Syncope
A novel approach to syncopal patients: association analysis of polymorphisms in G-protein genes and tilt outcome
1 Department of Cardiology, Medical University of Lodz, Sterling Str. 1/3, 91-425 Lodz, Poland; 2 Department of Medical Biotechnology, Medical University of Lodz, Mazowiecka Str. 6/8, 92-215 Lodz, Poland
Manuscript submitted 3 May 2008. Accepted after revision 15 September 2008.
* Corresponding author. Tel/fax: +48 42 6364471. E-mail address: mlelonek{at}poczta.fm
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Abstract |
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Aims: G-proteins signal transduction pathways play a basic role in cardiovascular reflexes. We hypothesized that the predisposition to reflex-mediated syncope may be associated with genetic variations in G-protein genes. The aim of this study was to evaluate the effect of three single-nucleotide polymorphisms in G-protein genes on tilting outcome in syncopal patients.
Methods and results: A total of 217 syncopal patients free from any other disease were genotyped and examined related to tilting results. Genotyping was performed by polymerase chain reaction followed by restriction fragment length polymorphism in gene encoding the Gs-protein alpha-subunit (polymorphism C393T), the G-protein β3 subunit—GNB3 (polymorphism C825T)—and for the cardiac regulator of G-protein signalling RGS2 (polymorphism C1114G). In multivariate logistic regression analysis, the homozygotes 825TT GNB3 (OR 0.37; 95% CI 0.14–0.97; P < 0.05) and body mass index (OR 0.87; 95% CI 0.78–0.97; P = 0.005) were independently associated with a lower chance of positive tilting results. No relationship was found between Vasovagal Syncope International Study type of syncope and the studied genotypes or the carriage of the polymorphic alleles.
Conclusions: An association between tilting results and C825T GNB3 polymorphism in syncopal patients was found. The syncopal homozygotes 825TT GNB3 had a significantly lower chance of syncope during tilt testing.
Key Words: Syncope, Tilt test, Genes polymorphisms
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Introduction |
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The intracellular signal transduction pathways represent the molecular mechanisms of cardiovascular reflexes. The heterotrimeric G-proteins system, enclosing G-protein-regulated effector molecules,1
,2 is critical for signal transduction from G-protein-coupled receptors (GPCRs).3 Alterations of the G-proteins intracellular signal transduction under single-nucleotide polymorphisms (SNPs) have been described in cardiovascular diseases.4–7 Recent reports have also investigated the role of SNPs8–11 on individual susceptibility to syncopal episodes, as well as a significance of a positive vasovagal family history.12–15
In the present study, we hypothesized that the predisposition to reflex-mediated syncope may be associated with genetic variations in G-protein genes. Under these circumstances, we sought to investigate the effects of three SNPs (C393T polymorphism of the gene encoding the Gs-protein 
-subunit, GNAS1; the C825T polymorphism of the gene encoding the G-protein β3 subunit, GNB3; and the C1114G polymorphism of the gene for the cardiac regulator of G-protein signalling, RGS2) in the candidate gene approach in relation to tilt results among syncopal patients.
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Methods |
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Patients
We investigated 217 subjects (87 males) with more than one incident of syncope and no history or symptoms of cardiovascular diseases. The baseline demographic and clinical characteristics of the study participants are shown in Table 1. Exclusionary criteria were as follows: positive family history for sudden cardiac death; syncopal episodes due to: carotid sinus hypersensitivity, catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, or short coupling variant of torsade de pointes; ECG abnormalities and/or abnormal exercise testing; and abnormal echocardiogram. The investigation conformed with the principles outlined in the Declaration of Helsinki. The study protocol was approved by the local Bioethics Committee.
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All subjects were tilted to an angle of 60° under the Italian protocol (20 min passive tilting) with nitroglycerin (NTG) 400 µg in spray used sublingually.16
A positive tilt-test was obtained when syncope was accompanied by a marked reduction of blood pressure (systemic hypotension <80 mmHg) and/or heart rate during passive titling17 or in the first 5 min after NTG administration.16 The type of positive response to tilting was defined according to VASIS (Vasovagal Syncope International Study) classification.18
- VASIS1: mixed (blood pressure falls before the heart rate falls not <40 bpm or <40 bpm for <10 s with or without asystole of <3 s);
- VASIS 2A: cardioinhibition without asystole (significant bradycardia with heart rate falls to <40 bpm for >10 s but asystole of >3 s does not occur, blood pressure falls before the heart rate fall);
- VASIS 2B: cardioinhibition with asystole (asystole occurs for >3 s, blood pressure fall coincides with or occurs before the heart rate fall);
- VASIS 3: vasodepressor with hypotension without bradycardia (heart rate does not fall for >10% from its peak at the time of syncope).
VASIS2 Groups A and B were analysed together as VASIS2 with regard to small number of patients.
During the tilt-test, ECG was monitored continuously and the blood pressure was assessed by a sphygmomanometer.
After signing the consent form, the genotyping of the investigated polymorphisms was performed in 217 subjects (152 with positive tilt-test) for the C393T polymorphism in GNAS1, in 213 subjects (142 with positive tilt-test) for the C825T polymorphism in GNB3, and in 138 patients (93 with positive tilt-test) for the C1114G polymorphism in RGS2. Genotypes were analysed in relation to tilt-test results (positive vs. negative and between VASIS types).
Genotyping
Genomic DNA was extracted from white blood cells using a commercially available kit (Chemagic DNA Blood 100, Kit, Chemagen AG Germany). Genotyping was performed by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism analysis. For amplification, the following primer pairs were used: for the C393T polymorphism in the GNAS1 (GeneID: 2778) gene,19 forward 5'-CTCCTAACTGACATGGTGCAA-3' and reverse 5'-TAAGGCCACACAAGTCGGGGT-3';7 for the C825T polymorphism in the GNB3 (GeneID:2784) gene, forward 5'-TGACCCACTTGCCACCCGTGC-3' and reverse 5'-GCAGCA GCCAGGGCTGGC-3'.20 The C/T transition within codon 131, Ile (C393T polymorphism) of exon 5 GNAS1, creates a target site for the endonuclease Fok I (Fok I+). For genotyping of the C1114G polymorphism in the RGS2 (GeneID: 5997) gene, we used two allele-specific (sense) primers and a common antisense primer (projected in Department of Medical Biotechnology, Lodz, Poland). The sequence of the oligonucleotide primers were as follows: C-allele-specific forward primer: 5'-AGTGAAGTGTTTACTATGTGCTAC-3'; G-allele-specific forward primer: 5'-AGTGAAGTGTTTACTATGTGCTAG-3'; and common reverse primer: 5'-TCAACACCATAGCACTCATTCTAT-3'. All primer pairs were synthesized by Eurogentec.
Statistical analysis
Skewed variables were analysed with the Mann–Whitney U-test and presented as means ± standard deviations (SD) or 95% confidence intervals (95% CI). Categorical variables are reported as counts and percentage. Categorical variables were analysed using the 
2 Pearson test, the Yates-corrected 2 test for 2 x 2 contingency tables, or Fisher's exact test, as appropriate. Body mass index (BMI) and systolic and diastolic blood pressure at rest were compared across groups using one-way analysis of variance. Univariate logistic regression followed by multivariate backward stepwise analysis was used to identify the potential predictors of tilting outcome. Genetic traits (carriage of polymorphic allele and genotypes) and the clinical variables associated with tilting outcome in univariate analysis (P < 0.15) were entered into the multivariate model as covariates. Results of logistic regression analysis are expressed as odds ratios (ORs) and 95% CIs. Statistica version 7.0 software (StatSoft, Tulsa, OK, USA) and Medcalc 8.1 (Medcalc, Mariekerke, Belgium) were used for data analysis. A P-value of <0.05 was considered statistically significant.
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Results |
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Seventy per cent of subjects had a positive tilt-test, 24% in the passive phase, 46% in the NTG phase, and 30% were negative to both. VASIS1 type of response had 91 patients, VASIS2 32, and VASIS3 29. The baseline characteristics of the study participants stratified to positive vs. negative tilting results (Table 1) showed the significant differences in BMI and gender distribution (P < 0.05).
The distribution of the selected polymorphisms alleles is depicted in Table 2. The frequency of the GNAS1 Fok I+ allele carriers was significantly higher in patients with positive than those with negative tilt results (82 vs. 65%, P = 0.01). In patients with positive and negative tilt results, the frequencies of the 825T allele carriers in the GNB3 were 50 and 59%, respectively (P > 0.05). As for the 1114G allele carriers in the RGS gene, the frequencies in patients with positive and negative tilting results were 34 and 44% (P > 0.05), respectively. No relationship between the carriers of the polymorphic alleles and syncope during the passive tilting was found (P > 0.05): for Fok I+ allele GNAS1 OR = 0.74, 95% CI 0.24–2.29; for 825T allele GNB3 OR = 5.17, 95% CI 0.61–43.62, and for 1114 G allele RGS2 OR = 0.99, 95% CI 0.35–2.80. Also there was no association between VASIS type (in the case of the small number of patients in the genotype-subgroups computed as: dominant vasodepressive response, VASIS 1+VASIS 3, vs. dominant cardioinhibition, VASIS2) and the studied genotypes or the carriage of polymorphic alleles (all P > 0.25).
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The homozygous TT genotype of the GNB3 C825T polymorphism was significantly associated with a lower supine systolic blood pressure (P < 0.05): TT, 104 ± 2.5 mmHg; TC, 112 ± 2.1 mmHg; and CC genotype, 112 ± 1.7 mmHg. The carriage of the 1114G allele in the RGS2 gene was significantly associated with a reduced number of syncopal episodes (P < 0.01).
No relationship between BMI and the investigated polymorphisms was evident (all P > 0.25). Clinical variables associated with tilting outcome in univariate analysis (i.e. female gender and BMI) were entered into the multivariate model. Other variables (age, systolic and diastolic blood pressure) did not reach the pre-specified level of significance (P < 0.15) for inclusion into the multivariate model (P = 0.73, 0.73, and 0.55, respectively). Among clinical variables, only BMI was found to be significantly associated with a lower risk of positive tilt results (OR 0.86; 95% CI: 0.77–0.96; P = 0.005).
Results of multivariate regression analysis from clinical and genetic variables are shown in Table 3. Notably, among clinical variables and the investigated polymorphisms, multivariate logistic regression analysis showed BMI and the homozygotes 825TT GNB3 to be independently associated with a significantly lower chance of positive tilt results in syncopal patients.
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Discussion |
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In extension to our previous results, in this study, three SNPs in G-protein genes were investigated, as the potential factors related to the susceptibility to faint during tilt testing among syncopal patients. The main finding of our report is the strong relationship between the homozygous 825TT genotype of the GNB3 gene and the decreased chance of positive tilt results, regardless of BMI. It can mean that although the patients have syncope, this genotype could preclude the use of tilt-test as a diagnostic tool, because it would be negative. In these genotype-patients, first of all the other diagnostic methods, such as quantitative evaluation of medical history or implantable loop recorder (ILR), should be used to diagnose the reason of syncope. Finally, the studied GNB3 polymorphism could be helpful in determining the syncopal person to ILR.
Although we found in this study no association between VASIS type and the studied genotypes or the carriage of polymorphic alleles, it does not exclude this relationship. These findings require further studies.
The frequencies of the 825T GNB3 allele carriers in positive vs. negative tilt-test did not reach the significance, what can be related to the number of patients in the subgroups. We plan to enlarge the population.
Our previous studies have reported a higher frequency of the 825T allele in the GNB3 gene among syncopal patients with non-typical vasovagal history9 and the association between FokI+ allele and positive tilting results.11 No other reports have investigated the association between G-protein genes polymorphisms and syncopal episodes. Solely, a Gly-to-Arg substitution at position 389 in the β1-adrenergic receptor gene has been previously associated with positive tilt-test results.8 On the other hand, Newton et al.21 failed to find a significant association between the ACE insertion/deletion polymorphism and an increased risk of vasovagal syncope.
Siffert et al.22 have previously reported an association between the 825T allele of the GNB3 gene and obesity. In our study, an inverse association between BMI and positive tilt results was evident, and no relationship between the 825T allele of the GNB3 gene and BMI was found (P = 0.87).
No reports have been published thus far on the distribution of the selected polymorphisms in Polish healthy individuals. The distribution of the silent polymorphisms in GNAS1 and RGS2 has been previously reported in Reference (SNP) Report (www.ncbi.nlm.nih.gov/SNPsnp_ref.cgi?rs=7121 and www.ncbi.nlm.nih.gov/SNPsnp_ref.cgi?rs=4606) and of the C825T polymorphism in the GNB3 has been described by Siffert et al.22 The distribution of genotypes in the entire study cohort was in keeping with previous data from healthy subjects (Table 2). Further analysis of genotypes regard to tilting results revealed the described discrepancies.
The exact molecular mechanisms behind the effects of the selected polymorphisms in syncopal patients are nowadays under investigation. In the cardiovascular system, the subunit of Gs (stimulating) protein couples with the activated β-adrenergic receptors to stimulate the production of cyclic adenosine monophosphate (cAMP). A silent single nucleotide C/T polymorphism at codon 131 in exon 5 of GNAS1 gene located on 20q13.2 (19) has been associated with enhanced adenylyl cyclase activity.7 This phenomenon results in turn in an enhanced protein kinase A (PKA) activity. The activated PKA phosphorylates many proteins23–25 that results, among other effects, in an increased cAMP-mediated cardiac contractility and increased heart rate. It seems to be responsible for excessively enhanced inotropism, which has been described in the early phase of the upright posture as a susceptibility marker of vasovagal syncope.26
Another potential molecular pathway underlying vasovagal syncope susceptibility may be the result of GPCRs desensitization and resensitization. Protein kinase A is able to phosphorylate GPCRs, which in turn results in their desensitization (heterologous desensitization). Additionally, PKA phosphorylates GPCR kinases (GRKs), which in turn phosphorylate agonist-occupied GPCRs only (homologous desensitization). This phenomenon provides recycling and resensitization of the internalized receptor.27,28 Thus, the studied GNAS1 polymorphism may result, via an overproduction of cAMP and an enhanced PKA activity, in a motif-dependent desensitization and resensitization of the β-adrenergic receptors.
The presence of the 393T allele located in an untranslated region may be associated with greater mRNA stability, which in turn results in more efficient process of translation. Hence, the GNAS1 393T allele among the patients with positive tilt results may be related to an accelerated adenylyl cyclase production.
The gene encoding the β3 subunit of the human G-protein (GNB3) is located on chromosome 12p13 and consists of 11 exons.20 The C825T silent polymorphism of the GNB3 is associated with the alternative splicing of exon 9 referred as G-protein β3 stimulating—Gβ3s.20 Expression of this variant leads to an enhanced activation of G-protein-mediated signal transduction5 probably via Gβ
/Gi (i-inhibition).29 The β2-adrenergic receptors activation inhibits, within Gi pathway, the production of cAMP and activates the phosphatidylinositol 3-kinase (PI3K) and Akt-kinase.30 The latter molecular pathway is counteracting to classical activation of β1-adrenergic receptors and adenylyl cyclase31 and effects in a decreased cardiac contractility. This may explain an important part of C825T GNB3 polymorphism in the protective mechanism for positive tilting results.
Regulator of G-protein signalling proteins stimulate the GTPase activity of G subunits of heterotrimeric G-proteins. Hence, these proteins provide a negative regulation of GPCR signalling and terminate G-protein signalling.2 Numerous reports have suggested an important role of RGS2 in cardiovascular regulation, with a selectivity for the Gq subclass of G-proteins.32 Regulator of G-protein signalling-2 can also interact with Gi.33,34 Regulator of G-protein signalling-2 decreases cAMP production and appears to interact with both adenylyl cyclase and its stimulatory G-protein Gs.35 Regulator of G-protein signalling-2 is part of a novel negative feedback control pathway for adenylyl cyclase signalling.35,36 The RGS2 gene is located at chromosome 1q31. This gene is relatively conserved with scarce genetic variations, especially in its coding sequence.6 Therefore, in this study, we focused our attention on the C1114G polymorphism, which acts indirectly, through the modulation of RGS2 gene expression (reduced expression). The reduced expression of RGS2 gene with the decreased negative regulation of G-protein signalling could underlie the predisposition to reflex-mediated syncope. However, we found no relationship between the C1114G RGS2 gene polymorphism and tilting results.
In conclusion, in this study, we have investigated three SNPs in G-protein genes in syncopal patients undergoing tilt-test. We have identified a marked and significant effect of the genotype TT 825 GNB3 on tilt results among syncopal patients. Specifically, the syncopal homozygotes TT 825 GNB3 were independently associated with a lower chance of positive tilt results. On the basis of the available data, it is difficult to establish whether the 825T allele in the GNB3 gene may exert a codominant or recessive effect on tilting results.
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Some limitations are inherent in the present study. The major limitation is the lack of a control group. A second limitation relies on the lack of the functional characterization of the investigated genetic variants.
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Conclusions |
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In the present study, we have found an association between tilting results and the C825T polymorphism in the GNB3 gene in syncopal patients. The homozygotes 825TT GNB3 had a significantly lower chance of syncope during tilt testing.
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This work was supported by the Medical University of Lodz grant No. 502-11-583 to M.L.
Conflict of interest: none declared.
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References |
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