Sun Lin, Jin Ya-qiong, Shen Chen, Qi Hui, Chu Ping, Yin Qing-qin, Li Jie-qiong, Tian Jian-ling, Jiao Wei-wei, Xiao Jing, Shen A-dong
Key Laboratory of Major Diseases in Children and National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China.
PLoS One. 2014 Mar 14;9(3):e92020. doi: 10.1371/journal.pone.0092020. eCollection 2014.
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.
结核病（TB）是全球因传染病导致死亡的主要原因，在发展中国家尤为如此。一系列候选基因被认为与结核病的发生有关。其中，人类细胞因子诱导的Src同源2（SH2）结构域蛋白（CISH）基因最近被报道参与了结核分枝杆菌感染后T细胞的激活和分化。在此，我们研究了CISH启动子多态性与儿童结核病之间的关联。一项病例对照研究纳入了352例结核病患者和527例健康对照，他们均为汉族，年龄在0.2至18岁之间。对所有受试者进行了CISH基因启动子单核苷酸多态性（SNP）rs414171、rs622502和rs809451的基因分型，并进一步检测了不同基因型受试者的转录活性、mRNA水平和血浆细胞因子水平。与野生型基因型相比，rs414171TT纯合子携带者和rs809451GC杂合子携带者患结核病的风险分别高出1.78倍（95%置信区间，1.16 - 2.74）和1.86倍（95%置信区间，1.26 - 2.74）。携带C（-809451）-T（-414171）-C（-622502）单倍型的人群患结核病的风险更高（比值比3.66，95%置信区间：2.12 - 6.32）。在Hela细胞系中，与含有C（-809451）-T（-414171）-C（-622502）的启动子相比，含有G（-809451）-A（-414171）-C（-622502）的CISH启动子驱动报告基因表达增加了5.43倍（P = 0.0009）。与携带野生型基因型的细胞相比，携带rs414171TT纯合子和rs809451GC杂合子的外周血单核细胞（PBMC）显示CISH mRNA水平降低。rs414171TT基因型个体的IL - 12p40和IL - 10产生显著增加。总之，CISH启动子rs414171和rs809451多态性可能在介导个体对结核病易感性方面发挥重要作用。
