Abstract:
:Genome-wide association studies (GWAS) have identified genetic variants in a number of chromosomal regions that are associated with atrial fibrillation (AF). The mechanisms underlying these associations are unknown, but are likely to involve effects of the risk haplotypes on expression of neighbouring genes. To investigate the association between genetic variants at AF-associated loci and expression of nearby candidate genes in human atrial tissue and peripheral blood. Right atrial appendage (RAA) samples were collected from 122 patients undergoing cardiac surgery, of these, 12 patients also had left atrial appendage samples taken. 22 patients had a history of AF. Peripheral blood samples were collected from 405 patients undergoing diagnostic cardiac catheterisation. In order to tag genetic variation at each of nine loci, a total of 367 single nucleotide polymorphisms (SNPs) were genotyped using the Sequenom platform. Total expression of 16 candidate genes in the nine AF-associated regions was measured by quantitative PCR. The relative expression of each allele of the candidate genes was measured on the Sequenom platform using one or more transcribed SNPs to distinguish between alleles in heterozygotes. We tested association between the SNPs of interest and gene expression using total gene expression (integrating cis and trans acting sources of variation), and allelic expression ratios (specific for cis acting influences), in atrial tissue and peripheral blood. We adjusted for multiple comparisons using a Bonferroni approach. In subsidiary analyses, we compared the expression of candidate genes between patients with and without a history of AF. Total expression of 15 transcripts of 14 genes and allelic expression ratio of 14 transcripts of 14 genes in genomic regions associated with AF were measured in right atrial appendage tissue. 8 of these transcripts were also expressed in peripheral blood. Risk alleles at AF-associated SNPs were associated in cis with an increased expression of PITX2a (2.01-fold, p=6.5×10(-4)); and with decreased expression of MYOZ1 (0.39 fold; p=5.5×10(-15)), CAV1 (0.89 fold; p=5.9×10(-8)), C9orf3 (0.91 fold; 1.5×10(-5)), and FANCC (0.94-fold; p=8.9×10(-8)) in right atrial appendage. Of these five genes, only CAV1 was expressed in peripheral blood; association between the same AF risk alleles and lower expression of CAV1 was confirmed (0.91 fold decrease; p=4.2×10(-5)). A history of AF was also associated with a decrease in expression of CAV1 in both right and left atria (0.84 and 0.85 fold, respectively; p=0.03), congruent with the magnitude of the effect of the risk SNP on expression, and independent of genotype. The analyses in peripheral blood showed association between AF risk SNPs and decreased expression of KCNN3 (0.85-fold; p=2.1×10(-4)); and increased expression of SYNE2 (1.12-fold; p=7.5×10(-24)); however, these associations were not detectable in atrial tissue. We identified novel cis-acting associations in atrial tissue between AF risk SNPs and increased expression of PITX2a/b; and decreased expression of CAV1 (an association also seen in peripheral blood), C9orf3 and FANCC. We also confirmed a previously described association between AF risk variants and MYOZ1 expression. Analyses of peripheral blood illustrated tissue-specificity of cardiac eQTLs and highlight the need for larger-scale genome-wide eQTL studies in cardiac tissue. Our results suggest novel aetiological roles for genes in four AF-associated genomic regions.
journal_name
J Mol Cell Cardioljournal_title
Journal of molecular and cellular cardiologyauthors
Martin RI,Babaei MS,Choy MK,Owens WA,Chico TJ,Keenan D,Yonan N,Koref MS,Keavney BDdoi
10.1016/j.yjmcc.2015.06.005subject
Has Abstractpub_date
2015-08-01 00:00:00pages
207-14eissn
0022-2828issn
1095-8584pii
S0022-2828(15)00191-1journal_volume
85pub_type
杂志文章abstract::Atrial cardiac myocytes secrete the vasoactive hormone atrial natriuretic peptide (ANP) by both constitutive and regulated exocytotic fusion of ANP-containing large dense core vesicles (LDCV) with the sarcolemma. Detailed information, however, regarding the identity and function of specific membrane fusion proteins (S...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2005.12.007
更新日期:2006-03-01 00:00:00
abstract::Ventricular hypertrophy is associated with an increase in action potential (AP) duration which is potentially arrhythmogenic. The implication of the Na-Ca exchange current (I(Na-Ca)) in the lengthening of the AP is controversial. The role of this current in the increased duration of the low plateau of the AP in hypert...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.2000.1106
更新日期:2000-04-01 00:00:00
abstract::The two-pore domain potassium (K(+)) channel TWIK-1 (or K2P1.1) contributes to background K(+) conductance in diverse cell types. TWIK-1, encoded by the KCNK1 gene, is present in the human heart with robust expression in the atria, however its physiological significance is unknown. To evaluate the cardiac effects of T...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2016.04.006
更新日期:2016-08-01 00:00:00
abstract::Recent improvements in survival from AIDS have been accompanied by an increased recognition of the potential importance of other manifestations of HIV infection, including cardiomyopathy. Mechanisms responsible for HIV cardiomyopathy are unknown, but may include direct effects of HIV proteins on the heart. We previous...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2005.10.006
更新日期:2006-01-01 00:00:00
abstract::Atrial fibrillation (AF) causes myocyte stress by inducing structural changes, predominantly myolysis, which is related to the progression of AF. As heat shock proteins (Hsp) protect against cellular stress, their efficacy in preventing myolysis was investigated in a tachy-paced cell model for AF and in patients with ...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2006.06.068
更新日期:2006-09-01 00:00:00
abstract::Cardiac alpha(1)-adrenoceptors (AR) have two predominant subtypes (alpha(1A)-AR and alpha(1B)-AR) however, their roles in regulating contraction are unclear. We determined the effects of stimulating alpha(1A)-AR (using the subtype-selective agonist A61603) and alpha(1B)-AR (using a gene knockout mouse lacking alpha(1A...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.2002.2049
更新日期:2002-08-01 00:00:00
abstract:BACKGROUND:Pulmonary arterial hypertension (PAH) results in right ventricular (RV) failure, electro-mechanical dysfunction and heightened risk of sudden cardiac death (SCD), although exact mechanisms and predisposing factors remain unclear. Because impaired chronotropic response to exercise is a strong predictor of ear...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2018.11.017
更新日期:2019-02-01 00:00:00
abstract::Platelet-derived growth factor (PDGF) has protean manifestations, including the regulation of growth and migration, in many cell types. We have previously reported that PDGF-BB induces the accumulation of monocyte chemoattractant protein (MCP)-1 mRNA in smooth muscle cells (SMC), in large part due to an increase in mR...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2006.03.426
更新日期:2006-07-01 00:00:00
abstract::The transcription factor scleraxis has been implicated in regulating the development of collagen-rich tissues such as tendons and cardiac valves, but its role in general collagen synthesis in the heart is unknown. Scleraxis expression in cardiac fibroblasts was examined, and its ability to regulate gene expression of ...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2009.03.024
更新日期:2009-08-01 00:00:00
abstract::Pulmonary arterial hypertension (PAH) is a complex disease that causes significant morbidity and mortality and is clinically characterized by an increase in pulmonary vascular resistance. The histopathology is marked by vascular proliferation/fibrosis, remodeling, and vessel obstruction. Development of PAH involves th...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章,评审
doi:10.1016/j.yjmcc.2007.09.006
更新日期:2008-01-01 00:00:00
abstract:RATIONALE:Circulating monocytes play pivotal roles in chronic inflammatory diseases. Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, are known to have anti-inflammatory effects and are hydrolyzed by soluble epoxide hydrolase (sEH). OBJECTIVE:We aimed to investigate the effect of sEH inhibition in at...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2016.08.001
更新日期:2016-09-01 00:00:00
abstract::To investigate the interaction of cytoskeleton with the receptor modulation of ionic currents, we studied the effect of muscarinic and beta-adrenergic stimulation in adult guinea-pig ventricular cardiac myocytes treated with paclitaxel and colchicine, two drugs that respectively stabilize or destabilize microtubules. ...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/s0022-2828(02)00312-7
更新日期:2003-02-01 00:00:00
abstract::This paper examines the quantitative relationship between the expression of myosin heavy chain (MHC) and actin at both the levels of their mRNAs and their proteins. Explanted human left ventricle tissues were obtained from non-diseased (ND) individuals and from dilated cardiomyopathy (DCM) patients with terminally fai...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.1996.0317
更新日期:1997-03-01 00:00:00
abstract::We examined the relative roles of the mitogen-activated protein kinases (MAPK) in mediating the alpha1-adrenergic receptor (alpha1-AR) stimulated hypertrophic phenotype in adult rat ventricular myocytes (ARVM). Norepinephrine (NE; 1 microM) in the presence of the beta -AR antagonist propranolol (Pro; 2 microM) caused ...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.2001.1348
更新日期:2001-04-01 00:00:00
abstract::Biglycan, a small dermatan sulphate proteoglycan, has been postulated to interact with other components of the extracellular matrix (ECM), specifically collagens. We hypothesized that biglycan messenger ribonucleic acid (mRNA) is increased in the myocardial infarct zone. Biglycan mRNA expression after acute myocardial...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.1998.0737
更新日期:1998-09-01 00:00:00
abstract::The regulation of vascular smooth muscle cell (VSMC) proliferation is an important issue because it has major implications for the prevention of pathological vascular conditions. Using microRNA array screen, we found the expression levels of 200 unique miRNAs in hyperplasic tissues. Among them, miR-200c expression sub...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2015.03.011
更新日期:2015-05-01 00:00:00
abstract::This report examines the blocking effects that several antiarrhythmic drugs have on rapid upstroke velocities of action potentials recorded from guinea-pig papillary muscle. A mathematical analysis is developed, that measures an effective "blocking rate' that acts during the action potential with the purpose being to ...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/0022-2828(83)90334-6
更新日期:1983-11-01 00:00:00
abstract::In general, in most organ systems, intracellular protein homeostasis is the sum of many factors, including chromosomal state, protein synthesis, post-translational processing and transport, folding, assembly and disassembly into macromolecular complexes, protein stability and clearance. In the heart, there has been a ...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章,评审
doi:10.1016/j.yjmcc.2013.12.015
更新日期:2014-06-01 00:00:00
abstract::Neural structures have been shown to be present in valve cusp tissue. We aimed to characterise the influence of neuronal stimulation on the component structures of the aortic root and cusps. Specimens of sinus, sinotubular junction (STJ), annulus and cusp tissue were dissected from porcine aortic roots and either stim...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2008.03.014
更新日期:2008-06-01 00:00:00
abstract::The progression of cardiomyopathy to congestive heart failure is often associated with the expression of fetal cardiac-specific genes. In mice, the basic helix-loop-helix transcription factors, dHAND and eHAND, are expressed in a cardiac chamber-specific fashion and are essential for fetal cardiac development, but are...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.2001.1434
更新日期:2001-09-01 00:00:00
abstract::The modulating effects of Ca2+ on single K+ channel currents in canine heart sarcoplasmic reticulum were studied using a planar lipid bilayer technique. The open-state probability and the unitary open-state current both decreased gradually as the Ca2+ concentration was reduced from pCa 3 to pCa 7.5. Each single-channe...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.1994.1022
更新日期:1994-02-01 00:00:00
abstract::Heart and skeletal muscle cells rapidly lose potassium ions after withdrawal of oxygen. In myocardial ischemia, cellular release of potassium and interruption of extracellular washout produce a rapid and marked increase of extracellular K+ concentration. Harris et al. were the first to observe the coincidence of the K...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/s0022-2828(87)80608-9
更新日期:1987-10-01 00:00:00
abstract::Baroreflex control of heart rate was studied in conscious diabetic rats at 12, 24 and 48 weeks after the induction of diabetes with streptozotocin. Baseline blood pressure (mean arterial blood pressure) of diabetic rats was significantly lower at 12 weeks after the induction of diabetes when compared to age-matched co...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/s0022-2828(86)80969-5
更新日期:1986-06-01 00:00:00
abstract::The purpose of this study was to investigate whether vitamin D3 deficiency affects the cardiac function of chick hearts directly or whether the influence is secondary through the hormone's effect on serum calcium levels. To this end, three experimental groups were studied: (a) the control group of vitamin D3 supplemen...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.1993.1010
更新日期:1993-01-01 00:00:00
abstract::Common cardiovascular diseases such as hypertension and myocardial infarction require that myocytes develop greater than normal force to maintain cardiac pump function. This requires increases in [Ca(2+)]. These diseases induce cardiac hypertrophy and increases in [Ca(2+)] are known to be an essential proximal signal ...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2012.08.005
更新日期:2012-11-01 00:00:00
abstract::Current pharmacologic therapy for ischemic heart disease suffers multiple limitations such as compliance issues and side effects of medications. Revascularization procedures often end with need for repeat procedures. Patients remain symptomatic despite maximal medical therapy. Gene therapy offers an attractive alterna...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章,评审
doi:10.1016/j.yjmcc.2010.06.007
更新日期:2011-05-01 00:00:00
abstract::We have investigated whether translocation of constitutive low molecular weight stress proteins (alphaB-crystallin and HSP27) to the myofilament/cytoskeletal compartment occurs during ischemic preconditioning and assessed if this is causally associated with cardioprotection. Triton-insoluble preparations from fresh or...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.2000.1136
更新日期:2000-06-01 00:00:00
abstract::Spectrin is a large, flexible protein that stabilizes membranes and organizes proteins and lipids into microdomains in intracellular organelles and at the plasma membrane. Alternative splicing occurs in spectrins, but it is not yet clear if these small variations in structure alter spectrin's functions. Three alternat...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2010.01.001
更新日期:2010-06-01 00:00:00
abstract::Leptin is a 16 kDa product of the obesity gene secreted primarily by adipocytes. We recently identified cardiomyocytes as a target for the direct hypertrophic effects of leptin and suggested that leptin may be a biological link between obesity and cardiovascular pathologies. Activation of the renin-angiotensin and end...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2006.05.001
更新日期:2006-08-01 00:00:00
abstract::Although 17beta-estradiol (E2) administration following trauma-hemorrhage (T-H) improves cardiac function in male rodents, it is not known whether the salutary effects of E2 are mediated via estrogen receptor (ER)-alpha or ER-beta, and whether cardiac heat shock proteins (Hsp) are affected by E2 administration. Male S...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2005.10.001
更新日期:2006-01-01 00:00:00