Genetic variants associated with risk of atrial fibrillation regulate expression of PITX2, CAV1, MYOZ1, C9orf3 and FANCC

Martin, Ruairidh; Babaei, Mahsa Sheikhali; Choy, Mun-Kit; Owens, W. Andrew; Chico, Timothy J. A.; Keenan, Daniel; Yonan, Nizar; Koref, Mauro Santibáñez; Keavney, Bernard

doi:10.1016/j.yjmcc.2015.06.005

Cited by 44 publications

(32 citation statements)

References 49 publications

(54 reference statements)

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“…We speculate that this SNP may increase PITX2 expression and thereby decrease downstream cardiac channel gene regulatory network expression. This model is consistent with previously published work, in which AF risk SNPs at PITX2 are associated with increased PITX2 expression (28). …”

Section: Discussionsupporting

confidence: 93%

Pitx2 modulates a Tbx5 -dependent gene regulatory network to maintain atrial rhythm

et al. 2016

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Cardiac rhythm is extremely robust, generating 2 billion contraction cycles during the average human life span. Transcriptional control of cardiac rhythm is poorly understood. We found that removal of the transcription factor gene Tbx5 from the adult mouse caused primary spontaneous and sustained atrial fibrillation (AF). Atrial cardiomyocytes from the Tbx5-mutant mice exhibited action potential abnormalities, including spontaneous depolarizations, which were rescued by chelating free calcium. We identified a multitiered transcriptional network that linked seven previously defined AF risk loci: TBX5 directly activated PITX2, and TBX5 and PITX2 antagonistically regulated membrane effector genes Scn5a, Gja1, Ryr2, Dsp, and Atp2a2. In addition, reduced Tbx5 dose by adult-specific haploinsufficiency caused decreased target gene expression, myocardial automaticity, and AF inducibility, which were all rescued by Pitx2 haploinsufficiency in mice. These results defined a transcriptional architecture for atrial rhythm control organized as an incoherent feed-forward loop, driven by TBX5 and modulated by PITX2. TBX5/PITX2 interplay provides tight control of atrial rhythm effector gene expression, and perturbation of the co-regulated network caused AF susceptibility. This work provides a model for the molecular mechanisms underpinning the genetic implication of multiple AF genome-wide association studies loci and will contribute to future efforts to stratify patients for AF risk by genotype.

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Section: Discussionsupporting

confidence: 93%

Pitx2 modulates a Tbx5 -dependent gene regulatory network to maintain atrial rhythm

et al. 2016

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“…Besides, Chinchilla et al identified that PITX2c was significantly lower in patients with sustained AF [27]. In addition, Martin et al [28] found a strong association between variant rs2200733 and total expression of PITX2a in human atrial appendages. However, another study showed that although the variants were significantly associated with the risk of AF independently, neither of them was associated with PITX2c expression in human adult left atrial appendages [29].…”

Section: Discussionmentioning

confidence: 98%

Chromosome 4q25 Variants and Age at Onset of Ischemic Stroke

Sun

Tian

et al. 2016

Mol Neurobiol

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Recent genome-wide association studies have identified two variants rs10033464 and rs2200733 on chromosome 4q25, significantly associated with ischemic stroke risk. We conducted this study to investigate whether these two variants were associated with age at onset and prognosis of ischemic stroke in a Chinese population. Genotyping of rs10033464 and rs2200733 was performed by improved multiple ligase detection reaction. One-way ANOVA was used to compare the mean age of ischemic stroke onset for each variant. Combined effects of these two variants on age at ischemic stroke onset were then estimated. Kaplan-Meier method, log-rank test, and the Cox proportional hazards regression models were used to assess the effect of the two variants on ischemic stroke prognosis. A total of 914 ischemic stroke patients were included in the study. Rs10033464 and rs2200733 were not associated with ischemic stroke recurrence (P > 0.05). However, rs10033464 TT genotype was significantly correlated with early age of ischemic stroke onset (60.76 for GG, 61.74 for GT, 55.47 for TT, TT vs. GT: P = 0.043). Combined effects analysis revealed that mean age at ischemic stroke onset decreased with increasing genetic risk score (P = 0.038). The findings indicated that the chromosome 4q25 variants might associate with early age at onset of ischemic stroke. Further larger studies in other populations are warranted to validate our results.

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“…The most extensively studied genetic factors implicated in the development of postoperative AF [20], or in symptomatic responses to antiarrhythmic drug therapy for chronic AF [47], are the noncoding polymorphisms near PITX2 in the chromosome 4q25 region. A recent study of patients who underwent cardiac surgery [48] showed cis -acting associations between risk SNPs at 4q25 and increased PITX2a isoform expression in atrial tissue. However, in our study we did not observe differential expression of PITX2 in RAA tissue, and variants in the gene showed only nominally significant trans- acting associations with VOPP1 .…”

Section: Discussionmentioning

confidence: 99%

Gene signatures of postoperative atrial fibrillation in atrial tissue after coronary artery bypass grafting surgery in patients receiving β-blockers

Kertai

et al. 2016

Journal of Molecular and Cellular Cardiology

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Atrial tissue gene expression profiling may help to determine how differentially expressed genes in the human atrium before cardiopulmonary bypass (CPB) are related to subsequent biologic pathway activation patterns, and whether specific expression profiles are associated with an increased risk for postoperative atrial fibrillation (AF) or altered response to β-blocker (BB) therapy after coronary artery bypass grafting (CABG) surgery. Right atrial appendage (RAA) samples were collected from 45 patients who were receiving perioperative BB treatment, and underwent CABG surgery. The isolated RNA samples were used for microarray gene expression analysis, to identify probes that were expressed differently in patients with and without postoperative AF. Gene expression analysis was performed to identify probes that were expressed differently in patients with and without postoperative AF. Gene set enrichment analysis (GSEA) was performed to determine how sets of genes might be systematically altered in patients with postoperative AF. Of the 45 patients studied, genomic DNA from 42 patients was used for target sequencing of 66 candidate genes potentially associated with AF, and 2,144 single-nucleotide polymorphisms (SNPs) were identified. We then performed expression quantitative trait loci (eQTL) analysis to determine the correlation between SNPs identified in the genotyped patients, and RAA expression. Probes that met a false discovery rate < 0.25 were selected for eQTL analysis. Of the 17,678 gene expression probes analyzed, 2 probes met our prespecified significance threshold of false discovery rate < 0.25. The most significant probe corresponded to vesicular overexpressed in cancer – prosurvival protein 1 gene (VOPP1; 1.83 fold change; P = 3.47 × 10−7), and was up-regulated in patients with postoperative AF, whereas the second most significant probe, which corresponded to the LOC389286 gene (0.49 fold change; P = 1.54 × 10−5), was down-regulated in patients with postoperative AF. GSEA highlighted the role of VOPP1 in pathways with biologic relevance to myocardial homeostasis, and oxidative stress and redox modulation. Candidate gene eQTL showed a trans-acting association between variants of G protein-coupled receptor kinase 5 gene, previously linked to altered BB response, and high expression of VOPP1. In patients undergoing CABG surgery, RAA gene expression profiling, and pathway and eQTL analysis suggested that VOPP1 plays a novel etiological role in postoperative AF despite perioperative BB therapy.

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Genetic variants associated with risk of atrial fibrillation regulate expression of PITX2, CAV1, MYOZ1, C9orf3 and FANCC

Cited by 44 publications

References 49 publications

Pitx2 modulates a Tbx5 -dependent gene regulatory network to maintain atrial rhythm

Pitx2 modulates a Tbx5 -dependent gene regulatory network to maintain atrial rhythm

Chromosome 4q25 Variants and Age at Onset of Ischemic Stroke

Gene signatures of postoperative atrial fibrillation in atrial tissue after coronary artery bypass grafting surgery in patients receiving β-blockers

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