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European Heart Journal Advance Access originally published online on June 7, 2006
European Heart Journal 2006 27(14):1712-1718; doi:10.1093/eurheartj/ehl087
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Analysis of minK and eNOS genes as candidate loci for predisposition to non-valvular atrial fibrillation

Cinzia Fatini1,*, Elena Sticchi1,2, Maurizio Genuardi3, Francesco Sofi1, Francesca Gensini3, Anna Maria Gori1, Meri Lenti1, Antonio Michelucci1, Rosanna Abbate1 and Gian Franco Gensini1,2

1 Department of Medical and Surgical Critical Care; Thrombosis Centre, Azienda Ospedaliero-Universitaria Careggi; Center or the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases to Develop Novel Therapies, University of Florence, Viale Morgagni 85, 50134, Italy
2 Fondazione Don Carlo Gnocchi ONLUS, Centro S. Maria degli Ulivi-IRCCS, Florence, Italy
3 Department of Clinical Pathophysiology, Unit of Medical Genetic, University of Florence Italy

Received 2 November 2005; revised 2 May 2006; accepted 12 May 2006; online publish-ahead-of-print 7 June 2006.

* Corresponding author. Tel: +39 (0) 557949417; fax: +39 (0) 557949418. E-mail address: cinziafatini{at}hotmail.com

See page 1640 for the editorial comment on this article (doi:10.1093/eurheartj/ehl076)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Aim Mink protein, a ß-subunit of Iks potassium channels modulate cardiac cellular electrophysiology, and experimental data demonstrated that NO is involved in cardiac vagal activity and in the inhibition of sympathetic activity. We evaluated the role of eNOS –786T>C, 894G>T, 4a/4b and of minK S38G polymorphisms as predisposing factors to non-valvular atrial fibrillation (NVAF).

Methods and results We studied 331 consecutive patients with documented NVAF and in 441 control subjects, comparable for age and gender. A significant difference in allele frequencies between patients and controls for minK S38G and eNOS –786T>C, but not for eNOS 894G>T and 4a/4b polymorphisms, was observed. The minK 38G allele was significantly associated with susceptibility to NVAF at both univariate and multivariable analysis, according to dominant and recessive genetic model (multivariable analysis, dominant: OR=1.73, P=0.004 and recessive: OR=1.59, P=0.006). The eNOS –786C allele weakly influenced NVAF at univariate analysis, according to the dominant model (OR=1.50, P=0.01). The contemporary presence of minK 38G and eNOS –786C alleles increased the predisposition to NVAF, after adjustment with cardiovascular risk factors (OR minK 38G*eNOS –786C=2.11, P<0.0001; OR=2.58, P=0.003; OR=3.08, P=0.002, according to dominant, recessive, and additive model, respectively).

Conclusion Our findings suggest a role for minK and eNOS genes as predisposing factors to NVAF.

Key Words: eNOS –786T>C • 894G>T • 4a/4b polymorphisms • minK S38G polymorphism • Non-valvular atrial fibrillation


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Atrial fibrillation (AF) is characterized by rapid and irregular activation of the atrium. The ionic properties of the atria play a relevant role on the occurrence of atrial arrhythmias, and sustained AF is associated with atrial electric remodelling. Both a decrease of the L-type calcium current (ICa,L) and an increase of Ik1 and IK,AchK+ currents have been reported in AF.1 In isolated myocytes, it has been demonstrated that the larger basal inward rectifier K+ current in AF consists of increased Ik1 activity and constitutively active IK,Ach.2 In atrial myocytes from chronic AF patients an increased density of Ik1, but a reduced activity of IK,Ach has been found.3 The decreased expression of IK,Ach channel subunit may be interpreted as an adaptation of atrial myocytes to the high beating rate, in order to counteract the shortening of action potential duration (APD) observed in AF.2 A marked reduction in ion channel protein expression of both L-type Ca2+ and several K+ channels4 in the atrial appendages is also observed. As most of the studies have been performed in the atrial appendages, they may not reflect alterations in the rest of the atria, which are heterogeneous tissues.

Although several families with autosomal dominant AF have been observed, and possible loci on different chromosomes5–8 have been identified by linkage analyses, major genetic components do not seem to play a relevant role in the aetiology of this arrhythmia. Indeed, AF is a common disorder and, apart from isolated families, it appears to result from the complex interaction between genetic and environmental factors.

Human minK protein is the ß-subunit of Iks potassium channel and plays a role in cardiac cellular electrophysiology,9 so contributing to atrial repolarization; moreover, in atrial tissue of patients with persistent AF significantly increased minK mRNA expression has been documented.10,11 A missense polymorphism in the minK gene has been reported to be associated with AF in patients from Taiwan.12 This polymorphism consists of an A/G substitution at nucleotide 112 of the minK gene, leading to a serine-to-glycine change in the 38th aminoacidic position of the minK protein. Recently, a functional role for this polymorphism has been demonstrated by expressing the corresponding channel subunits in Chinese hamster ovary cells.13

Vagal stimulation can promote AF initiation, by causing uneven shortening of refractoriness in the atria and, hence, electrophysiological heterogeneity.14 Experimental data demonstrated that nitric oxide (NO) enhances cardiac vagal activity and participates in the inhibition of sympathetic activity;15 moreover, endothelial NO synthase (eNOS) regulates L-type calcium channel and modulates myocyte contractility.16 The L-type calcium channel is essential for normal sinus function,17 and NO, by stimulating the formation of cGMP,18 which affects this channel, might play a role in suppressing arrhythmias through a cGMP-mediated pathway. A decrease in NO levels might contribute to modulate AF through an increase in ICa,L current.16 On the other hand, low NO levels, by reducing vagal stimulation, might reduce IK,Ach current, thus contributing to the complex signalling inside the autonomic activity. Recently, Kim et al.19 suggested that increased atrial superoxide production may have relevant implications in the electrophysiological remodelling process, and demonstrated that inducible NOS (NOS2), which contributes to superoxide production, is significantly increased in fibrillating atrial myocardium. NOS can release superoxide when deprived either of its critical cofactor tetrahydrobiopterin (BH4) or of the substrate L-arginine.19 In the presence of increased oxidative stress, oxidation of BH4 can uncouple NOS to generate reactive oxygen species (ROS), as demonstrated by Cai et al.20 in a porcine model of AF. In this model AF is associated with a marked decrease in endocardial NOS expression and NO availability in the left atrium, thus suggesting that organized atrial contraction is needed to maintain normal endocardial expression of NOS.20

Data from an in vivo study indicate that a deficiency of NO formation could be associated with increased vulnerability to arrhythmia.21 NO plasma levels are mainly regulated by eNOS activity. The gene encoding for eNOS exhibits several polymorphisms, some of which seem to be related with the variability in NO plasma levels:22 a substitution of guanine to thymine at nucleotide 894 in exon 7 of the eNOS gene (894G>T polymorphism) is associated with reduced basal NO production;23 the rare C allele of the –786T>C polymorphism in the 5'-flanking region of the gene results in a significant reduction in eNOS promoter activity;24 and finally, a 27 bp variable tandem repeats polymorphism in intron 4 (also called eNOS 4a4b) has been associated with variations in NO, nitrite, and nitrate plasma levels.22,25 We previously showed no influence of eNOS gene polymorphisms on predisposition to AF in 148 patients with persistent AF when compared with 210 healthy controls.26 To the best of our knowledge, no information is available about the role of minK S38G polymorphism in the modulation of AF in Caucasians. Aims of this study were to investigate: (i) the role of the minK S38G polymorphism in the predisposition to non-valvular atrial fibrillation (NVAF); and (ii) the relationship between minK and eNOS genes in predisposing to the disease in an Italian population.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Study population
The study population consisted of 331 consecutive haemodynamically stable patients with documented NVAF lasting >24 h without periods of sinus rhythm (mean duration 5±0.4 weeks), as documented by electrocardiography) referred to the Division of Cardiology, University of Florence, Careggi Hospital, Florence, and 441 control subjects, comparable for age and gender, invited to participate in the study, and consisted of partners or friends of patients, and subjects from a population study ‘Progetto Nutrizione per la Salute e la Prevenzione di Malattia’ conducted between 2002 and 2004 and aimed to evaluate lifestyle and dietary habits of clinically healthy persons living in Florence, Italy. Exclusion criteria for the controls were: personal and family history of cardiovascular disease. A detailed interview addressed to personal and familial history was performed in the frame of a physical examination by expert physicians, in order to identify symptom-free subjects and to exclude those who were suspected of having any form of vascular disease. Moreover, we accurately interviewed our control subjects, in order to identify the existence of symptoms related to dysrhythmias.

For all subjects, patients and controls, a 12-lead ECG, 24 h ECG recordings, stress-test, chest roentgenogram, routine laboratory screening, thyroid function test, and echocardiography were obtained. Transthoracic echocardiography was performed to measure left atrial dimension. In particular, in patients showing symptoms related to the presence of cardiovascular disease, a more accurate clinical and instrumental evaluation was performed (e.g. echo-stress testing, myocardial scintigraphy, and/or coronarography).

For the inclusion in the current study, all subjects needed to have performed one or more complete echocardiographic examinations. All of the original echocardiographic data were available for the offline measurements of left atrial dilation and ejection fraction (EF).

Exclusion criteria for patients included one of the following: familial AF, hyperthyroidism, valvular heart disease, including mitral valve prolapse, symptomatic heart failure, cardiomyopathy, chronic obstructive pulmonary disease, cardiomegaly apparent on the chest radiography, AF due to trauma, surgery, or acute medical illness. The number of patients initially assessed for inclusion into the study was 413. Seventy-nine patients were ineligible for inclusion after initial assessment as 20 had thyroid disease, 15 valvular heart disease, 19 symptomatic heart failure, 9 cardiomyopathy, 12 pulmonary disease, and 4 a familial history of AF. Moreover, three AF patients refused to assent with the genetic analysis.

Patients who were younger than 65 years and had no identifiable cause of AF were classified as ‘lone’ NVAF patients.

The presence of traditional cardiovascular risk factors was assessed on the basis of patients' interview, echocardiography data, and hospital records. Current smoking status was determined at the time of blood collection. The subjects were considered to have hypertension according to the guidelines of European Society of Hypertension/European Society of Cardiology27 or if they were taking antihypertensive drugs. Dyslipidaemia was defined according to the third report of the National Cholesterol Education Program (NCEP),28 and diabetes in agreement with the American Diabetes Association.29

Coronary heart disease was defined on the basis of a history of myocardial infarction or stable and unstable angina. Left atrial dilation was defined as a diameter >38 mm at echocardiography,30 and left ventricular (LV) dysfunction was defined as EF <50%.

All subjects in the patient and control group were Caucasian, unrelated to each other, and resident in the same geographic area. All subjects gave informed consent and the study complies with the Declaration of Helsinki and was approved by the local Ethics Committee.

Molecular analysis
Genomic DNA extraction was performed from peripheral blood leucocytes using a QIAmp Blood Kit (QIAGEN, Hilden, Germany).

Detection of eNOS polymorphisms
The eNOS –786T>C and 4a/4b polymorphisms were analysed by PCR–RFLP analysis as previously described.31 Detection of the eNOS 894G>T polymorphism was performed by real-time fluorescence PCR with a Light Cycler instrument (Roche Diagnostics).32

Detection of minK S38G polymorphism
The S38G (112A>G) minK gene polymorphism was analysed through PCR–RFLP analysis. PCR reaction was performed in a final volume of 20 µL using primers 5'-TGT GGC AGG AGA CAG TTC AG-3' (primer sense) and 5'-GCT TCT TGG AGC GGA GTG AG-3' (primer antisense) at an annealing temperature of 56°C. The reaction mixture consisted of 2 µL of 10X PCR buffer (500 mM KCl, 200 mM Tris–HCl pH 8.4) MgCl2 1.5 mM, 0.2 mM of each dNTPs, 1 µL of each primer (10 pmol/µL), 0.5 U of Amersham Pharmacia Taq DNA polymerase. Two microlitres of genomic DNA (50 ng/µL) were used for amplification. Cycling conditions for S38G minK gene polymorphism detection included an initial denaturation at 95°C for 5 min followed by 35 cycles with a fast denaturation at 94°C for 1 min, an annealing step at 56°C for 1 min and an extension step at 72°C for 1 min, with a final incubation at 72°C of 7 min. The amplification reaction was followed by a digestion with the reaction enzyme, Bts I (New England Biolabs Inc., Milano, Italy) at 37°C for 16 h and electrophoresis on 3% agarose gel.

Statistical analysis
Statistical analysis was performed using the SPSS (Statistical Package for Social Sciences, Chicago, USA) software for Windows (Version 11.5). The {chi}2-test was used to test the deviation of genotype distribution from Hardy–Weinberg equilibrium. The association between minK and eNOS polymorphisms and NVAF was assessed using logistic regression analysis under a dominant, recessive, and additive genetic model. The dominant genetic model compares individuals with one or more polymorphic alleles of a baseline group with no polymorphic alleles (e.g. minK 38GG+GS vs. SS). The recessive genetic model compares the 38GG genotype with the combined GS+SS genotypes, which form the baseline group. The additive genetic model assumes that there is a linear gradient in risk between the 38GG, 38GS, and 38SS genotypes (38SS genotype baseline). This is equivalent to a comparison of the 38G allele vs. the 38S allele (baseline). All variables that resulted with a P-value <0.2 in the univariate analysis (hypertension, diabetes, dyslipidaemia, and smoking habit) were introduced into a multivariable model. Variables as age and gender were also included into the multivariable model. Odds ratio (OR) with 95% CI was determined. Statistical significance was accepted at P-value <0.05 (two-sided P-value). The Bonferroni correction was used for multiple testing (the four candidate polymorphisms were treated as four independent statistical tests) by multiplying the nominal P-value of each test by the number of tests conducted. In order to evaluate the interaction between minK and eNOS alleles we put the dummy variables and their ‘product’ into the logistic regression analysis. Because of the lack of information about the prevalence of minK S38G polymorphism allele frequency in Caucasians, and based on previous observations from Lai et al.9 in Taiwanese, a sample size of at least 262 subjects/group was deemed sufficient to prove/exclude an association between minK S38G polymorphism and AF with a statistical power (ß) of 90%, and significance value of 0.05 ({alpha}).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The demographic and clinical characteristics of the study population are reported in Table 1. Hypertension, diabetes, and smoking habit, but not dyslipidaemia were significantly more prevalent in patients than in healthy subjects (P<0.0001, <0.0001, 0.02, and 0.1, respectively).


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  		Table 1 Demographic and clinical characteristics of study population

 
No deviation from the expected population genotype proportions predicted by Hardy–Weinberg equilibrium was detected at the minK and eNOS polymorphic sites (Table 2). A significant difference in genotype distribution and allele frequency between patients and controls were observed for minK S38G and eNOS –786T>C polymorphisms, but not for the other eNOS polymorphisms investigated (Table 2). The minK 38G variant was associated with a significant predisposing effect on NVAF under a dominant, recessive, or additive model (Table 3), which remained significant under dominant and recessive, but not additive model after adjusting for smoking habit, hypertension, and diabetes (in addition to age and sex) (Table 4). The eNOS –786C, but not 894T and 4a, variant was associated with a significant predisposing effect on NVAF only under a dominant model (Table 3), which did not remain significant after adjustment for the other risk factors and Bonferroni correction (Table 4).


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  		Table 2 Genotype distribution and allele frequencies of minK and eNOS polymorphisms

 

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  		Table 3 Univariate analysis for minK and eNOS genes polymorphisms according to dominant, recessive, and additive genetic models

 

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  		Table 4 Multivariable analysis for minK and eNOS genes polymorphisms according to dominant, recessive, and additive genetic models

 
The contemporary presence of minK 38G and eNOS –786C, but not 894T and 4a variants, significantly influenced the predisposition to NVAF under a dominant, recessive, or additive model at both univariate (Table 5), and multivariable analysis after adjustment for smoking habit, hypertension, and diabetes (in addition to age and sex), and Bonferroni correction. We observed an interaction between minK and eNOS genes (Table 6). In order to investigate the relevance of this interaction we performed a multivariable analysis, in which the weight of each genetic variable has been tested. We observed an interaction between minK 38G and eNOS –786C variants in predisposing to NVAF under a recessive and additive, but not a dominant model (Table 7).


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  		Table 5 Univariate analysis for the interaction between minK and eNOS variants according to dominant, recessive, and additive genetic models

 

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  		Table 6 Multivariable analysis for the interaction between minK and eNOS variants according to dominant, recessive, and additive genetic models

 

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  		Table 7 Multivariable analysis for the interaction between minK and eNOS variants according to dominant, recessive, and additive genetic models

 
As atrial dimension was considered, no difference in genotype distribution and allele frequency between patients with left atrial dimension >38 mm (N=277) and <38 mm (N=54), was found for all polymorphisms analysed. A total of 110 (33.2%) NVAF patients had LVEF below 50%. No difference in genotype distribution and allele frequency between patients with LVEF <50% and patients with LVEF >50% (n=221) was found for all polymorphisms analysed.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This is the first study in which the effect of the contemporary presence of both minK and eNOS genes has been evaluated as potential predisposing factor to NVAF in Caucasian subjects. Our results show an interaction of these two genes in conferring a higher susceptibility to the disease, thus suggesting a role for genetic components in modulating the molecular mechanisms of AF.

MinK gene is one of the candidate AF genes, and encodes for the minK protein, the ß-subunit of cardiac Iks channel, and its expression in atrial tissue has been documented,10 both at messenger RNA and ion channel levels.10,33 Evidence shows that Iks is involved in the pathophysiology of AF.5 Nevertheless, minK interacts with other K+ channel subunits, such as hERG, thus modulating the Ikr, other than Iks potassium current,34 and its role in affecting AF is speculative. MinK might promote either the initiation, or the maintenance of AF, through the association with additional proteins,5 thus resulting in an arrhythmogenic substrate. To date, cardiac Iks channels contribute to atrial repolarization, in particular at the late phase of the action potential. Channels in open state tend to accumulate during fast heart rate because the diastolic period is as short as the channels do not have enough time to be deactivated. Accordingly, this channel plays a relevant role in the rate-dependent shortening of APD and restitution properties of the atrial tissue.

Cardiac Iks channels can contribute to atrial repolarization, by modulating the APD and restitution properties of the atrial tissue, and the Iks channel has been demonstrated to be involved in hereditary forms of arrhythmias.5

Currently, the role of minK gene is not well defined, and the functional significance of minK S38G polymorphism remains unclear. The mink 38G variant has been found to be associated with a higher risk of AF in a population from Taiwan.12 Recently, an experimental study demonstrated a functional role for the mink S38G polymorphism using a simulation model, which documented that the 38G isoform was associated with reduced Iks current, related to an increased APD.13 There is evidence that APD prolongation could promote atrial tachyarrhythmias in both experimental35 and clinical36 studies.

Our results, which are in keeping with those observed in the Taiwanese population,12 are based on the analysis of a three-fold larger population from a different ethnic group.

The mink gene encoding for mink protein might represent a candidate gene at the same time as other genes encoding for other channel or endothelial components, such as eNOS able to modulate myocytes contractility.

NO plays a role in mediating vagal neurotransmission and vagal modulation of sympathetic effects, by inhibiting sympathetic activity.15 Data from experimental studies demonstrated that NOS is localized in cardiac ganglion cells and nerve fibers innervating the sinus and atrioventricular nodes.37 NO, by acting as a second messenger to stimulate the formation of cGMP,38 modulates the cardiac L-type calcium channel, which is essential for normal sinus function, and myocyte contractility.16 An experimental study on cardiac myocytes isolated from eNOS-deficient mice suggested that eNOS deficiency may predispose to arrhythmia vulnerability.39 On the basis of the aforementioned data, NO modulation in the heart has been proposed to have cardioprotective effects in preventing malignant arrhythmias,40 and it has been hypothesized that NO deficiency might affect the electrophysiological phenotype.

The eNOS –786T>C polymorphism in the promoter of the eNOS gene modulates the function of the gene product; the –786C rare variant has been associated with a reduction in eNOS promoter activity by ~50%, thus determining a reduction in NO levels. Low NO levels related to the presence of this genetic variant can contribute to the vulnerability of arrhythmia by affecting the L-type calcium channel, which is essential for normal sinus function,17 and data from an electrophysiologic study in eNOS-deficient mice21 demonstrated that the eNOS deficiency could influence heart rate variability.

Our results showed that eNOS –786C allele was weakly associated to the predisposition to NVAF, and demonstrated that the contemporary presence of minK 38G and eNOS –786C variants can influence the susceptibility to NVAF. These findings might suggest a double effect of eNOS and minK genes in influencing heart rate variability. On one hand, minK 38G isoform might reduce Iks current, so increasing APD and promoting atrial arrhythmias; on the other hand low NO availability, related to an altered eNOS gene function, which by modulating L-type calcium channel, is involved in direct autonomic modulation of cardiac electrophysiology. Although at the beginning low NO levels might increase L-type calcium channel initiating AF, the reduced stimulation of vagal activity may offset this effect.

A limitation of the study lies in the fact that we cannot exclude the presence of asymptomatic AF in the control group, although an accurate interview weighted to symptoms related to dysrhythmias has been performed.

In conclusion, the evaluation of minK and eNOS polymorphisms, which are known to be involved in the modulation of the ionic properties of the atria, has demonstrated a possible role for these genes as predisposing factors to NVAF, thus providing new highlights for investigating the susceptibility to the irregular activation, which is implicated in the AF pathway.

Conflict of interest: none declared.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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