ZFHX3 knockdown increases arrhythmogenesis and dysregulates calcium homeostasis in HL-1 atrial myocytes

Kao, Yu Hsun; Hsu, Jung Chieh; Chen, Yao Chang; Lin, Yung Kuo; Lkhagva, Baigalmaa; Chen, Shih Ann; Chen, Yi Jen

doi:10.1016/j.ijcard.2016.02.091

Cited by 41 publications

(45 citation statements)

References 34 publications

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“…The SNPs in certain genes, for example, IRS1 , endothelin receptor type A ( EDNRA ), DCN , and ZFHX3 , are frequently associated with CVD or related traits, including our study. Insulin signaling and function was shown to reduce atherosclerosis through the endothelin receptors, whereas downregulation of DCN and ZFHX3 were associated with anti‐inflammatory/antiapoptotic and perturbed Ca2 + homeostasis, respectively . Functional studies are available for a few but future research is needed to ascertain the separate or combined effects of these genes that have been consistently associated with CVEs.…”

Section: Discussionmentioning

confidence: 99%

Local Ancestry and Clinical Cardiovascular Events Among African Americans From the Atherosclerosis Risk in Communities Study

Shendre

Irvin

Wiener

et al. 2017

JAHA

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BackgroundLocal ancestry in relation to clinical cardiovascular events (CVEs) among African Americans can provide insight into their genetic susceptibility to the disease.Methods and ResultsWe examined local European ancestry (LEA) association with CVEs among 3000 African Americans from the Atherosclerosis Risk in Communities Study (ARIC). We estimated LEA using Local Ancestry Inference in adMixed Populations using Linkage Disequilibrium (LAMP‐LD) and examined its association with myocardial infarction, stroke, coronary heart disease and its composite and cardiovascular disease composite using logistic regression. Genome‐wide significance was achieved by 121 LEA regions in relation to myocardial infarction and 2 in relation to the cardiovascular disease composite. The LEA region downstream of 4q32.1 was significantly associated with 2 times higher odds of myocardial infarction (P=1.45×10−6). The LEA region upstream of 6q11.1 was associated with 0.37 times lower odds of fatal coronary heart disease (P=7.34×10−4), whereas the LEA region downstream of 21q21.1 was associated with 1.55 times higher odds of composite coronary heart disease (P=3.45×10−4). Association of LEA with stroke was observed in the region upstream of 6p22.3 with a 1.57 times higher odds of stroke (P=9.69×10−4). Likewise, the LEA region on 4q32.3 was associated with a 1.53 times higher odds of composite cardiovascular disease (P=3.04×10−4). We also found 20 of the LEA regions at previously significant cardiovascular disease single‐nucleotide polymorphisms to be associated with CVE in our study.ConclusionsFuture studies are needed to replicate and/or determine the causal variants driving our associations and explore clinical applications for those consistently associated with CVEs.

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Section: Discussionmentioning

confidence: 99%

Local Ancestry and Clinical Cardiovascular Events Among African Americans From the Atherosclerosis Risk in Communities Study

Shendre

Irvin

Wiener

et al. 2017

JAHA

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“…A knockdown of ZFHX3 dysregulates Ca 2+ , shortens the APD, and promotes arrhythmia susceptibility. 47 …”

Section: Risk Factors For Developing Afmentioning

confidence: 99%

Atrial Fibrillation

Stærk

Sherer

et al. 2017

Circulation Research

900

380

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The last three decades have been characterized by an exponential growth in knowledge and advances in the clinical treatment of atrial fibrillation (AF). It is now known that AF genesis requires a vulnerable atrial substrate and that the formation and composition of this substrate may vary depending on comorbid conditions, genetics, sex, and other factors. Population-based studies have identified numerous factors that modify the atrial substrate and increase AF susceptibility. To date, genetic studies have reported seventeen independent signals for AF at fourteen genomic regions. Studies have established that advanced age, male sex, and European ancestry are prominent AF risk factors. Other modifiable risk factors, including sedentary lifestyle, smoking, obesity, diabetes mellitus, obstructive sleep apnea, and elevated blood pressure predispose to AF and each factor has been shown to induce structural and electrical remodeling of the atria. Both heart failure and myocardial infarction increase risk of AF and vice versa creating a feed forward loop that increases mortality. Other cardiovascular outcomes attributed to AF, including stroke and thromboembolism, are well established and epidemiology studies have championed therapeutics that mitigate these adverse outcomes. However, the role of anticoagulation for preventing dementia attributed to AF is less established. Our review is a comprehensive examination of the epidemiological data associating unmodifiable and modifiable risk factors for AF and of the pathophysiological evidence supporting the mechanistic link between each risk factor and AF genesis. Our review also critically examines the epidemiological data on clinical outcomes attributed to AF and summarizes current evidence linking each outcome with AF.

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“…The minor allele of ZFHX3 SNP rs2106261 was also associated with high BMI [19], but in our study BMI was similar among ZFHX3 SNP rs2106261 genotypes. ZFHX3 knockdown in atrial myocytes was reported to dysregulate calcium homeostasis and increase atrial arrhythmogenesis, ultimately contributing to AF occurrence [20]. Huang et al reported that interaction between ZFHX3 SNP and PITX2 SNP.…”

Section: Discussionmentioning

confidence: 99%

Maintenance of low inflammation level by the ZFHX3 SNP rs2106261 minor allele contributes to reduced atrial fibrillation recurrence after pulmonary vein isolation

et al. 2018

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IntroductionThe single nucleotide polymorphism (SNP) rs2106261 in the transcription factor gene ZFHX3 (16q22), a major regulator of inflammation, has been reported linking to atrial fibrillation (AF) by genome-wide association studies. Inflammation is known to be a strong predictor of atrial fibrillation recurrence after ablation, so we examined the association of the ZFHX3 SNP rs2106261 to inflammation marker expression and recurrence after AF ablation.MethodsWe genotyped ZFHX3 SNP rs2106261 and compared the minor (T) allele frequency between 362 paroxysmal AF (PAF) patients underwent pulmonary vein isolation (PVI) and 627 non-AF controls. We also analyzed associations between ZFHX3 SNP rs2106261 genotype and recurrence rate after pulmonary vein isolation and the inflammation markers.ResultsThe minor (T) allele frequency of the ZFHX3 SNP rs2106261 was significantly higher in AF patients than non-AF controls (odds ratio 1.52, p = 2.2×10−5). Multivariable analysis revealed that the minor allele (T) decreased AF recurrence rate after pulmonary vein isolation (hazard ratio 0.53, p = 0.04). Further, neutrophil/lymphocyte (N/L) ratio, C-reactive protein (CRP), and interleukin-6 (IL-6) expression levels were lower in PAF patients with the ZFHX3 SNP rs2106261 minor allele (TT+TC) than in CC patients (N/L ratio: CC 2.22 ± 0.08, TT+TC 1.98 ± 0.06, p = 0.018; CRP: CC 0.103 ± 0.009 mg/dl, TT+TC 0.076 ±0.007 mg/dl, p = 0.016; IL-6: CC 60.3 ± 3.0 pg/ml, TT+TC 52.8 ± 2.3 pg/ml, p = 0.04).ConclusionsThe ZFHX3 SNP rs2106261 minor allele is associated with lower AF recurrence rate after pulmonary vein isolation. Low baseline inflammation conferred by this allele may reduce AF recurrence risk.

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ZFHX3 knockdown increases arrhythmogenesis and dysregulates calcium homeostasis in HL-1 atrial myocytes

Cited by 41 publications

References 34 publications

Local Ancestry and Clinical Cardiovascular Events Among African Americans From the Atherosclerosis Risk in Communities Study

Local Ancestry and Clinical Cardiovascular Events Among African Americans From the Atherosclerosis Risk in Communities Study

Atrial Fibrillation

Maintenance of low inflammation level by the ZFHX3 SNP rs2106261 minor allele contributes to reduced atrial fibrillation recurrence after pulmonary vein isolation

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