The IL-33-ST2L pathway is associated with coronary artery disease in a Chinese Han population.
The effects of interleukin-33 (IL-33) on the immune system have been clearly demonstrated; however, in cardiovascular diseases, especially in coronary artery disease (CAD), these effects have not yet been clarified. In this study, we investigate the genetic role of the IL-33-ST2L pathway in CAD. We performed three-stage case-control association analyses on a total of 4,521 individuals with CAD and 4,809 controls via tag SNPs in the genes encoding IL-33 and ST2L-IL-1RL1. One tag SNP in each gene was significantly associated with CAD (rs7025417(T) in IL33, padj = 1.19 × 10(-28), OR = 1.39, 95% CI: 1.31-1.47; rs11685424(G) in IL1RL1, padj = 6.93 × 10(-30), OR = 1.40, 95% CI: 1.32-1.48). Combining significant variants in two genes, the risk for CAD increased nearly 5-fold (padj = 8.90 × 10(-21), OR = 4.98, 95% CI: 3.56-6.97). Traditional risk factors for CAD were adjusted for the association studies by SPSS with logistic regression analysis. With the two variants above, both located within the gene promoter regions, reporter gene analysis indicated that the rs7025417 C>T and rs11685424 A>G changes resulted in altered regulation of IL33 and IL1RL1 gene expression, respectively (p < 0.005). Further studies revealed that the rs7025417 genotype was significantly associated with plasma IL-33 levels in the detectable subjects (n = 227, R(2) = 0.276, p = 1.77 × 10(-17)): the level of IL-33 protein increased with the number of rs7025417 risk (T) alleles. Based on genetic evidence in humans, the IL-33-ST2L pathway appears to have a causal role in the development of CAD, highlighting this pathway as a valuable target for the prevention and treatment of CAD.
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan 430074, China.
Xin
X
Tu
Shaofang
S
Nie
Yuhua
Y
Liao
Hongsong
H
Zhang
Qian
Q
Fan
Chengqi
C
Xu
Ying
Y
Bai
Fan
F
Wang
Xiang
X
Ren
Tingting
T
Tang
Ni
N
Xia
Sisi
S
Li
Yuan
Y
Huang
Juan
J
Liu
Qing
Q
Yang
Yuanyuan
Y
Zhao
Qiulun
Q
Lv
Qingxian
Q
Li
Yue
Y
Li
Yunlong
Y
Xia
Jin
J
Qian
Bin
B
Li
Gang
G
Wu
Yanxia
Y
Wu
Yan
Y
Yang
Qing K
QK
Wang
Xiang
X
Cheng
D000483:Alleles; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics*; D005260:Female; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000097:blood* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000097:blood* / Q000235:genetics; D012307:Risk Factors
C079241:IL1RL1 protein, human; C506536:IL33 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D011956:Receptors, Cell Surface