection or clearance of HBV (Tong et al 2012;Hu et al 2014;Song et al 2014). The molecular mechanism of CISH-related infection regulation remains to be clarified.…”

SOCS Proteins as Regulators of Inflammatory Responses Induced by Bacterial Infections: A Review

“…Nonetheless, the activity of SOCS2 seems to be scarce and redundant and still requires a better understanding. CIS, on the other hand, is associated with increased susceptibility to TB (Sun et al, 2014 ; McCormick and Heller, 2015 ), likely by negatively regulating SOCS1 and SOCS3 (Trengove and Ward, 2013 ).…”

Regulation of Macrophage, Dendritic Cell, and Microglial Phenotype and Function by the SOCS Proteins

“…In line with these findings, knockdown in CIS impaired vaccine-induced responses, CTL development, and anti-tumor immunity ( 91 ). Human polymorphisms in the CIS promoter have been linked with increased susceptibility to ( 92 ) pediatric M. tuberculosis infection ( 93 ). Given the critical role of CIS in antigen presentation, cytokine production, and DC-mediated T cell priming, it is easy to appreciate how decreased CIS expression could interfere with vaccination efforts as well as predispose children to unchecked bacterial dissemination once contracting tuberculosis.…”