Genetic variability of the distal promoter of the ST2 gene is associated with angiographic severity of coronary artery disease

Tsapaki, Andy; Zaravinos, Apostolos; Apostolakis, Stavros; Voudris, Konstantinos; Vogiatzi, Konstantina; Kochiadakis, Georgios E.; Spandidos, Demetrios Α.

doi:10.1007/s11239-010-0496-y

Cited by 13 publications

(11 citation statements)

References 13 publications

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“…Though Tsapaki et al investigated the association between the distal promoter variants in IL1RL1 and CAD with small sample size, their significant results indicated that the IL-33-ST2L pathway might genetically associate with CAD. 50 In the present study, with a large discovery sample size with sufficient statistical power, we detected that two tag SNPs in the two genes analyzed (rs7025417 in IL33 and rs11685424 in IL1RL1) were significantly associated with CAD not only in the subgroup of anatomical disease (severe coronary stenosis) but also in the subgroup of clinical disease (myocardial infarction or revascularization). Furthermore, additional functional studies using reporter gene and circulation level analysis suggested that the rs7025417 genotype affects the level of circulating IL-33, which indicates that rs7025417 might influence the development of CAD by regulating the expression of IL33.…”

Section: Discussionsupporting

confidence: 47%

The IL-33-ST2L Pathway Is Associated with Coronary Artery Disease in a Chinese Han Population

Nie

Liao

et al. 2013

The American Journal of Human Genetics

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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.

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Section: Discussionsupporting

confidence: 47%

The IL-33-ST2L Pathway Is Associated with Coronary Artery Disease in a Chinese Han Population

Nie

Liao

et al. 2013

The American Journal of Human Genetics

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“…Previously, genetic variability of the distal promoter of the ST2 gene was shown to be associated with angiographic severity of CAD [23]. Interestingly, we found no differences in sST2 levels between patients with stable angina and individuals without significant stenosis on coronary angiography, although both STEMI and NSTEMI patients demonstrated significantly higher sST2 serum levels than the control group.…”

Section: Discussioncontrasting

confidence: 45%

Soluble ST2 and Interleukin-33 Levels in Coronary Artery Disease: Relation to Disease Activity and Adverse Outcome

et al. 2014

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ObjectivesST2 is a receptor for interleukin (IL)-33. We investigated an association of soluble ST2 (sST2) and IL-33 serum levels with different clinical stages of coronary artery disease. We assessed the predictive value of sST2 and IL-33 in patients with stable angina, non-ST elevation myocardial infarction (NSTEMI) and ST elevation myocardial infarction (STEMI).MethodsWe included 373 patients of whom 178 had stable angina, 97 had NSTEMI, and 98 had STEMI. Patients were followed for a mean of 43 months. The control group consisted of 65 individuals without significant stenosis on coronary angiography. Serum levels of sST2 and IL-33 were measured by ELISAs.ResultssST2 levels were significantly increased in patients with STEMI as compared to patients with NSTEMI and stable angina as well as with controls. IL-33 levels did not differ between the four groups. During follow-up, 37 (10%) patients died and the combined endpoint (all cause death, MI and rehospitalisation for cardiac causes) occurred in 66 (17.6%) patients. sST2 serum levels significantly predicted mortality in the total cohort. When patients were stratified according to their clinical presentation, the highest quintile of sST2 significantly predicted mortality in patients with STEMI, but not with NSTEMI or stable coronary artery disease. sST2 was a significant predictor for the combined endpoint in STEMI patients and in patients with stable angina. Serum levels of IL-33 were not associated with clinical outcome in the total cohort, but the highest quintile of IL-33 predicted mortality in patients with STEMI.ConclusionsSerum levels of sST2 are increased in patients with acute coronary syndromes as compared to levels in patients with stable coronary artery disease and in individuals without coronary artery disease. sST2 and IL-33 were associated with mortality in patients with STEMI but not in patients with NSTEMI or stable angina.

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“…These lines of important evidence indicate that the development of coronary atherosclerosis, which was considered to be a kind of inflammatory disease, can also be affected by the pathway. Previous data have demonstrated the association between the distal promoter variants in ST2 and angiographic severity of CAD, and suggest that the IL-33/ST2L pathway might be genetically associated with CAD [22] . Moreover, IL33/ST2 pathway was significantly associated not only with patients with severe coronary stenosis, but with the subgroup of MI or revascularization, and affected the level of circulating IL-33 genetically [23] .…”

Section: Discussionmentioning

confidence: 92%

Association of IL33/ST2 signal pathway gene polymorphisms with myocardial infarction in a Chinese Han population

Yang

Wen

et al. 2015

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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This study investigated the relationship between IL-33/ST2 signal pathway gene polymorphisms and myocardial infarction (MI) in Han Chinese. A case-control association analysis was performed on a total of 490 MI patients (MI group) and 929 normal subjects (NC group). Sequenom Mass Array and Taqman genotyping technique were used to analyze the tag single nucleotide polymorphisms (SNPs) in the genes encoding IL-33, ST2, and IL-1RaP (rs11792633, rs1041973 and rs4624606). The results showed that the frequencies of rs4624606 genotypes AA, TT, AT were 0.031, 0.647, 0.322 in MI group and 0.026, 0.712, 0.263 in NC group, and the allele frequencies of A and T were 0.192, 0.808 in MI group and 0.157, 0.843 in NC group. There were significant differences in rs4624606 genotypes and allele frequencies between MI group and NC group (P<0.05). For rs11792633, the allele frequencies of C and T were 0.45, 0.55 in MI group and 0.454, 0.546 in NC group with no significant differences found between the two groups. Compared with genotype CC+TC, rs11792633 genotype TT had an increased risk of hypertension (P<0.05). However, there were no significant differences in the frequencies of rs11792633 genotypes between the two groups. No significant differences were noted in the frequencies of rs1041973 genotype and allele between the two groups. Logistic regression analysis showed that rs4624606 genotypes AT and AA+AT were both significantly associated with MI (AT: OR=1.325, P=0.029, 95% CI=1.03-1.705; AA+AT: OR=1.316, P=0.028, 95% CI=1.03-1.681) after factors such as age, gender, smoking, drinking, body mass index (BMI), triglyceride (TG) and cholesterol were adjusted. Those carrying rs4624606 genotype AT or AA+AT had an increased risk of MI. No associations were found between the polymorphisms of the other two loci with MI. It was concluded that, in the IL33/ST2 signal pathway, the A allele of rs4624606 polymorphism of IL-1RaP gene is a potential independent risk factor for MI, and the genotypes AA+AT and AT are associated with the incidence of MI.

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Genetic variability of the distal promoter of the ST2 gene is associated with angiographic severity of coronary artery disease

Cited by 13 publications

References 13 publications

The IL-33-ST2L Pathway Is Associated with Coronary Artery Disease in a Chinese Han Population

The IL-33-ST2L Pathway Is Associated with Coronary Artery Disease in a Chinese Han Population

Soluble ST2 and Interleukin-33 Levels in Coronary Artery Disease: Relation to Disease Activity and Adverse Outcome

Association of IL33/ST2 signal pathway gene polymorphisms with myocardial infarction in a Chinese Han population

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