A novel HOIP frameshift variant alleviates NF-kappaB signalling and sensitizes cells to TNF-induced death.

BACKGROUND: HOIP is the catalytic subunit of the E3 ligase complex (linear ubiquitin chain assembly complex), which is able to generate linear ubiquitin chains. However, the role of rare HOIP functionally deficient variants remains unclear. The pathogenic mechanism and the relationship with immune deficiency phenotypes remain to be clarified. METHODS: Based on a next-generation sequencing panel of 270 genes, we identified a HOIP deletion variant that causes common variable immunodeficiency disease. Bioinformatics analysis and cell-based experiments were performed to study the molecular mechanism by which the variant causes immunodeficiency diseases. FINDINGS: A homozygous loss-of-function variant in HOIP was identified. The variant causes a frameshift and generates a premature termination codon in messenger RNA, resulting in a C-terminal truncated HOIP mutant, that is, the loss of the linear ubiquitin chain-specific catalytic domain. The truncated HOIP mutant has impaired E3 ligase function in linear ubiquitination, leading to the suppression of canonical NF-κB signalling and increased TNF-induced multiple forms of cell death. INTERPRETATION: The loss-of-function HOIP variant accounts for the immune deficiencies. The canonical NF-κB pathway and cell death are involved in the pathogenesis of the disease. FUNDING: This study was funded by the National Natural Science Foundation of China (No. 82270444 and 81501851). RESEARCH IN CONTEXT: Evidence before this study LUBAC is the only known linear ubiquitin chain assembly complex for which HOIP is an essential catalytic subunit. Three HOIP variants have now been identified in two immunodeficient patients and functionally characterised. However, there have been no reports on the pathogenicity of only catalytic domain deletion variants in humans, or the pathogenic mechanisms of catalytic domain deletion variants. Added value of this study We report the first case of an autosomal recessive homozygous deletion variant that results in deletion of the HOIP catalytic structural domain. We demonstrate that this variant is a loss-of-function variant using a heterologous expression system. The variant has impaired E3 ligase function. It can still bind to other subunits of LUBAC, but it fails to generate linear ubiquitin chains. We also explored the underlying mechanisms by which this variant leads to immunodeficiency. The variant attenuates the canonical NF-κB and MAPK signalling cascades and increases the sensitivity of TNFα-induced diverse cell death and activation of mitochondrial apoptosis pathways. These findings provide support for the treatment and drug development of patients with inborn errors of immunity in HOIP and related signalling pathways. Implications of all the available evidence First, this study expands the HOIP pathogenic variant database and phenotypic spectrum. Furthermore, studies on the biological functions of pathogenic variants in relation to the NF-κB signalling pathway and cell death provided new understanding into the genetic basis and pathogenesis of HOIP-deficient immune disease, indicating the necessity of HOIP and related signalling pathway variants as diagnostic targets in patients with similar genetic deficiency phenotypes..

An Efficient Approach to the Accurate Prediction of Mutational Effects in Antigen Binding to the MHC1.

The major histocompatibility complex (MHC) can recognize and bind to external peptides to generate effective immune responses by presenting the peptides to T cells. Therefore, understanding the binding modes of peptide-MHC complexes (pMHC) and predicting the binding affinity of pMHCs play a crucial role in the rational design of peptide vaccines. In this study, we employed molecular dynamics (MD) simulations and free energy calculations with an Alanine Scanning with Generalized Born and Interaction Entropy (ASGBIE) method to investigate the protein-peptide interaction between HLA-A*02:01 and the G9209 peptide derived from the melanoma antigen gp100. The energy contribution of individual residue was calculated using alanine scanning, and hotspots on both the MHC and the peptides were identified. Our study shows that the pMHC binding is dominated by the van der Waals interactions. Furthermore, we optimized the ASGBIE method, achieving a Pearson correlation coefficient of 0.91 between predicted and experimental binding affinity for mutated antigens. This represents a significant improvement over the conventional MM/GBSA method, which yields a Pearson correlation coefficient of 0.22. The computational protocol developed in this study can be applied to the computational screening of antigens for the MHC1 as well as other protein-peptide binding systems.

Crosstalk between KIF1C and PRKAR1A in left atrial myxoma.

Cardiac myxoma (CM) is the most common benign cardiac tumor, and most CMs are left atrial myxomas (LAMs). Six variations of KIF1C, c.899 A > T, c.772 T > G, c.352 A > T, c.2895 C > T, c.3049 G > A, and c.*442_*443dup in left atrial myxoma tissues are identified by whole-exome sequencing (WES) and Sanger sequencing. RNA-seq and function experiments show the reduction of the expression of KIF1C and PRKAR1A caused by rare variations of KIF1C. KIF1C is observed to be located in the nucleus, bind to the promoter region of PRKAR1A, and regulate its transcription. Reduction of KIF1C decreases PRKAR1A expression and activates the PKA, which causes an increase in ERK1/2 phosphorylation and SRC-mediated STAT3 activation, a reduction of CDH1, TP53, CDKN1A, and BAX, and eventually promotes tumor formation both in vitro and in vivo. The results suggest that inhibition of KIF1C promotes the pathogenesis of LAM through positive feedback formed by the crosstalk between KIF1C and PRKAR1A.

Identifying the intervention mechanisms of polydatin in hyperuricemia model rats by using UHPLC-Q-Exactive Orbitrap mass spectroscopy metabonomic approach.

Introduction: Polydatin is a biologically active compound found in mulberries, grapes, and Polygonum cuspidatum, and it has uric acid-lowering effects. However, its urate-lowering effects and the molecular mechanisms underlying its function require further study. Methods: In this study, a hyperuricemic rat model was established to assess the effects of polydatin on uric acid levels. The body weight, serum biochemical indicators, and histopathological parameters of the rats were evaluated. A UHPLC-Q-Exactive Orbitrap mass spectrometry-based metabolomics approach was applied to explore the potential mechanisms of action after polydatin treatment. Results: The results showed a trend of recovery in biochemical indicators after polydatin administration. In addition, polydatin could alleviate damage to the liver and kidneys. Untargeted metabolomics analysis revealed clear differences between hyperuricemic rats and the control group. Fourteen potential biomarkers were identified in the model group using principal component analysis and orthogonal partial least squares discriminant analysis. These differential metabolites are involved in amino acid, lipid, and energy metabolism. Of all the metabolites, the levels of L-phenylalanine, L-leucine, O-butanoylcarnitine, and dihydroxyacetone phosphate decreased, and the levels of L-tyrosine, sphinganine, and phytosphingosine significantly increased in hyperuricemic rats. After the administration of polydatin, the 14 differential metabolites could be inverted to varying degrees by regulating the perturbed metabolic pathway. Conclusion: This study has the potential to enhance our understanding of the mechanisms of hyperuricemia and demonstrate that polydatin is a promising potential adjuvant for lowering uric acid levels and alleviating hyperuricemia-related diseases.

MED12 Regulates Smooth Muscle Cell Functions and Participates in the Development of Aortic Dissection.

Aortic dissection (AD) is a life-threatening disease with high morbidity and mortality, and effective pharmacotherapeutic remedies for it are lacking. Therefore, AD's molecular pathogenesis and etiology must be elucidated. The aim of this study was to investigate the possible mechanism of mediator complex subunit 12 (human: MED12, mouse: Med12)involvement in AD. Firstly, we examined the expression of MED12 protein (human: MED12, mouse: Med12) in the aortic tissues of AD patients and AD mice. Subsequently, Med12 gene silencing was accomplished with RNA interference (siRNA). The effects of Med12 on AD and the possible biological mechanisms were investigated based on the proliferation, senescence, phenotypic transformation, and its involved signal pathway of mouse aortic smooth muscle cells (MOVAS), s. The results show that the expression of MED12 in the aortae of AD patients and AD mice was decreased. Moreover, the downregulation of Med12 inhibited the proliferation of MOVAS and promoted senescence. Further research found that Med12, as an inhibitor of the TGFß1 signaling pathway, reduced the expression of Med12 and enhanced the activity of the TGFß1 nonclassical signaling pathway, while TGFß1 inhibited the phenotype transformation and proliferation of MOVAS by inhibiting Med12 synthesis. In conclusion, Med12 affected the phenotype, proliferation, and senescence of MOVAS through the TGFß signaling pathway. This study provides a potential new target for the prevention and treatment of AD.

Kidney stone disease and cardiovascular events: a study on bidirectional causality based on mendelian randomization.

BACKGROUND: Kidney stone disease (KSD) has been reported to be associated with several cardiovascular diseases. However, the causality between the conditions remains unknown. In the study, we performed a study on bidirectional causality by two-sample Mendelian randomization (MR) to investigate the causality between KSD and cardiovascular diseases including coronary atherosclerosis, hypertension, and cardiomyopathy. METHODS: In the recent study, we performed a bidirectional two-sample MR study using available genome-wide association summary data from the online database MRBASE. We identified genetic variants associated with KSD in one European population from UK Biobank (version 2, n=462,933). Two phenotypes of samples were chosen from the population to define our genetic instrumental variables: (I) samples with the phenotype of kidney stone/ureter stone/bladder stone (ukb-b-8297), and (II) samples with the phenotype of kidney stone surgery/lithotripsy (ukb-b-13537). For cardiovascular diseases, we picked up another independent European population from FinnGen Biobank (n=93,421). We selected the exposure and outcome SNPs and then performed the two-sample MR using R package. RESULTS: After bidirectional causality by two-sample MR, we verified that genetic predisposition to KSD could increase the risk of coronary atherosclerosis (OR: 4.45×1037; SE=±7.80×1014, P for MR-Egger =0.024) and cardiomyopathy (OR: 5.35×1013; SE=±7.18×106, P for IVW=0.045 for finn-a-I9_CARDMYO, and OR: 3.60×1025; SE=±3.26×1012, P for IVW=0.041 for finn-a-I9_CARDMYOOTH) when we used ukb-b-13537 as exposure group. Furthermore, hypertension could increase the risk of KSD (OR: 1.001; SE=±1.00, P for IVW=0.003) when we used ukb-b-8297 as exposure group, without detected pleiotropy bias (P>0.05). CONCLUSIONS: We confirmed KSD may trigger causal pathological processes including coronary atherosclerosis and cardiomyopathy. Furthermore, hypertension may causally affect KSD.

Causal Association between Periodontal Diseases and Cardiovascular Diseases.

Observational studies have revealed that dental diseases such as periodontitis and dental caries increase the risk of cardiovascular diseases (CVDs). However, the causality between periodontal disease (PD) and CVDs is still not clarified. In the present study, two-sample Mendelian randomization (MR) studies were carried out to assess the association between genetic liability for periodontal diseases (dental caries and periodontitis) and major CVDs, including coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), and stroke-including ischemic stroke as well as its three main subtypes-based on large-scale genome-wide association studies (GWASs). Our two-sample MR analyses did not provide evidence for dental caries and periodontitis as the causes of cardiovascular diseases; sensitivity analyses, including MR-Egger analysis and weighted median analysis, also supported this result. Gene functional annotation and pathway enrichment analyses indicated the common pathophysiology between cardiovascular diseases and periodontal diseases. The associations from observational studies may be explained by shared risk factors and comorbidities instead of direct consequences. This also suggests that addressing the common risk factors-such as reducing obesity and improving glucose tolerance-could benefit both conditions.

miR-190a-5p Partially Represses the Abnormal Electrical Activity of SCN3B in Cardiac Arrhythmias by Downregulation of IL-2.

Cardiac arrhythmias (CAs) are generally caused by disruption of the cardiac conduction system; interleukin-2 (IL-2) is a key player in the pathological process of CAs. This study aimed to investigate the molecular mechanism underlying the regulation of IL-2 and the sodium channel current of sodium voltage-gated channel beta subunit 3 (SCN3B) by miR-190a-5p in the progression of CAs. ELISA results suggested the concentration of peripheral blood serum IL-2 in patients with atrial fibrillation (AF) to be increased compared to that in normal controls; fluorescence in situ hybridization indicated that the expression of IL-2 in the cardiac tissues of patients with AF to be upregulated and that miR-190a-5p to be downregulated. Luciferase reporter assay, quantitative real-time-PCR, and whole-cell patch-clamp experiments confirmed the downregulation of IL-2 by miR-190a-5p and influence of the latter on the sodium current of SCN3B. Overall, miR-190a-5p suppressed the increase in SCN3B sodium current caused by endogenous IL-2, whereas miR-190a-5p inhibitor significantly reversed this effect. IL-2 was demonstrated to be directly regulated by miR-190a-5p. We, therefore, concluded that the miR-190a-5p/IL-2/SCN3B pathway could be involved in the pathogenesis of CAs and miR-190a-5p might acts as a potential protective factor in pathogenesis of CAs.

Inhibition of miR-21 alleviated cardiac perivascular fibrosis via repressing EndMT in T1DM.

In type 1 and type 2 diabetes mellitus, increased cardiac fibrosis, stiffness and associated diastolic dysfunction may be the earliest pathological phenomena in diabetic cardiomyopathy. Endothelial-mesenchymal transition (EndMT) in endothelia cells (ECs) is a critical cellular phenomenon that increases cardiac fibroblasts (CFs) and cardiac fibrosis in diabetic hearts. The purpose of this paper is to explore the molecular mechanism of miR-21 regulating EndMT and cardiac perivascular fibrosis in diabetic cardiomyopathy. In vivo, hyperglycaemia up-regulated the mRNA level of miR-21, aggravated cardiac dysfunction and collagen deposition. The condition was recovered by inhibition of miR-21 following with improving cardiac function and decreasing collagen deposition. miR-21 inhibition decreased cardiac perivascular fibrosis by suppressing EndMT and up-regulating SMAD7 whereas activating p-SMAD2 and p-SMAD3. In vitro, high glucose (HG) up-regulated miR-21 and induced EndMT in ECs, which was decreased by inhibition of miR-21. A highly conserved binding site of NF-κB located in miR-21 5'-UTR was identified. In ECs, SMAD7 is directly regulated by miR-21. In conclusion, the pathway of NF-κB/miR-21/SMAD7 regulated the process of EndMT in T1DM, in diabetic cardiomyopathy, which may be regarded as a potential clinical therapeutic target for cardiac perivascular fibrosis.

Long-term outcome of patients with atrial myxoma after surgical intervention: analysis of 403 cases.

OBJECTIVE: To assess long-term survival and late cardiovascular events in patients with atrial myxoma after surgical intervention. METHODS: Retrospective analysis of 403 patients undergoing resection of atrial myxoma from January 2002 to December 2016 was conducted with a median follow-up period of 4.5 (range: 0.5-15) years. RESULTS: The cross-clamp time and cardiopulmonary bypass times were 41.1 ± 21.4 and 65.2 ± 27.3 min, respectively. A diagnosis of myxoma was histopathologically confirmed in all cases. The early in-hospital mortality rate was 0.7% (n = 3). During the follow-up period, tumor recurrence occurred in six patients and cerebral infarction in nine. There were 48 (11.9%) patients with late onset atrial fibrillation (AF). By multivariate analysis, age (HR = 1.05, 95% CI: 1.02-1.09, P < 0.001), left atrial diameter (HR = 1.23, 95% CI: 1.08-1.36, P = 0.012), and mitral valve surgery (HR = 1.17, 95% CI: 1.05-1.29, P = 0.027) were independent predictors of late onset AF. Twenty-one (5.2%) patients died during the follow-up period. Advanced age (HR = 1.07, 95% CI: 1.04-1.10, P = 0.003) and multiple surgical procedures (HR = 1.18, 95% CI: 1.06-1.29, P = 0.012) were significantly associated with overall mortality. CONCLUSIONS: Atrial myxoma can be resected with good long-term survival. Late onset AF is common after surgery in patients with atrial myxoma. Advanced age, left atrial diameter, and mitral valve surgery were independent predictors of outcomes.

Multiple Recurrent Cardiac Myxomas With Protein Kinase A Regulatory Subunit 1α Gene Mutation.

Multiple recurrent cardiac myxomas are quite rare in clinical practice. A young male patient had four myxoma occurrences, twice in the left atrium and twice in the left ventricle. He had no medical history of cardiovascular diseases, familial cardiac neoplasm, or endocrinopathy. He underwent surgical resection four times. Genetic analysis revealed a heterozygous base pair mutation in the gene of protein kinase A regulatory subunit 1α (PRKAR1A) on chromosome 17 in both peripheral blood mononuclear cells and myxoma tissues. Regular postoperative examinations are recommended for patients with cardiac myxoma.

Type I Diabetic Akita Mouse Model is Characterized by Abnormal Cardiac Deformation During Early Stages of Diabetic Cardiomyopathy with Speckle-Tracking Based Strain Imaging.

BACKGROUND/AIMS: Diabetes mellitus (DM) has been demonstrated to have a strong association with heart failure. Conventional echocardiographic analysis cannot sensitively monitor cardiac dysfunction in type I diabetic Akita hearts, but the phenotype of heart failure is observed in molecular levels during the early stages. METHODS: Male Akita (Ins2WT/C96Y) mice were monitored with echocardiographic imaging at various ages, and then with conventional echocardiographic analysis and speckle-tracking based strain analyses. RESULTS: With speckle-tracking based strain analyses, diabetic Akita mice showed changes in average global radial strain at the age of 12 weeks, as well as decreased longitudinal strain. These changes occurred in the early stage and remained throughout the progression of diabetic cardiomyopathy in Akita mice. Speckle-tracking showed that the detailed and precise changes of cardiac deformation in the progression of diabetic cardiomyopathy in the genetic type I diabetic Akita mice were uncoupled. CONCLUSIONS: We monitored early-stage changes in the heart of diabetic Akita mice. We utilize this technique to elucidate the underlying mechanism for heart failure in Akita genetic type I diabetic mice. It will further advance the assessment of cardiac abnormalities, as well as the discovery of new drug treatments using Akita genetic type I diabetic mice.

De Novo FGF12 (Fibroblast Growth Factor 12) Functional Variation Is Potentially Associated With Idiopathic Ventricular Tachycardia.

BACKGROUND: Idiopathic ventricular tachycardia (VT) is a type of cardiac arrhythmia occurring in structurally normal hearts. The heritability of idiopathic VT remains to be clarified, and numerous genetic factors responsible for development of idiopathic VT are as yet unclear. Variations in FGF12 (fibroblast growth factor 12), which is expressed in the human ventricle and modulates the cardiac Na+ channel NaV1.5, may play an important role in the genetic pathogenesis of VT. METHODS AND RESULTS: We tested the hypothesis that genetic variations in FGF12 are associated with VT in 2 independent Chinese cohorts and resequenced all the exons and exon-intron boundaries and the 5' and 3' untranslated regions of FGF12 in 320 unrelated participants with idiopathic VT. For population-based case-control association studies, we chose 3 single-nucleotide polymorphisms-rs1460922, rs4687326, and rs2686464-which included all the exons of FGF12. The results showed that the single-nucleotide polymorphism rs1460922 in FGF12 was significantly associated with VT after adjusting for covariates of sex and age in 2 independent Chinese populations: adjusted P=0.015 (odds ratio: 1.54 [95% CI, 1.09-2.19]) in the discovery sample, adjusted P=0.018 (odds ratio: 1.64 [95% CI, 1.09-2.48]) in the replication sample, and adjusted P=2.52E-04 (odds ratio: 1.59 [95% CI, 1.24-2.03]) in the combined sample. After resequencing all amino acid coding regions and untranslated regions of FGF12, 5 rare variations were identified. The result of western blotting revealed that a de novo functional variation, p.P211Q (1.84% of 163 patients with right ventricular outflow tract VT), could downregulate FGF12 expression significantly. CONCLUSIONS: In this study, we observed that rs1460922 of FGF12 was significantly associated with VT and identified that a de novo variation of FGF12 may be an important genetic risk factor for the pathogenesis of VT.

Genomic Variant in IL-37 Confers A Significant Risk of Coronary Artery Disease.

The interleukin 1 family plays an important role in the immune and inflammatory responses. Coronary artery disease (CAD) is a chronic inflammatory disease. However, the genetic association between IL-37, the seventh member of the IL-1 family, and CAD is unknown. Here we show that a single nucleotide polymorphism in the IL-37 gene (rs3811047) confers a significant risk of CAD. We have performed an association analysis between rs3811047 and CAD in two independent populations with 2,501 patients and 3,116 controls from China. Quantitative RT-PCR analysis has been performed to determine if the IL-37 expression level is influenced by rs3811047. We show that the minor allele A of rs3811047 is significantly associated with CAD in two independent populations under a recessive model (Padj = 5.51 × 10-3/OR = 1.56 in the GeneID Northernern population and Padj = 1.23 × 10-3/OR = 1.45 in the GeneID Central population). The association became more significant in the combined population (Padj = 9.70 × 10-6/OR = 1.47). Moreover, the association remains significant in a CAD case control population matched for age and sex. Allele A of rs3811047 shows significant association with a decreased mRNA expression level of IL-37 (n = 168, P = 3.78 × 10-4). These data suggest that IL37 is a new susceptibility gene for CAD, which provides a potential target for the prevention and treatment of CAD.

Regulation of SCN3B/scn3b by Interleukin 2 (IL-2): IL-2 modulates SCN3B/scn3b transcript expression and increases sodium current in myocardial cells.

BACKGROUND: In the initiation and maintenance of arrhythmia, inflammatory processes play an important role. IL-2 is a pro-inflammatory factor which is associated with the morbidity of arrhythmias, however, how IL-2 affects the cardiac electrophysiology is still unknown. METHODS: In the present study, we observed the effect of IL-2 by qRT-PCR on the transcription of ion channel genes including SCN2A, SCN3A, SCN4A, SCN5A, SCN9A, SCN10A, SCN1B, SCN2B, SCN3B, KCNN1, KCNJ5, KCNE1, KCNE2, KCNE3, KCND3, KCNQ1, KCNA5, KCNH2 and CACNA1C. Western blot assays and electrophysiological studies were performed to demonstrate the effect of IL-2 on the translation of SCN3B/scn3b and sodium currents. RESULTS: The results showed that transcriptional level of SCN3B was up-regulated significantly in Hela cells (3.28-fold, p = 0.022 compared with the control group). Consistent results were verified in HL-1 cells (3.73-fold, p = 0.012 compared with the control group). The result of electrophysiological studies showed that sodium current density increased significantly in cells which treated by IL-2 and the effect of IL-2 on sodium currents was independent of SCN3B (1.4 folds, p = 0.023). Western blot analysis showed IL-2 lead to the significantly increasing of p53 and scn3b (2.1 folds, p = 0.021 for p53; 3.1 folds, p = 0.023 for scn3b) in HL-1 cells. Consistent results were showed in HEK293 cells using qRT-PCR analysis (1.43 folds for P53, p = 0.022; 1.57 folds for SCN3B, p = 0.05). CONCLUSIONS: The present study suggested that IL-2, may play role in the arrhythmia by regulating the expression of SCN3B and sodium current density.

Post-transcriptional regulation of cardiac sodium channel gene SCN5A expression and function by miR-192-5p.

The SCN5A gene encodes cardiac sodium channel Nav1.5 and causes lethal ventricular arrhythmias/sudden death and atrial fibrillation (AF) when mutated. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, and involved in the pathogenesis of many diseases. However, little is known about the regulation of SCN5A by miRNAs. Here we reveal a novel post-transcriptional regulatory mechanism for expression and function of SCN5A/Nav1.5 via miR-192-5p. Bioinformatic analysis revealed that the 3'-UTR of human and rhesus SCN5A, but not elephant, pig, rabbit, mouse, and rat SCN5A, contained a target binding site for miR-192-5p and dual luciferase reporter assays showed that the site was critical for down-regulation of human SCN5A. With Western blot assays and electrophysiological studies, we demonstrated that miR-192-5p significantly reduced expression of SCN5A and Nav1.5 as well as peak sodium current density INa generated by Nav1.5. Notably, in situ hybridization, immunohistochemistry and real-time qPCR analyses showed that miR-192-5p was up-regulated in tissue samples from AF patients, which was associated with down-regulation of SCN5A/Nav1.5. These results demonstrate an important post-transcriptional role of miR-192-5p in post-transcriptional regulation of Nav1.5, reveal a novel role of miR-192-5p in cardiac physiology and disease, and provide a new target for novel miRNA-based antiarrhythmic therapy for diseases with reduced INa.

The role of transcription factors in atrial fibrillation.

Atrial fibrillation (AF) is a complex disease that results from genetic and environmental factors and their interactions. In recent years, genome-wide association studies (GWAS) and family-based linkage analysis have found amounts of genetic variants associated with AF. Some of them lie in coding sequences and thus mediate the encoded proteins, some in non-coding regions and influence the expression of adjacent genes. These variants exert influence on the development of cardiovascular system and normal cardiac electrical activity in different levels, and eventually contribute to the occurrence of AF. Among these affected genes, as a crucial means of transcriptional regulation, several transcription factors play important roles in the pathogenesis of AF. In this review, we will focus on the potential role of PITX2, PRRX1, ZHFX3, TBX5, and NKX2.5 in AF.