Abstract 17259: Identification of Biological Pathways of Candidate Atrial Fibrillation Risk Genes Through the Use of Weighted Gene Coexpression Network Analysis
Sojin Y. WassCatherine CantlayMeghan McHaleJulie H. RennisonHan SunJeffery HsuErik OffermanA. Marc GillinovChristine S. MoravecJohn BarnardJonathan D. SmithDavid R. Van WagonerMina K. Chung
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Introduction: Over 135 genetic loci have been linked to atrial fibrillation (AF), yet the biological pathways of AF pathophysiology remain elusive. Weighted gene coexpression network analysis (WGCNA) constructs gene modules within a network based on correlations in gene expression, and identifies mechanisms related to AF risk. Objective: To identify biological pathways of candidate AF risk genes that will advance our understanding of AF mechanisms. Methods: RNA-sequencing was performed on left atrial appendage tissue from 265 patients. RNA-seq data were adjusted for differences in AF rhythm state and other known AF risk factors. Correlations from adjusted data were further adjusted for latent factors then spatial quantile normalized to correct for mean-variance bias. WGCNA was applied to the resulting adjusted and normalized gene-gene correlations to identify gene modules. Ingenuity Pathway Analysis and gene set over representation analysis (GSOR) were applied to each module. Results: WGCNA identified 63 modules from 17,434 genes; 47 of these contained at least one candidate AF risk gene. AF risk genes were overrepresented in 7 modules (Table 1). Notable top pathways of AF overrepresented modules include apelin signaling, heme metabolism, intracellular ion homeostasis, and the unfolded protein response. These are known to be involved in calcium signaling, iron homeostasis, glucose regulation, heat shock response, and protein ubiquitination during states of high energy demand and stress. These pathways coincide with larger cellular processes of myocyte remodeling, apoptosis, and cell survival, which were also prominent. Conclusions: Biological pathways identified through WGCNA and GSOR suggest that sustained increases in energy demand during AF promotes stress-induced cellular remodeling. Changes in calcium signaling, iron homeostasis, the unfolded protein response and glucose regulation are likely primary mechanisms of AF pathophysiology.Keywords:
Biological pathway
Candidate gene
Gene regulatory network
The prevalence of atrial fibrillation varies widely depending on the population studied. To understand the incidence of atrial fibrillation and its significance in relation to other diseases, 3 years (1989 through 1991) of consecutive hospital discharges from the neurology and internal medicine services at Henry Ford Hospital were studied. Of the 26,964 patients who qualified for analysis, 1346 (5%) had atrial fibrillation as 1 of their 5 recorded discharge diagnoses. Comparing the group without atrial fibrillation to those with atrial fibrillation, there were 51% males in both groups (p = 0.88). African-Americans comprised 33% of the patients with atrial fibrillation and 50% of the patients without atrial fibrillation (p < 0.001). The average age of those with atrial fibrillation was 72 +/- 13 years, and 58 +/- 18 years for those without atrial fibrillation (p < 0.001). Length of hospital stay was 9.6 +/- 8.6 days with atrial fibrillation and 7.6 +/- 9.2 days for those without atrial fibrillation (p < 0.001). After adjusting for the effects of age, significant positive associations were noted in those patients with atrial fibrillation whose co-existing condition was either stroke, heart failure, myocardial infarction, hyperthyroidism, or mitral valve disease. There was also a significant negative relationship between hypertension and atrial fibrillation. The most common of the 5 discharge diagnoses observed in patients with atrial fibrillation was congestive heart failure (40%), followed by hypertension (23%) and ischemic heart disease (21%). The existence of a comorbid disease in patients with atrial fibrillation is important, as it can influence medical management and prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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Several candidate genes have been so far implicated in the pathogenesis of proliferative diabetic retinopathy (PDR) in subjects with type 2 diabetes. Since the principal pathogenetic mechanisms for diabetic retinopathy (DR) and PDR are different, the main pathogenetic mechanism in DR is increased vascular permeability, whereas in PDR the crucial pathogenetic mechanisms are fibrosis and neoangiogenesis. Due to that fact, different candidate genes are expected to be involved in the development of either DR or PDR. None of the candidate genes, however, can be fully and solely responsible for the development of PDR and for DR progression into PDR. Epigenetic mechanisms are expected to be involved in the pathogenesis of PDR as well. Gene polymorphisms responsible for PDR and epigenetic mechanisms responsible for PDR are reviewed in this paper.
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Abstract Objectives To determine rates of stroke or transient ischaemic attack (TIA) and all cause mortality in patients with a diagnosis of “resolved” atrial fibrillation compared to patients with unresolved atrial fibrillation and without atrial fibrillation. Design Two retrospective cohort studies. Setting General practices contributing to The Health Improvement Network, 1 January 2000 to 15 May 2016. Participants Adults aged 18 years or more with no previous stroke or TIA: 11 159 with resolved atrial fibrillation, 15 059 controls with atrial fibrillation, and 22 266 controls without atrial fibrillation. Main outcome measures Primary outcome was incidence of stroke or TIA. Secondary outcome was all cause mortality. Results Adjusted incidence rate ratios for stroke or TIA in patients with resolved atrial fibrillation were 0.76 (95% confidence interval 0.67 to 0.85, P<0.001) versus controls with atrial fibrillation and 1.63 (1.46 to 1.83, P<0.001) versus controls without atrial fibrillation. Adjusted incidence rate ratios for mortality in patients with resolved atrial fibrillation were 0.60 (0.56 to 0.65, P<0.001) versus controls with atrial fibrillation and 1.13 (1.06 to 1.21, P<0.001) versus controls without atrial fibrillation. When patients with resolved atrial fibrillation and documented recurrent atrial fibrillation were excluded the adjusted incidence rate ratio for stroke or TIA was 1.45 (1.26 to 1.67, P<0.001) versus controls without atrial fibrillation. Conclusion Patients with resolved atrial fibrillation remain at higher risk of stroke or TIA than patients without atrial fibrillation. The risk is increased even in those in whom recurrent atrial fibrillation is not documented. Guidelines should be updated to advocate continued use of anticoagulants in patients with resolved atrial fibrillation.
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Hypoxia is a pathophysiological condition which arises due to low oxygen concentration in conditions like cardiovascular diseases, inflammation, ascent to higher altitude, malignancies, deep sea diving, prenatal birth, etc. A number of microRNAs (miRNAs), Transcription Factors (TFs) and genes have been studied separately for their role in hypoxic adaptation and controlling cell-cycle progression and apoptosis during this stress.We hypothesize that miRNAs and TFs may act in conjunction to regulate a multitude of genes and play a crucial and combinatorial role during hypoxia-stress-responses and associated cellcycle control mechanisms.We collected a comprehensive and non-redundant list of human hypoxia-responsive miRNAs (also known as hypoxiamiRs). Their experimentally validated gene-targets were retrieved from various databases and a comprehensive hypoxiamiR-gene regulatory network was built.Functional characterization and pathway enrichment of genes identified phospho-proteins as enriched nodes. The phospho-proteins which were localized both in the nucleus and cytoplasm and could potentially play important role as signaling molecules were selected; and further pathway enrichment revealed that most of them were involved in NFkB signaling. Topological analysis identified several critical hypoxiamiRs and network perturbations confirmed their importance in the network. Feed Forward Loops (FFLs) were identified in the subnetwork of enriched genes, miRNAs and TFs. Statistically significant FFLs consisted of four miRNAs (hsa-miR-182-5p, hsa- miR-146b-5p, hsa-miR-96, hsa-miR-20a) and three TFs (SMAD4, FOXO1, HIF1A) both regulating two genes (NFkB1A and CDKN1A).Detailed BioCarta pathway analysis identified that these miRNAs and TFs together play a critical and combinatorial role in regulating cell-cycle under hypoxia, by controlling mechanisms that activate cell-cycle checkpoint protein, CDKN1A. These modules work synergistically to regulate cell-proliferation, cell-growth, cell-differentiation and apoptosis during hypoxia. A detailed mechanistic molecular model of how these co-regulatory FFLs may regulate the cell-cycle transitions during hypoxic stress conditions is also put forth. These biomolecules may play a crucial and deterministic role in deciding the fate of the cell under hypoxic-stress.
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Background Atrial fibrillation is an important risk factor for stroke but there are limited data on atrial fibrillation-related stroke from the Middle East. Methods We interrogated the Qatar Stroke Database to establish the occurrence, clinical features, and outcomes of atrial fibrillation-related stroke at Hamad General Hospital, the sole provider of acute stroke care in Qatar. Results A total of 4079 patients (81.4% male, mean age 55.4 ± 13.3 years) were enrolled in the stroke database between January 2014 and 21 October 2017. Atrial fibrillation was present in 260 (6.4%) patients, of whom 106 (2.6%) had newly diagnosed atrial fibrillation. The National Institute of Health Stroke Scale (NIHSS) was significantly higher (7.9 + 7.0 (median 6; IQR 11) vs. 5.9 + 6.4 (median 4; IQR 6), P < 0.001) in atrial fibrillation patients. The modified Rankin Score (mRS) (P < 0.001) and mortality at 90-day follow-up (P = 0.002) were significantly higher in atrial fibrillation compared to non-atrial fibrillation stroke patients. Conclusion We demonstrate a low rate of atrial fibrillation and stroke in Qatar, perhaps reflecting the relatively young age of these patients. Atrial fibrillation-related strokes had higher admission NIHSS, greater disability, and higher mortality at 90 days when compared to non-atrial fibrillation strokes.
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Background Atrial fibrillation can be categorized into nonpermanent and permanent atrial fibrillation. There is less information on permanent than on nonpermanent atrial fibrillation patients. This analysis aimed to describe the characteristics and current management, including the proportion of patients with successful atrial fibrillation control, of these atrial fibrillation subsets in a large, geographically diverse contemporary sample. Methods and Results Data from RealiseAF, an international, observational, cross-sectional survey of 10,491 patients with atrial fibrillation, were used to characterize permanent atrial fibrillation (N = 4869) and nonpermanent atrial fibrillation (N = 5622) patients. Permanent atrial fibrillation patients were older, had a longer time since atrial fibrillation diagnosis, a higher symptom burden, and were more likely to be physically inactive. They also had a higher mean (SD) CHADS2 score (2.2 [1.3] vs. 1.7 [1.3], p<0.001), and a higher frequency of CHADS2 score ≥2 (67.3% vs. 53.0%, p<0.001) and comorbidities, most notably heart failure. Physicians indicated using a rate-control strategy in 84.2% of permanent atrial fibrillation patients (vs. 27.5% in nonpermanent atrial fibrillation). Only 50.2% (N = 2262/4508) of permanent atrial fibrillation patients were controlled. These patients had a longer time since atrial fibrillation diagnosis, a lower symptom burden, less obesity and physical inactivity, less severe heart failure, and fewer hospitalizations for acute heart failure than uncontrolled permanent atrial fibrillation patients, but with more arrhythmic events. The most frequent causes of hospitalization in the last 12 months were acute heart failure and stroke. Conclusion Permanent atrial fibrillation is a high-risk subset of atrial fibrillation, representing half of all atrial fibrillation patients, yet rate control is only achieved in around half. Since control is associated with lower symptom burden and heart failure, adequate rate control is an important target for improving the management of permanent atrial fibrillation patients.
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