Evidence for CTLA4 as a susceptibility gene for dilated cardiomyopathy

Ruppert, Volker; Meyer, Thomas; Struwe, Clarissa; Petersen, Jana; Perrot, Andreas; Posch, Maximilian; Özcelik, C.; Richter, Anette; Maisch, Bernhard; Pankuweit, Sabine

doi:10.1038/ejhg.2010.3

Cited by 22 publications

(17 citation statements)

References 35 publications

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“…T-cells that do not express the CTLA4-B7-inhibitory signal exhibit an unregulated proliferation of lymphocytes in the heart, which can lead to a severe damage of myocardium, and the development of cardiomyopathies [36,37]. Cardiomyopathy patients present higher levels of CTLA4 SNP (+49A>G; Thr17Ala), which lead to a loss of function of CTLA4, than healthy subjects (14.7% vs. 7.4%, p = 0.005) [38]. Therefore, the correct activation of CD4 + T-cells in cardiac autoimmunity is mediated by (1) antigen-presenting cells that phagocytosed death cardiomyocytes or cardiac autoantigens and (2) a second co-stimulatory signal mediated by B7 (Figure 1).…”

Section: Development Of Cardiac Autoimmunitymentioning

confidence: 99%

IFN-γ versus IL-17: A Battle During Cardiac Autoimmunity Evolution

Kurtenbach¹,

Martinez²

2017

Immunopathogenesis and Immune-Based Therapy for Selected Autoimmune Disorders

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Cardiovascular diseases are the leading global cause of death. Cardiomyopathies are the most prevalent forms of heart failure diseases currently. They may have genetic or environmental etiology, and the development of an autoimmune process is essential for the progression of the disease. During an autoimmune response, there is the breakdown of self-tolerance and generation of a T-lymphocytes-mediated cellular autoimmune response and B-lymphocytes-mediated humoral autoimmune response. Lymphocytes perpetuate the autoimmune response throughout the release of cytokines, expansion of autoreactive clones, and attenuation of regulatory mechanisms. Increasing evidences indicate that interferon (IFN)-γ and interleukin (IL)-17 participate during autoimmune disorders development. The use of autoimmune cardiomyopathy models revealed antagonistic functions for both cytokines during the evolution of autoimmune cardiomyopathy: while enhanced IFN-γ levels are associated to a lower disease severity, the levels of IL-17 are inversely correlated to a favorable prognosis. More precisely, recent findings indicate that the IFN-γ/IL-17 ratio in combination with other cytokine levels dictates heart's autoimmunity development and dilatation. In this chapter, we discuss the role played by the autoimmune response in the development of cardiomyopathy. We also discuss some immune mechanisms focused on IFN-γ and IL-17's ability to induce and perpetuate cardiac autoimmunity.

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Section: Development Of Cardiac Autoimmunitymentioning

confidence: 99%

IFN-γ versus IL-17: A Battle During Cardiac Autoimmunity Evolution

Kurtenbach¹,

Martinez²

2017

Immunopathogenesis and Immune-Based Therapy for Selected Autoimmune Disorders

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“…Most DCMs are sporadic and nonfamilial with multifactorial causes linked to genetic susceptibility. Many genetic polymorphisms have been shown to be associated with an increased risk of developing DCM [ 5 , 6 ]. Therefore, genetic studies should not be restricted to familial DCM.…”

Section: Introductionmentioning

confidence: 99%

Association of Nicotinamide Phosphoribosyltransferase (NAMPT) Gene Polymorphisms and of Serum NAMPT Levels with Dilated Cardiomyopathy in a Chinese Population

Dou

Peng

Zhou

et al. 2015

IJMS

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Nicotinamide phosphoribosyltransferase (NAMPT) has crucial roles for myocardial development, cardiomyocyte energy metabolism and cell death/survival by regulating NAD+-dependent sirtuin-1 (SIRT1) deacetylase. This study aimed to determine if the single nucleotide polymorphisms (SNPs) of the NAMPT gene may affect the susceptibility and prognosis for patients with dilated cardiomyopathy (DCM) and to describe the association of serum NAMPT levels with clinical features of DCM. Three SNPs (rs61330082, rs2505568, and rs9034) were analyzed by the polymerase chain reaction-restriction fragment length polymorphism method in a case-control study of 394 DCM patients and 395 controls from China. Serum NAMPT levels were measured by enzyme-linked immunosorbent assay kits. The homozygote for the minor allele at rs2505568 and rs9034 could not be detected in this study. Rs9034 T allele and CT genotype were associated with increased DCM risk (OR: 1.63, 95% CI = 1.16–2.27, p = 0.005 and OR: 1.72, 95% CI = 1.20–2.50, p = 0.0027, respectively). Nominally significant decreased DCM risk was found to be associated with the A allele and AT genotype of rs2505568 (OR: 0.48, 95% CI = 0.35–0.67, p < 0.0001 and OR: 0.44, 95% CI = 0.31–0.62, p < 0.0001, respectively), but it should be interpreted with caution because of Hardy-Weinberg disequilibrium in the control group. Of five haplotypes constructed, TAC (rs61330082-rs2505568-rs9034) was a protective haplotype to DCM (OR: 0.22, 95% CI = 0.13–0.39, p = 1.84 × 10−8). The Cox multivariate survival analysis indicated that the rs9034 CT genotype (hazard ratio (HR): 0.59, 95% CI = 0.37–0.96, p = 0.03) was an independently multivariate predictor for longer overall survival in DCM patients. Serum NAMPT levels were significantly higher in the DCM group than controls (p < 0.0001) and gradually increased with the increase of New York Heart Association grade in DCM patients. However, there was a lack of association of the three SNPs with serum NAMPT levels. Spearman correlation test revealed that the NAMPT level was positively associated with brain natriuretic peptide (r = 0.56, p = 0.001), left ventricular end-diastolic diameter (r = 0.293, p = 0.011) and left ventricular end-diastolic volume (r = 0.294, p = 0.011). Our study suggested that NAMPT may play an important role in the development of DCM.

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“…A promoter SNP ( −318 C/T ) and a functional SNP ( +49 A/G ) of the CTLA4 gene were investigated in two independent cohorts of DCM patients and healthy controls. 33 In patients with DCM, the +49GG genotype predicted high susceptibility for DCM. 33 …”

Section: Resultsmentioning

confidence: 99%

Genetic polymorphisms associated with heart failure: A literature review

Guo

2016

J Int Med Res

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ObjectiveTo review possible associations reported between genetic variants and the risk, therapeutic response and prognosis of heart failure.MethodsElectronic databases (PubMed, Web of Science and CNKI) were systematically searched for relevant papers, published between January 1995 and February 2015.ResultsEighty-two articles covering 29 genes and 39 polymorphisms were identified.ConclusionGenetic association studies of heart failure have been highly controversial. There may be interaction or synergism of several genetic variants that together result in the ultimate pathological phenotype for heart failure.

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Evidence for CTLA4 as a susceptibility gene for dilated cardiomyopathy

Cited by 22 publications

References 35 publications

IFN-γ versus IL-17: A Battle During Cardiac Autoimmunity Evolution

IFN-γ versus IL-17: A Battle During Cardiac Autoimmunity Evolution

Association of Nicotinamide Phosphoribosyltransferase (NAMPT) Gene Polymorphisms and of Serum NAMPT Levels with Dilated Cardiomyopathy in a Chinese Population

Genetic polymorphisms associated with heart failure: A literature review

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