Leukocyte TRP channel gene expressions in patients with non-valvular atrial fibrillation

Düzen, İrfan Veysel; Yavuz, Fethi; Vuruşkan, Ertan; Saraçoğlu, Erhan; Poyraz, Fatih; Göksülük, Hüseyin; Candemir, Başar; Demiryürek, Şeniz

doi:10.1038/s41598-017-10039-0

Cited by 27 publications

(21 citation statements)

References 57 publications

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“…9 The phenotypic spectrum associated with FLNC variation is intriguing, suggesting that variants act through divergent and tissue specific manner and/or that variants are modified by other genetic factors present in the given family. Although sequencing results suggested some possible genetic modifiers in the present study, including a variant in TRPV4 , 40 a gene which increases in expression with atrial fibrillation, a concrete link between modifiers and phenotype would require a larger sample size or greatly expanded functional modeling. In the present study, we support the role for FLNC variation in RCM, while adding evidence that FLNC variation should be considered in manifestations of congenital heart defects.…”

Section: Discussionmentioning

confidence: 81%

Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy

Tucker

McLellan

et al. 2017

Circ Cardiovasc Genet

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Background Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy characterized by impaired diastolic ventricular function resulting in a poor clinical prognosis. Rarely, heritable forms of RCM have been reported and mutations underlying RCM have been identified in genes that govern the contractile function of the cardiomyocytes. Methods and Results We evaluated 8 family members across four generations by history, physical examination, electrocardiography and echocardiography. Affected individuals presented with a pleitropic syndrome of progressive RCM, atrioventricular septal defects, and a high prevalence of atrial fibrillation. Exome sequencing of 5 affected members identified a single novel missense variant in a highly conserved residue of FLNC (p.V2297M). FLNC encodes Filamin C, a protein that acts as both a scaffold for the assembly and organization of the central contractile unit of striated muscle, and also as a mechanosensitive signaling molecule during cell migration and shear stress. Immunohistochemical analysis of Filamin C localization in cardiac tissue from an affected family member revealed a diminished localization at the z-disk, whereas traditional localization at the intercalated disk was preserved. Stem-cell derived cardiomyocytes mutated to carry the effect allele had diminished contractile activity when compared to controls. Conclusion We have identified a novel variant in FLNC as pathogenic variant for familial RCM, a finding that further expands upon the genetic basis of this rare and morbid cardiomyopathy.

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Section: Discussionmentioning

confidence: 81%

Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy

Tucker

McLellan

et al. 2017

Circ Cardiovasc Genet

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“…Moreover, none of the genes on odd‐numbered autosomes reached the overall Bonferroni correction threshold. The other two protein coding genes identified at chromosomal significance levels including MCOLN2 (mucolipin 2) on chromosome 1 and KIF3A (Kinesin Family Member 3A) on chromosome 5 (Table ) have also been linked to hypertension relevant pathways (Duzen et al, ; H. Saad & M., ). Our mega‐analysis results confirm these previous research findings.…”

Section: Resultsmentioning

confidence: 99%

“…threshold. The other two protein coding genes identified at chromosomal significance levels including MCOLN2 (mucolipin 2) on chromosome 1 and KIF3A (Kinesin Family Member 3A) on chromosome 5 (Table 4) have also been linked to hypertension relevant pathways (Duzen et al, 2017;H. Saad & M., 2017).…”

Section: Application To Gaw19 Datamentioning

confidence: 99%

General retrospective mega‐analysis framework for rare variant association tests

Chien

Chiu

2018

Genetic Epidemiology

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Here, we describe a retrospective mega-analysis framework for gene- or region-based multimarker rare variant association tests. Our proposed mega-analysis association tests allow investigators to combine longitudinal and cross-sectional family- and/or population-based studies. This framework can be applied to a continuous, categorical, or survival trait. In addition to autosomal variants, the tests can be applied to conduct mega-analyses on X-chromosome variants. Tests were built on study-specific region- or gene-level quasiscore statistics and, therefore, do not require estimates of effects of individual rare variants. We used the generalized estimating equation approach to account for complex multiple correlation structures between family members, repeated measurements, and genetic markers. While accounting for multilevel correlations and heterogeneity across studies, the test statistics were computationally efficient and feasible for large-scale sequencing studies. The retrospective aspect of association tests helps alleviate bias due to phenotype-related sampling and type I errors due to misspecification of phenotypic distribution. We evaluated our developed mega-analysis methods through comprehensive simulations with varying sample sizes, covariates, population stratification structures, and study designs across multiple studies. To illustrate application of the proposed framework, we conducted a mega-association analysis combining a longitudinal family study and a cross-sectional case-control study from Genetic Analysis Workshop 19.

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“…van Duijnhoven et al reported that the development and characterization of radiolabeled matrix metalloproteinases (MMP)-2/9 sensitive activatable cell-penetrating peptide probes (ACPPs) to assess MMP activity in myocardial remodeling in vivo, and found that radiolabeled MMP sensitive ACPP probes enable to assess MMP activity in the course of remodeling postmyocardial infarction [30]. Düzen et al observed marked increases in TRPML1-3, TRPA1, transient receptor potential melastatin subtype (TRPM)1-8, TRPC1-7, TRPV1-6, and PKD2 (TRPP2) gene expressions in nonvalvular atrial fibrillation (NVAF) patients, whereas there was no change in PKD1 (TRPP1) gene expression, suggesting that elevated gene expressions of TRP channels may be associated with the pathogenesis of NVAF [31]. Xiong et al pointed that activation of TRPM8 attenuates cold-induced hypertension through ameliorating vascular mitochondrial dysfunction [32].…”

Section: Discussionmentioning

confidence: 99%

Altered myocardial gene expression profiling in the ischemic tissues at different time points after cardiac ischemia/reperfusion in rats

Li¹,

Lin²,

He³

et al. 2018

Oncotarget

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We used Agilent Gene Expression microarray to analyze differential gene and lncRNA expression patterns in the myocardial ischemia regions during ischemia/ reperfusion (I/R)-induced cardiac injury in rats. Male SD rats were assigned into control group, 2 h group (30 min ischemia followed by 2 h reperfusion), 0.5 h (30 min ischemia followed by 0.5h reperfusion) group. We observed that of 18090 lncRNAs, an average of 233 lncRNAs was up-regulated in ischemic tissues of 2 h group, compared with those in control group, while an average of 6115 lncRNAs was down-regulated (with a > 2.0 fold-change and p < 0.05). Further, a total of 3135 mRNAs were differentially expressed between control group and 2h group, in which 542 mRNAs were up-regulated and 2593 mRNAs were down-regulated. Some differentially expressed genes were validated by qRT-PCR analyses of select lncRNAs in different time points after cardiac I/R injury. We unveiled that the expressions of lncRNA XR_345533.2, NONRATT025386, NONRATT024318, XR_599241.1, and NONRATT025509 were significantly up-regulated in 2h group compared with control group and 0.5h group, whereas the expression of lncRNA NR_130708.1 was downregulated after cardiac I/R injury and had no statistically different between 0.5h group and 2h group. Otherwise, the expressions of lncRNA NONRATT028627, NONRATT021959, XR_590005.1 and NONRATT023191 were significantly up-regulated in 2h group compared with 0.5h group. These findings provide evidence for differential expression patterns of mRNAs and lncRNAs in the ischemic tissues after cardiac I/R injury in rats.

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Leukocyte TRP channel gene expressions in patients with non-valvular atrial fibrillation

Cited by 27 publications

References 57 publications

Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy

Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy

General retrospective mega‐analysis framework for rare variant association tests

Altered myocardial gene expression profiling in the ischemic tissues at different time points after cardiac ischemia/reperfusion in rats

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