AUTHOR=Nie Shao-Fang , Zha Ling-Feng , Fan Qian , Liao Yu-Hua , Zhang Hong-Song , Chen Qian-Wen , Wang Fan , Tang Ting-Ting , Xia Ni , Xu Cheng-Qi , Zhang Jiao-Yue , Lu Yu-Zhi , Zeng Zhi-Peng , Jiao Jiao , Li Yuan-Yuan , Xie Tian , Zhang Wen-Juan , Wang Dan , Wang Chu-Chu , Fa Jing-Jing , Xiong Hong-Bo , Ye Jian , Yang Qing , Wang Peng-Yun , Tian Sheng-Hua , Lv Qiu-Lun , Li Qing-Xian , Qian Jin , Li Bin , Wu Gang , Wu Yan-Xia , Yang Yan , Yang Xiang-Ping , Hu Yu , Wang Qing K. , Cheng Xiang , Tu Xin 

TITLE=Genetic Regulation of the Thymic Stromal Lymphopoietin (TSLP)/TSLP Receptor (TSLPR) Gene Expression and Influence of Epistatic Interactions Between IL-33 and the TSLP/TSLPR Axis on Risk of Coronary Artery Disease

JOURNAL=Frontiers in Immunology

VOLUME=Volume 9 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.01775

DOI=10.3389/fimmu.2018.01775

ISSN=1664-3224

ABSTRACT=The thymic stromal lymphopoietin (TSLP)/TSLP receptor axis is involved in multiple inflammatory immune diseases, including coronary artery disease (CAD). To explore the causal relationship between this axis and CAD, we performed a three-stage case-control association analysis with 3628 CAD cases and 3776 controls using common variants in the genes TSLP, interleukin 7 receptor (IL7R), and TSLP receptor (TSLPR). Three common variants in the TSLP/TSLP receptor axis were significantly associated with CAD in a Chinese Han population (rs3806933T in TSLP, Padj=4.35×10-5, OR=1.18; rs6897932T in IL7R, Padj=1.13×10-7, OR=1.31; g.19646A>GA in TSLPR, Padj=2.04×10-6, OR=1.20). Reporter gene analysis demonstrated that rs3806933 and rs6897932 could influence TSLP and IL7R expression, respectively. Furthermore, the “T” allele of rs3806933 might increase plasma TSLP levels (R2=0.175, P<0.01). In a stepwise procedure, the risk for CAD increased by nearly 5-fold compared with the maximum effect of any single variant (Padj=6.99×10-4, OR=4.85). In addition, the epistatic interaction between TSLP and IL33 produced a nearly 3-fold increase in the risk of CAD in the combined model of rs3806933TT-rs7025417TT (Padj=3.67×10-4, OR=2.98). Our study illustrates that the TSLP/TSLPR axis might be involved in the pathogenesis of CAD through up-regulation of mRNA or protein expression of the referenced genes and might have additive effects on the CAD risk when combined with IL-33 signaling.