Publications by authors named "Shaofang Nie"

13 Publications

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Genetic association analysis between IL9 and coronary artery disease in a Chinese Han population.

Cytokine 2021 Nov 20;150:155761. Epub 2021 Nov 20.

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address:

Interleukin-9 (IL-9) plays important role in coronary artery disease (CAD). However, the exact relationship between them is not explored yet. Here, four tag SNPs covering IL9 (rs31563, rs2069868, rs2069870 and rs31564) were selected to conduct case-control association analyses in a total of 3704 individuals from Chinese Han population (1863 CAD vs 1841 control). Results showed that: first, rs2069868 was associated with CAD combined with hypertension (P = 0.027); second, IL9 haplotype (CGAT) was associated with CAD (P = 0.035), and the combination genotype of "rs31563_CC/rs31564_TT" would remarkably decrease the risk of CAD (P = 0.001); third, significant associations were found between rs2069870 and decreased LDL-c levels and decreased total cholesterol levels, and between rs31563 and increased HDL-c levels (P < 0.05). Therefore, we conclude that IL9 might play a causal role in CAD by interacted with CAD traditional risk factors, which might confer a new way to improve the prevention and treatment of CAD.
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http://dx.doi.org/10.1016/j.cyto.2021.155761DOI Listing
November 2021

Regulatory B cells improve ventricular remodeling after myocardial infarction by modulating monocyte migration.

Basic Res Cardiol 2021 07 24;116(1):46. Epub 2021 Jul 24.

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

Overactivated inflammatory responses contribute to adverse ventricular remodeling after myocardial infarction (MI). Regulatory B cells (Bregs) are a newly discovered subset of B cells with immunomodulatory roles in many immune and inflammation-related diseases. Our study aims to determine whether the expansion of Bregs exerts a beneficial effect on ventricular remodeling and explore the mechanisms involved. Here, we showed that adoptive transfer of Bregs ameliorated ventricular remodeling in a murine MI model, as demonstrated by improved cardiac function, decreased scar size and attenuated interstitial fibrosis without changing the survival rate. Reduced Ly6C monocyte infiltration was found in the hearts of the Breg-transferred mice, while the infiltration of Ly6C monocytes was not affected. In addition, the replenishment of Bregs had no effect on the myocardial accumulation of T cells or neutrophils. Mechanistically, Bregs reduced the expression of C-C motif chemokine receptor 2 (CCR2) in monocytes, which inhibited proinflammatory monocyte recruitment to the heart from the peripheral blood and mobilization from the bone marrow. Breg-mediated protection against MI was abrogated by treatment with an interleukin 10 (IL-10) antibody. Finally, IL-10 neutralization reversed the effect of Bregs on monocyte migration and CCR2 expression. The present study suggests a therapeutic value of Bregs in limiting ventricular remodeling after MI through decreasing CCR2-mediated monocyte recruitment and mobilization.
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http://dx.doi.org/10.1007/s00395-021-00886-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310480PMC
July 2021

Inhibition of fibroblast IL-6 production by ACKR4 deletion alleviates cardiac remodeling after myocardial infarction.

Biochem Biophys Res Commun 2021 04 18;547:139-147. Epub 2021 Feb 18.

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address:

Fibrotic scarring is tightly linked to the development of heart failure in patients with post-myocardial infarction (MI). Atypical chemokine receptor 4 (ACKR4) can eliminate chemokines, such as C-C chemokine ligand 21 (CCL21), which is independently associated with heart failure mortality. However, the role of ACKR4 in the heart during MI is unrevealed. This study aimed to determine whether ACKR4 modulates cardiac remodeling following MI and to illuminate the potential molecular mechanisms. The expression of ACKR4 was upregulated in the border/infarct area, and ACKR4 was predominantly expressed in cardiac fibroblasts (CFs). Knockout of ACKR4 protected against adverse ventricular remodeling in mice post-MI. These protective effects of ACKR4 deficiency were independent of dendritic cell immune response but could be attributed to downregulated CF-derived IL-6, affecting CF proliferation and endothelial cell (EC) functions, which consequently inhibited cardiac fibrosis. ACKR4 promoted IL-6 generation and proliferation of CFs. Besides, ACKR4 induced endothelial-to-mesenchymal transition (EndMT) in ECs through IL-6 paracrine effect. The p38 MAPK/NF-κB signaling pathway was involved in ACKR4 facilitated IL-6 generation. Moreover, ACKR4 overexpression in vivo via AAV9 carrying a periostin promoter aggravated heart functional impairment post-MI, which was abolished by IL-6 neutralizing antibody. Therefore, our study established a novel link between ACKR4 and IL-6 post-MI, indicating that ACKR4 may be a novel therapeutic target to ameliorate cardiac remodeling.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.013DOI Listing
April 2021

A Unique Population of Regulatory T Cells in Heart Potentiates Cardiac Protection From Myocardial Infarction.

Circulation 2020 11 28;142(20):1956-1973. Epub 2020 Sep 28.

Department of Cardiology, Union Hospital, and Key Laboratory of Biological Targeted Therapy of the Ministry of Education (N.X., Y. Lu, M.G., N.L., M.L., J.J., Z.Z., J.L., D.L., T.T., B.L., S.N., M.Z., M.L., Y. Liao, X.C.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Regulatory T cells (Tregs), traditionally recognized as potent suppressors of immune response, are increasingly attracting attention because of a second major function: residing in parenchymal tissues and maintaining local homeostasis. However, the existence, unique phenotype, and function of so-called tissue Tregs in the heart remain unclear.

Methods: In mouse models of myocardial infarction (MI), myocardial ischemia/reperfusion injury, or cardiac cryoinjury, the dynamic accumulation of Tregs in the injured myocardium was monitored. The bulk RNA sequencing was performed to analyze the transcriptomic characteristics of Tregs from the injured myocardium after MI or ischemia/reperfusion injury. Photoconversion, parabiosis, single-cell T-cell receptor sequencing, and adoptive transfer were applied to determine the source of heart Tregs. The involvement of the interleukin-33/suppression of tumorigenicity 2 axis and Sparc (secreted acidic cysteine-rich glycoprotein), a molecule upregulated in heart Tregs, was further evaluated in functional assays.

Results: We showed that Tregs were highly enriched in the myocardium of MI, ischemia/reperfusion injury, and cryoinjury mice. Transcriptomic data revealed that Tregs isolated from the injured hearts had plenty of differentially expressed transcripts in comparison with their lymphoid counterparts, including heart-draining lymphoid nodes, with a phenotype of promoting infarct repair, indicating a unique characteristic. The heart Tregs were accumulated mainly because of recruitment from the circulating Treg pool, whereas local proliferation also contributed to their expansion. Moreover, a remarkable case of repeatedly detected T-cell receptor of heart Tregs, more than that of spleen Tregs, suggests a model of clonal expansion. Besides, HeliosNrp-1 phenotype proved the mainly thymic origin of heart Tregs, with a small contribution of phenotypic conversion of conventional CD4 T cells, proved by the analysis of T-cell receptor repertoires and conventional CD4 T cells adoptive transfer experiments. The interleukin-33/suppression of tumorigenicity 2 axis was essential for sustaining heart Treg populations. Last, we demonstrated that Sparc, which was highly expressed by heart Tregs, acted as a critical factor to protect the heart against MI by increasing collagen content and boosting maturation in the infarct zone.

Conclusions: We identified and characterized a phenotypically and functionally unique population of heart Tregs that may lay the foundation to harness Tregs for cardioprotection in MI and other cardiac diseases.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046789DOI Listing
November 2020

Interleukin 35 ameliorates myocardial ischemia-reperfusion injury by activating the gp130-STAT3 axis.

FASEB J 2020 02 9;34(2):3224-3238. Epub 2020 Jan 9.

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Myocardial ischemia-reperfusion injury (MIRI) is common clinical complication, which represents significant challenge in the treatment of acute myocardial infarction (AMI) diseases. Interleukin 35 (IL-35) exhibits anti-inflammatory properties via the engagement of the gp130, IL-12Rβ2 and IL-27Rα receptors. However, whether IL-35 plays a beneficial role in the treatment of MIRI and potential underling mechanism are unclear. We showed that IL-35 conferred protection from MIRI as demonstrated by reduced infarct size and cardiac troponin T, improved cardiac function and decreased cardiomyocyte apoptosis in a mouse model. Despite activation of both STAT3 and STAT5 phosphorylation in the heart by IL-35, signal transducers and activators of transcription 3 (STAT3) was essential for mediating the IL-35-mediated protective effect on MIRI using cardiomyocyte-specific STAT3 deficient mice. Furthermore, gp130 was required for the STAT3 activation and cardio-protection induced by IL-35. Interestingly, IL-35 induced gp130 homodimer and gp130/IL-12Rβ2 heterodimers in cardiomyocyte. Our results indicate that IL-35 can execute a protective role against MIRI through a novel signaling pathway, IL-35-gp130-STAT3 pathway, in cardiomyocytes, which may be beneficial for the development of novel and effective therapeutic approaches to treat the MIRI.
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http://dx.doi.org/10.1096/fj.201901718RRDOI Listing
February 2020

IL (Interleukin)-33 Suppresses Abdominal Aortic Aneurysm by Enhancing Regulatory T-Cell Expansion and Activity.

Arterioscler Thromb Vasc Biol 2019 03;39(3):446-458

From the Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, and Key Lab for Biological Targeted Therapy of Education Ministry and Hubei Province, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., N.X., S.W., D.L., Y.L., M.G., T.T., J.J., B.L., S.N., M.L.,Y.L., X.C.).

Objective- Inflammation occurs during the progression of abdominal aortic aneurysm (AAA). IL (interleukin)-33 is a pleiotropic cytokine with multiple immunomodulatory effects, yet its role in AAA remains unknown. Approach and Results- Immunoblot, immunohistochemistry, and immunofluorescent staining revealed increased IL-33 expression in adventitia fibroblasts from mouse AAA lesions. Daily intraperitoneal administration of recombinant IL-33 or transgenic IL-33 expression ameliorated periaorta CaPO injury- and aortic elastase exposure-induced AAA in mice, as demonstrated by blunted aortic expansion, reduced aortic wall elastica fragmentation, enhanced AAA lesion collagen deposition, attenuated T-cell and macrophage infiltration, reduced inflammatory cytokine production, skewed M2 macrophage polarization, and reduced lesion MMP (matrix metalloproteinase) expression and cell apoptosis. Flow cytometry analysis, immunostaining, and immunoblot analysis showed that exogenous IL-33 increased CD4Foxp3 regulatory T cells in spleens, blood, and aortas in periaorta CaPO-treated mice. Yet, ST2 deficiency muted these IL-33 activities. Regulatory T cells from IL-33-treated mice also showed significantly stronger activities in suppressing smooth muscle cell inflammatory cytokine and chemokine expression, macrophage MMP expression, and in increasing M2 macrophage polarization than those from vehicle-treated mice. In contrast, IL-33 failed to prevent AAA and lost its beneficial activities in CaPO-treated mice after selective depletion of regulatory T cells. Conclusions- Together, this study established a role of IL-33 in protecting mice from AAA formation by enhancing ST2-dependent aortic and systemic regulatory T-cell expansion and their immunosuppressive activities.
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http://dx.doi.org/10.1161/ATVBAHA.118.312023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393188PMC
March 2019

IL-21 promotes myocardial ischaemia/reperfusion injury through the modulation of neutrophil infiltration.

Br J Pharmacol 2018 04 12;175(8):1329-1343. Epub 2017 Apr 12.

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background And Purpose: The immune system plays an important role in driving the acute inflammatory response following myocardial ischaemia/reperfusion injury (MIRI). IL-21 is a pleiotropic cytokine with multiple immunomodulatory effects, but its role in MIRI is not known.

Experimental Approach: Myocardial injury, neutrophil infiltration and the expression of neutrophil chemokines KC (CXCL1) and MIP-2 (CXCL2) were studied in a mouse model of MIRI. Effects of IL-21 on the expression of KC and MIP-2 in neonatal mouse cardiomyocytes (CMs) and cardiac fibroblasts (CFs) were determined by real-time PCR and ELISA. The signalling mechanisms underlying these effects were explored by western blot analysis.

Key Results: IL-21 was elevated within the acute phase of murine MIRI. Neutralization of IL-21 attenuated myocardial injury, as illustrated by reduced infarct size, decreased cardiac troponin T levels and improved cardiac function, whereas exogenous IL-21 administration exerted opposite effects. IL-21 increased the infiltration of neutrophils and increased the expression of KC and MIP-2 in myocardial tissue following MIRI. Moreover, neutrophil depletion attenuated the IL-21-induced myocardial injury. Mechanistically, IL-21 increased the production of KC and MIP-2 in neonatal CMs and CFs, and enhanced neutrophil migration, as revealed by the migration assay. Furthermore, we demonstrated that this IL-21-mediated increase in chemokine expression involved the activation of Akt/NF-κB signalling in CMs and p38 MAPK/NF-κB signalling in CFs.

Conclusions And Implications: Our data provide novel evidence that IL-21 plays a pathogenic role in MIRI, most likely by promoting cardiac neutrophil infiltration. Therefore, targeting IL-21 may have therapeutic potential as a treatment for MIRI.

Linked Articles: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.
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http://dx.doi.org/10.1111/bph.13781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866974PMC
April 2018

Down-regulation of microRNA-451a facilitates the activation and proliferation of CD4 T cells by targeting Myc in patients with dilated cardiomyopathy.

J Biol Chem 2017 04 14;292(14):6004-6013. Epub 2016 Dec 14.

From the Laboratory of Cardiovascular Immunology, Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, 430022 Wuhan and

CD4 T cells are abnormally activated in patients with dilated cardiomyopathy (DCM) and might be associated with the immunopathogenesis of the disease. However, the underlying mechanisms of CD4 T cell activation remain largely undefined. Our aim was to investigate whether the dysregulation of microRNAs (miRNAs) was associated with CD4 T cell activation in DCM. CD4 T cells from DCM patients showed increased expression levels of CD25 and CD69 and enhanced proliferation in response to anti-CD3/28, indicating an activated state. miRNA profiling analysis of magnetically sorted CD4 T cells revealed a distinct pattern of miRNA expression in CD4 T cells from DCM patients compared with controls. The level of miRNA-451a (miR-451a) was significantly decreased in the CD4 T cells of DCM patients compared with that of the controls. The transfection of T cells with an miR-451a mimic inhibited their activation and proliferation, whereas an miR-451a inhibitor produced the opposite effects. Myc was directly inhibited by miR-451a via interaction with its 3'-UTR, thus identifying it as an miR-451a target in T cells. The knockdown of Myc suppressed the activation and proliferation of T cells, and the expression of Myc was significantly up-regulated at the mRNA level in CD4 T cells from patients with DCM. A strong inverse correlation was observed between the Myc mRNA expression and miR-451a transcription level. Our data suggest that the down-regulation of miR-451a contributes to the activation and proliferation of CD4 T cells by targeting the transcription factor Myc in DCM patients and may contribute to the immunopathogenesis of DCM.
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http://dx.doi.org/10.1074/jbc.M116.765107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392590PMC
April 2017

Analysis of the genetic association between IL27 variants and coronary artery disease in a Chinese Han population.

Sci Rep 2016 05 12;6:25782. Epub 2016 May 12.

Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Interleukin-27 (IL-27) is an important cytokine in inflammatory diseases, including coronary artery disease (CAD). To explore the precise role of IL-27 in CAD, we investigated the genetic association between IL27 and CAD in the GeneID Chinese Han population. A two-stage case control association analysis was performed for 3075 CAD cases and 2802 controls. Logistic regression analysis was used to adjust the traditional risk factors for CAD. Results showed that a promoter variant, rs153109, tended to be marginally associated with CAD in the discovery population (Padj = 0.028, OR = 1.27, 95%CI: 1.03-1.58). However, this association was not replicated in the validation stage (Padj = 0.559, OR = 1.04, 95%CI: 0.90-1.21). In addition, when we classified the combined population into two subgroups according to the age at disease onset or disease state, we again obtained no significant associations. Finally, we estimated the severity of coronary stenosis using the Gensini Scoring system and determined that the rs153109 genotypes were still not associated with the Gensini scores of the CAD patients. In conclusion, our study failed to find an association between common variants in the functional region of IL27 and CAD in a Chinese Han population, which indicated that IL-27 might only be an inflammatory marker during the development of CAD.
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http://dx.doi.org/10.1038/srep25782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865940PMC
May 2016

IL-9 aggravates the development of atherosclerosis in ApoE-/- mice.

Cardiovasc Res 2015 Jun 17;106(3):453-64. Epub 2015 Mar 17.

Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, China Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan 430022, China

Aims: Recently, interleukin (IL)-9 was found to be involved in the pathogenesis of many inflammatory diseases. Here, we tested whether IL-9 was related to atherosclerosis and investigated the underlying mechanisms.

Methods And Results: IL-9R was expressed in mouse aortic endothelial cells (MAECs) and aortic tissues, and IL-9 levels were elevated in plasma and aortic arches in Apolipoprotein E-deficient (ApoE-/-) mice. ApoE-/- mice fed a western diet for 10 weeks were administered recombinant mouse IL-9 (rIL-9) or anti-IL-9 neutralizing monoclonal antibody (mAb). Mice treated with rIL-9 developed markedly larger plaques in both the aorta and aortic root. Immunohistochemical studies demonstrated increases in both vascular endothelial adhesion molecule-1 (VCAM-1) expression and the infiltration of inflammatory cells, including T cells and macrophages, in plaques. However, treatment with the anti-IL-9 mAb caused the opposite effect. The administration of rIL-9 did not affect the splenic T cell or peripheral monocyte subsets. Meanwhile, IL-9 induced VCAM-1 expression in MAECs mainly via a STAT3-dependent pathway, consequently increasing monocyte-endothelial adhesion. Moreover, treatment with anti-VCAM-1 mAb partially abrogated the IL-9-induced increase in plaque area. In addition, CD4(+)IL-9(+) T cells and IL-9 were increased in patients with acute coronary syndrome, and the levels of IL-9 in culture supernatants and soluble VCAM-1 (sVCAM-1) in plasma were significantly positively correlated in the enrolled patients.

Conclusion: Our results demonstrated that IL-9 exerted pro-atherosclerotic effects in ApoE-/- mice at least partially by inducing VCAM-1 expression, which mediated inflammatory cell infiltration into atherosclerotic lesions.
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http://dx.doi.org/10.1093/cvr/cvv110DOI Listing
June 2015

Regulation of CARD8 expression by ANRIL and association of CARD8 single nucleotide polymorphism rs2043211 (p.C10X) with ischemic stroke.

Stroke 2014 Feb 2;45(2):383-8. Epub 2014 Jan 2.

From the Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute (Y.B., G.J., Yingchao Zhou, M.Z., Yuanyuan Zhao, S.L., F.W., Q. Lu, Y.H., Q.Y., T.K., H.L., X.R., C.X., X.T., Q.K.W.), and College of Life Science and Technology and Center for Human Genome Research, Institute of Cardiology (S.N., X.C., Y. Liao), Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Jining Medical College Affiliated Hospital, Jining, China (Q. Li); Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China (Y. Li); Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China (Y.X., Y. Liu, J.L., Y.Y.); Department of Cardiology, Suizhou Central Hospital, Suizhou, China (J.Q.); Department of Cardiology, Xiangyang Central Hospital, Xiangyang, China (B.L.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (G.W.); Department of Cardiology, Wuhan No. 1 Hospital, Wuhan, China (Y.W.); Research Institute of the National Population and Family Planning Commission, Beijing, China (B.W., X.M.); and Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, OH (Q.K.W.).

Background And Purpose: ANRIL has long been considered as the strongest candidate gene at the 9p21 locus, robustly associated with stroke and coronary artery disease. However, the underlying molecular mechanism remains unknown. The present study works to elucidate such a mechanism.

Methods: Using expression quantitative loci analysis, we identified potential genes whose expression may be influenced by genetic variation in ANRIL. To verify the identified gene(s), knockdown and overexpression of ANRIL were evaluated in human umbilical vein endothelial cells and HepG2 cells. Ischemic stroke and coronary artery disease risk were then evaluated in the gene(s) demonstrated to be mediated by ANRIL in 3 populations of Chinese Han ancestry: 2 ischemic stroke populations consisting of the Central China cohort (903 cases and 873 controls) and the Northern China cohort (816 cases and 879 controls) and 1 coronary artery disease cohort consisting of 772 patients and 873 controls.

Results: Expression quantitative loci analysis identified CARD8 among others, with knockdown of ANRIL expression decreasing CARD8 expression and overexpression of ANRIL increasing CARD8 expression. The minor T allele of a previously identified CARD8 variant (rs2043211) was found to be significantly associated with a protective effect of ischemic stroke under the recessive model in 2 independent stroke cohorts. No significant association was found between rs2043211 and coronary artery disease.

Conclusions: CARD8 is a downstream target gene regulated by ANRIL. Single nucleotide polymorphism rs2043211 in CARD8 is significantly associated with ischemic stroke. ANRIL may increase the risk of ischemic stroke through regulation of the CARD8 pathway.
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http://dx.doi.org/10.1161/STROKEAHA.113.003393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962686PMC
February 2014

The IL-33-ST2L pathway is associated with coronary artery disease in a Chinese Han population.

Am J Hum Genet 2013 Oct 26;93(4):652-60. Epub 2013 Sep 26.

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.

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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http://dx.doi.org/10.1016/j.ajhg.2013.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791271PMC
October 2013

The same chromosome 9p21.3 locus is associated with type 2 diabetes and coronary artery disease in a Chinese Han population.

Diabetes 2011 Feb;60(2):680-4

Institute of Cardiology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Objective: Recent genome-wide association studies (GWAS) revealed that a 9p21.3 locus was associated with type 2 diabetes. In this study, we carried out a large-scale case-control study in the GeneID Chinese Han population to 1) further replicate the association of 9p21.3 type 2 diabetes GWAS single nucleotide polymorphisms (SNPs) and 2) assess the association of these SNPs with coronary artery disease.

Research Design And Methods: Three SNPs (rs2383208, rs10811661, and rs10757283) were genotyped in two GeneID cohorts of 3,167 Chinese Han individuals. Case-control association design was used to determine the association of the SNPs with type 2 diabetes and coronary artery disease. Gensini scores were calculated in the coronary artery disease subjects and were tested for association with the variants. Multivariate logistic regressions were performed on association studies.

Results: The association between two of the three SNPs and type 2 diabetes was replicated in the GeneID population (rs2383208, P = 0.936; rs10811661-T, P = 0.02, odds ratio [OR] = 1.23; rs10757283-C, P = 0.003, OR = 1.30). The same two SNPs also contributed to the risk of coronary artery disease (CAD) (rs10811661-T, P = 0.002, OR = 1.19; rs10757283-C, P = 0.003, OR = 1.18). In addition, rs10757283 was associated with severity of coronary atherosclerosis estimated by the Gensini scoring system (risk allele C, quantitative-trait regression adjusted P = 0.002).

Conclusions: For the first time to our knowledge, our results indicated that the same 9p21.3 locus, represented by SNPs rs10811661 and rs10757283, contributed to the risk of type 2 diabetes and coronary artery disease in our GeneID Chinese Han population.
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http://dx.doi.org/10.2337/db10-0185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3028370PMC
February 2011
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