[Association of Polymorphic Genome Variants in the 2q32.1 Locus with the Development of Vasovagal Syncope].

The vasovagal syncope (VVS) is the most common form of syncope. The mechanisms of VVS development are not entirely clear. It is known that there is a genetic predisposition to this disease, but the data on the roles of individual genes are quite contradictory. Recently, a genome-wide association study identified a locus at chromosome 2q32.1 associated with a united group of diseases, that is, syncope and collapse; among the single nucleotide polymorphisms (SNPs) of this locus, the most significant association was observed for rs12465214. In a homogeneous sample of patients diagnosed with VVS, we analyzed the association of rs12465214, rs12621296, rs17582219 and rs1344706 located on chromosome 2q32.1 with this form of syncope. In the enrolled set, only rs12621296 was associated with VVS by itself, whereas associations of other SNPs were observed only in biallelic combinations. An epistatic interaction between the components of the combination rs12621296*A + rs17582219*A was revealed. The possible involvement of individual genes on the 2q32.1 locus in the genetic architecture of the VVS is discussed.

The effects of ALDH2 Glu487Lys polymorphism on vasovagal syncope patients undergoing head-up tilt test supplemented with sublingual nitroglycerin.

BACKGROUND AND OBJECTIVE: Head-up tilt test (HUTT) is clinically advantageous for diagnosing patients with vasovagal syncope (VVS). Nitroglycerin is mainly used as a stimulant during HUTT, and mitochondrial aldehyde dehydrogenase 2 (ALDH2) is involved in the metabolism of nitroglycerin (NTG). ALDH2 Glu487Lys polymorphism (ALDH2 rs671) is the most common variant in the East Asian population. This study aimed to assess the effects of ALDH2 rs671 on VVS patients undergoing HUTT supplemented with sublingual NTG (HUTT-NTG).  METHODS: Patients with recurrent VVS (at least 2 times) who were admitted to the syncope center of our hospital were enrolled. All VVS patients have undergone HUTT. The polymorphism of Glu487Lys gene of ALDH2 was measured by the DNA Microarray Chip Method. The results of HUTT-NTG of VVS patients with different ALDH2 genotypes were compared and their hemodynamic characteristics were assessed. RESULTS: A total of 199 VVS patients were enrolled, including 101 patients in the ALDH2*1/*1 group and 98 patients in the ALDH2*2 group. Among patients undergoing HUTT-NTG, 70.3% of patients in the ALDH2*1/*1 group and 68.4% of patients in the ALDH2*2 group were positive, and the difference between the two groups was not statistically significant (P = 0.77). The proportions of VASIS I, VASIS II, and VASIS III were 40.6%, 8.9%, and 20.8% in the ALDH2*1/*1 group, respectively, and the corresponding proportions in the ALDH2*2 group were 36.7%, 11.2%, and 20.4%, respectively. There was no statistically significant difference between the two groups (P = 0.91). The hemodynamic characteristics of different genotypes in VVS patients undergoing HUTT-NTG were compared, and no statistically significant difference was found. The median time of syncopal episode occurred after NTG administration in the ALDH2*1/*1 group was 6 min (interquartile range [IQR]: 5.0-9.0), and it was 6.0 min in the ALDH2*2 group (IQR: 4.25-8.0, P = 0.64). CONCLUSION: ALDH2 Glu487Lys polymorphism did not affect the outcome of VVS patients undergoing HUTT-NTG, and no significant change in the hemodynamic characteristics of different genotypes was found.

Towards Understanding the Genetic Nature of Vasovagal Syncope.

Syncope, defined as a transient loss of consciousness caused by transient global cerebral hypoperfusion, affects 30-40% of humans during their lifetime. Vasovagal syncope (VVS) is the most common cause of syncope, the etiology of which is still unclear. This review summarizes data on the genetics of VVS, describing the inheritance pattern of the disorder, candidate gene association studies and genome-wide studies. According to this evidence, VVS is a complex disorder, which can be caused by the interplay between genetic factors, whose contribution varies from monogenic Mendelian inheritance to polygenic inherited predisposition, and external factors affecting the monogenic (resulting in incomplete penetrance) and polygenic syncope types.

A case report of one vasovagal syncope patient with third-degree atrioventricular block caused by SCN5A gene mutation and literature review.

BACKGROUND: Vasovagal syncope (VVS) is common in children and significantly affects their quality of life. To our knowledge, this the first case report of SCN5A gene mutation associated with VVS and third-degree atrioventricular block (atrioventricular block, AVB), which could help pediatricians aware that VVS is not always a benign condition and help to identify VVS children at the risk of sudden death. CASE PRESENTATION: A twelve-year-old male child was admitted to Beijing Children's Hospital of Capital Medical University for chest tightness for 9 days and syncope in July 2018. The child was diagnosed as VVS with third-degree AVB after complete investagations. A heterozygous mutation in the exon coding region of the SCN5A gene, C. 5851G > T (coding region 5551 nucleotide changed from G to T), was detected in the peripheral blood of the child. Electrophysiological examination and modified vagal ganglion radiofrequency ablation were performed in the child. The ECG playback was normal on the second day after operation. Holter showed no abnormality and no chest tightness or syncope occurred after 3 months and 1 year follow-up. CONCLUSIONS: Our case report firstly reported that SCN5A mutation contributed to the pathogenesis of VVS with third-degree AVB. Vagal ganglion modified ablation have obtained good therapeutic effect. Gene analysis was of great value to the accurate diagnosis and treatment of VVS children.

POLYMORPHISMS IN ß-ADRENERGIC RECEPTORS ARE ASSOCIATED WITH INCREASED RISK TO HAVE A POSITIVE HEAD-UP TILT TABLE TEST IN PATIENTS WITH VASOVAGAL SYNCOPE.

BACKGROUND: Vasovagal syncope (VVS) is a frequent clinical condition in which a genetic background seems to be implicated. Considering that the adrenergic receptors (ARs) may play a role in VVS, the present study has as principal aim to determine if the α- and ß-AR (ADRA and ADRB) gene polymorphisms are associated with an increased risk to have a positive head-up tilt table (HUTT) test in patients with VVS. Methods: Nine polymorphisms in the ADRA1A (rs1048101, rs1383914, rs574584, and rs573542), ADRB1 (rs1801252 and rs1801253), ADRB2 (rs1042713 and rs1042714), and ADRB3 (rs4994) genes were analyzed using the 5' exonuclease TaqMan genotyping assay in a group of 134 patients with VVS. RESULTS: Under different models, the rs1801252 (OR = 8.63, 95% CI: 0.95-78.72, Precessive = 0.02), rs1042713 (OR = 1.94, 95% CI: 1.02-3.66, Padditive = 0.04), and rs4994 (OR = 2.46, 95% CI: 1.01-6.01, Pdominant = 0.042 and OR = 2.62, 95% CI: 1.04-6.63, Pover-dominant = 0.03) polymorphisms were associated with increased risk for a positive HUTT. All models were adjusted for statistically significant covariates. CONCLUSION: These results suggest that some polymorphisms of the ß-AR genes could contribute to a positive tilt test in patients with VVS.

Gene Polymorphism of the Adenosine A2a Receptor in Patients with Vasovagal Syncope.

BACKGROUND: Adenosine may play a role in the pathogenesis of vasovagal syncope (VVS). The aim of the study was to evaluate the adenosine A(2A) receptor gene 1083 T > C polymorphism in patients with syncope and its possible association with results of head-up tilt test (HUT). METHODS: Three hundred and forty-seven consecutive patients (mean age 47.3 ± 18.5 years, 132 men, 215 women) with one or more syncopal episodes underwent HUT as part of standardized diagnostic evaluation. HUT was positive in 207 patients (75 males, mean age 44.7 ± 18.6 years) and negative in 140 patients (58 males, mean age 48.17 ± 18.8 years). One thousand and eighty-three T > C single nucleotide polymorphism in the adenosine A(2A) receptor gene (rs5751876) was evaluated in 347 patients with syncope and in 85 subjects without history of syncope (54 men, mean age 41.7 ± 16.3). RESULTS: Adenosine A(2A) receptor 1083 T > C polymorphism was not associated with the positivity of HUT. Blood pressure and heart rate response to tilting was similar in all genotypes. Low frequency (LF) power was significantly lower in CC genotype compared to CT genotype in early phase of tilt (log LF 2.69 ± 0.61 vs 3.20 ± 0.60; P = 0.01) and at the time of syncope (log LF 2.60 ± 0.63 vs 2.77 ± 0.48; P = 0.04). CONCLUSIONS: Adenosine A(2A) receptor 1083 T > C polymorphism is not associated with the positivity of HUT and its proposed role in predisposition to VVS was not confirmed. CC genotype may be associated with lower sympathetic activity during HUT.

Genome-Wide Association Study of Copy Number Variations in Patients with Familial Neurocardiogenic Syncope.

Neurocardiogenic syncope (NCS) is the most frequent type of syncope characterized by a self-limited episode of systemic hypotension. In this study, we conducted the first genome-wide association study testing copy number variations for association with NCS. Study population consisted of 107 consecutive patients with recurrent syncope and positive head-up tilt table testing. Four families with NCS were selected for CNV analysis. Affymetrix GeneChip(®) SNP 6.0 array was used for CNV analysis. Data and statistical analysis were performed with Affymetrix genotyping console 4.0 and GraphPad Prism v6. Positive family history of NCS was present in 19.6 % (n = 21) in our study population (n = 107). Twenty-six CNV regions were found to be significantly altered in families with NCS (P < 0.05). Several CNVs were identified in families with NCS. Further studies comprising wider study population are required to determine the effect of these variations on NCS development.

Beta 3 subunit of G-protein and its influence on autonomic nervous system in patients with vasovagal syncope.

OBJECTIVES: The aim of this prospective study was to investigate the impact of genetic polymorphisms of ß3 subunit of G-protein on the occurrence of vasovagal syncope, hemodynamic parameters and heart rate variability during head-up tilt test (HUT). BACKGROUND: G-proteins play an important role in the intracellular transmission of impulses in cardiovascular autonomic reflexes. METHODS: In 157 patients with suspected vasovagal syncope HUT was performed. Ninety-one patients (38 men, 53 women, mean age 48 ± 17 years) had positive HUT. Control group consisted of 109 subjects (69 men, 40 women, mean age 37 ± 16 years) with no history of syncope. Results of HUT, hemodynamic parameters and LF, HF, LF/HF, SDNN, RMSSD parameters of heart rate variability were compared in patients with different genotypes. C825T polymorphism of ß3 subunit of G-protein was determined in the study subjects. RESULTS: There was no significant difference in the distribution of genotypes between patients and control group. Also, there was no significant difference in hemodynamic parameters. A statistically significant difference was found between genotypes in LF/HF in the early HUT (mean rank CC: 48.68 vs CT: 35.51 vs TT: 34.14; p = 0.039) and at RMSSD at the time of syncope (mean rank CC: 32.38 vs CT: 42.74 vs TT: 18.50; p = 0.026). CONCLUSIONS: In this study, the relation of C825T polymorphism of ß3 subunit of G-protein to vasovagal syncope was not documented (Tab. 2, Fig. 4, Ref. 37).

Alteration of gene expression profiling including GPR174 and GNG2 is associated with vasovagal syncope.

Vasovagal syncope (VVS) causes accidental harm for susceptible patients. However, pathophysiology of this disorder remains largely unknown. In an effort to understanding of molecular mechanism for VVS, genome-wide gene expression profiling analyses were performed on VVS patients at syncope state. A total of 66 Type 1 VVS child patients and the same number healthy controls were enrolled in this study. Peripheral blood RNAs were isolated from all subjects, of which 10 RNA samples were randomly selected from each groups for gene expression profile analysis using Gene ST 1.0 arrays (Affymetrix). The results revealed that 103 genes were differently expressed between the patients and controls. Significantly, two G-proteins related genes, GPR174 and GNG2 that have not been related to VVS were among the differently expressed genes. The microarray results were confirmed by qRT-PCR in all the tested individuals. Ingenuity pathway analysis and gene ontology annotation study showed that the differently expressed genes are associated with stress response and apoptosis, suggesting that the alteration of some gene expression including G-proteins related genes is associated with VVS. This study provides new insight into the molecular mechanism of VVS and would be helpful to further identify new molecular biomarkers for the disease.

Genetic variation in the parasympathetic signaling pathway in patients with reflex syncope.

Reflex syncope is defined by a self-terminating transient loss of consciousness associated with an exaggerated response of the vagal reflexes upon orthostatic challenges. A hereditary component has previously been suggested. We hypothesized that variations in genes encoding proteins mediating the vagal signaling in the heart may be involved in reflex syncope pathogenesis. We systematically resequenced the entire coding regions and flanking intron sequences in 5 genes in the cardiac post-synaptic parasympathetic signaling pathway [muscarinic acetylcholine receptor M2 (CHRM2); G-protein beta-1 subunit (GNB1); G-protein gamma-2 subunit (GNG2); potassium inwardly rectifying channel, subfamily J, member 3 (KCNJ3); and potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5)] in 74 patients with well-characterized reflex syncope of either cardioinhibitory [Vasovagal Syncope International Study (VASIS-IIB), N = 38] or vasodepressor (VASIS-III, N = 36) type. We identified 2 novel genetic variants (CHRM2 c.1114C>G and GNG2 c.87+34G>A) and several known variants (GNB1: c.267+14G>A, c.267+19C>T, and c.738C>T; KCNJ3: c.119A>G, c.591C>T, c.1038T>C, and c.1494T>C; KCNJ5: c. 171T>C, c.810T>G, c.834T>C, c.844C>G, c.938+7C>T, and c.938-10G>A). The minor allele frequency of the KCNJ5 c.938+7C>T variant was significantly lower in patients than in the control group (0.014 versus 0.089, P = 0.001), and the frequency of heterozygosity and homozygosity was lower in cardioinhibitory patients compared to controls. Genetic variations in genes responsible for the vagal signaling in the heart, including CHRM2, GNB1, GNG2, KCNJ3, and KCNJ5, are not major contributors to the pathogenesis of reflex syncope of vasodepressor or cardioinhibitory types.

KCNE3 T4A as the genetic basis of Brugada-pattern electrocardiogram.

BACKGROUND: Brugada syndrome (BrS) is genetically heterogeneous. In Japanese BrS patients, except for SCN5A and KCNE5, mutations in the responsible genes have not yet been identified, and therefore the genetic heterogeneity remains poorly elucidated. METHODS AND RESULTS: Forty consecutive patients with Brugada-pattern electrocardiogram (ECG) underwent comprehensive genetic analysis of BrS-causing genes including SCN5A, SCN1B, SCN3B, CACNA1C, CACNB2, KCNE3 and KCNE5. Besides identifying 8 SCN5A mutations in the present cohort, a KCNE3 T4A mutation was found in a 55-year-old male patient who had experienced several episodes of syncope. A head-up tilt test during passive tilt provoked both hypotension and bradycardia, followed by syncope. He was therefore diagnosed with neurally mediated syncope (NMS). To characterize the functional consequence of the mutant, electrophysiological experiments using whole-cell patch-clamp methods and computer simulations using human right ventricular wall model were carried out. It was found that KCNE3 T4A increased I(to) recapitulated by heterologously coexpressing Kv4.3+KChIP2b+KCNE3-wild type or KCNE3-T4A in CHO cells. CONCLUSIONS: A KCNE3 T4A mutation was identified in a Japanese patient presenting Brugada-pattern ECG and NMS. Its functional consequence was the gain of function of I(to), which could underlie the pathogenesis of Brugada-pattern ECG. The data provide novel insights into the genetic basis of Japanese BrS.

Familial predisposition to vasovagal syncope.

OBJECTIVE: A handful of studies suggest a familial predisposition to vasovagal syncope (WS) but the scope of information available to date is poor. The aim of our study was to evaluate the prevalence of vasovagal syncope and its familial occurrence in the young. METHODS AND RESULTS: The studied group consisted of 281 women and 111 men, aged 18-32 years. Forty-seven percent of the population had one brother or sister, and the mean number of individuals per family was 4.4 +/- 1.0. The questionnaire consisted of 30 questions regarding syncopal history. Syncope was reported in 32.1% of the patients studied (36.7% in women vs. 20.7% in men; P < 0.05), 29.1% of mothers, 16.8% of fathers, 30.9% of sisters and 14.2% of brothers. Logistic regression analysis revealed that positive history regarding the syncope in the whole group of students was related to the female gender (OR 2.17; CI: 1.28-3.7), the history of a syncope in mother (OR 1.74; CI: 1.09-2.78) and the history of a syncope in father (OR 2.22; CI: 1.28-3.86; P < 0.001). CONCLUSIONS: A positive history of syncope in male relatives increases the risk of syncope in men and women, whereas a positive history of syncope in female relatives increases the risk of syncope in women only. Female gender independently of the family history increases the risk of syncope. The genetics of the vasovagal syncope could be polygenic but the mechanisms of a transmission remain unclear to date.

[Postural orthostatic tachycardia syndrome (POTS): report of 15 cases]. / Taquicardia postural ortostática en 15 pacientes: disautonomía compleja.

BACKGROUND: Patients with postural orthostatic tachycardia syndrome (POTS) report dizziness, lightheadedness, weakness, blurred vision, and fatigue upon standing. The diagnosis of the syndrome is made when an orthostatic intolerance and tachycardia appear in the standing position. AIM: To report 15 patients with POTS. MATERIAL AND METHODS: Review of Tilt test reports in a period of 15 years. Those reports in which orthostatic postural tachycardia and symptoms compatible with POTS appeared, were selected for analysis. RESULTS: We identified 15 patients (3.1% of all positive Tilt test reports) with compatible signs and symptoms. There was a lag of 8 -10 years between the onset of symptoms and the time of diagnosis. Most patients complained of orthostatic intolerance, dizziness and frequent fainting. Orthostatic tachycardia and symptoms occurred on average after 2.9 and 6.1 minutes, respectively,of staying in the standing position. These patients had a high frequency of family history of syncope orpresyncope (66% frequency) and hyper mobility syndrome (53% prevalence). Only 33% of the patients reported relief of their symptoms after being treated (most of them with fludrocortisone). Most patients that reported little or no relief, did not use medications or were treated for a short period. CONCLUSIONS: POTS syndrome is uncommon but disturbs quality of life of those who suffer it. Its association with hyper mobility syndromes must be investigated.

Vasovagal Syncope Is Associated with Variants in Genes Involved in Neurohumoral Signaling Pathways.

Vasovagal syncope (VVS) is the most common cause of sudden loss of consciousness. VVS results from cerebral hypoperfusion, due to abnormal autonomic control of blood circulation, leading to arterial hypotension. It is a complex disease, and its development is largely associated with genetic susceptibility. Since abnormal neurohumoral regulation plays an important role in VVS development, we analyzed the association of VVS with polymorphic variants of ADRA1A, ADRB1, HTR1A, ADORA2A, COMT, and NOS3 genes, the products of which are involved in neurohumoral signaling, in patients with a confirmed VVS diagnosis (157 subjects) and individuals without a history of syncope (161 subjects). We were able to identify the associations between VVS and alleles/genotypes ADRA1A rs1048101, ADRB1 rs1801253, ADORA2A rs5751876, and COMT rs4680, as well as NOS3 rs2070744 in biallelic combination with COMT rs4680. Thus, we are the first to observe, within a single study, the role of the genes that encode α- and ß-adrenergic receptors, catechol-O-methyltransferase, adenosine receptors and nitric oxide synthase in VVS development. These findings demonstrate that the genes involved in neurohumoral signaling pathways contribute to the formation of a genetic susceptibility to VVS.

Association of polymorphisms in endothelin-1 and endothelin receptor a genes with vasovagal syncope.

The endothelin system may play a role in the pathogenesis of vasovagal syncope (VVS) because it is implicated in blood pressure regulation. We hypothesized that endothelin-related genetic polymorphisms might modulate susceptibility to VVS. This study aimed to evaluate the possible influence of endothelin-1 (EDN1) and endothelin receptor A (EDNRA) gene variants on the occurrence of tilt-induced VVS and autonomic nervous system activity during the head-up tilt test (HUT). Results were expressed as mean +/- SEM. In 254 patients with recurrent syncope (age 45.33+/-1.22 years, 94 males, 160 females), heart rate variability (HRV) was measured during HUT. EDN1 rs5370 G>T and EDNRA rs5333 T>C gene polymorphisms were assessed using high-resolution melting analysis. There was no statistically significant association between polymorphisms EDN1 rs5370 and EDNRA rs5333 and positivity of HUT or hemodynamic types of VVS. Patients with GT or TT genotypes at the rs5370 locus of the EDN1 had significantly higher values of high-frequency (HF) and the standard deviation of the average NN intervals at the time of the syncope, and they tended to have lower low-frequency (LF) and LF/HF ratio when compared to homozygotes (GG). No statistically significant differences were found in HRV parameters concerning the EDNRA rs5333 genotypes. Our findings suggest the potential role of EDN1 rs5370 variants in regulating autonomic nervous activity and pathogenesis of VVS.

Genetic variation in gsα protein as a new indicator in screening test for vasovagal syncope.

BACKGROUND: A quantitative history using Calgary syncope syndrome score (CSSS) is able to define the likely cause of syncope, but there is still a lack of diagnostic screening tests for vasovagal syncope (VVS). The aim of the present study was to develop a screening test for VVS on the basis of CSSS and the relationship between polymorphic variants of the G-system signaling protein genes and tilting results. METHODS AND RESULTS: From 730 syncopal patients, 307 consecutive subjects without structural and electrical abnormalities were genotyped and examined on blood pressure (BP) and tilt testing. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism in genes encoding Gsα-protein GNAS1 (rs7121), G-protein ß 3 subunit (rs5443) and the cardiac regulator of G-protein signaling RGS2 (rs4606). The control group consisted of 100 healthy volunteers with a negative history of syncope. From multivariate regression analysis, being a carrier of 393T GNAS1 (odds ratio [OR], 2.29) and systolic BP (OR, 0.98) remained as independent factors associated with positive tilt results. The resultant screening test for VVS consisted of the following: carrier of 393T GNAS1; systolic BP < 131 mm Hg (from the receiver operating characteristic [ROC] curve); and CSSS ≥-2. Using ROC curve analysis for systolic BP and CSSS, 2 final models for the screening test were constructed: highest sensitivity (89%) and highest specificity (99%). CONCLUSIONS: The novel screening test including the variation of Gsα protein gene seems to be helpful to identify tilt-induced vasovagal patients.

Genetic markers of vasovagal syncope.

Vasovagal syncope may have a genetic predisposition. It has a high prevalence in some families, and children of a fainting parent are more likely to faint than those without a parent who faints. Having two fainting parents or a fainting twin increases the likelihood even further. Several genotypes appear to associate with the phenotype of positive tilt tests, but the control subjects are usually those who faint and have negative tilt tests. Twin studies, highly focused genome-wide association studies, and copy number variation studies all suggest there are loci in the genome that associate with vasovagal syncope, although the specific genes, pathways, and proteins are unknown. A recent multigenerational kindred candidate gene study identified 3 genes that associate with vasovagal syncope. The best evidence to date is for central signaling genes involving serotonin and dopamine. Genome-wide association studies to date have not yet been helpful. Our understanding of the genetic correlates of vasovagal syncope leaves ample opportunity for future work.

Vasovagal syncope: state or trait?

PURPOSE OF REVIEW: The absence of a satisfactory comprehensive theory for vasovagal syncope has prompted attention towards a possible genetic origin. There are several features of this trait that suggest a genetic origin. The purposes of this review are to present a rationale for considering a genetic origin and critically summarize recent findings. RECENT FINDINGS: Key characteristics that suggest a genetic origin are incomplete effect in the population, a persistent clinical phenotype, and the absence of obvious infectious or autoimmune causes. There are familial pedigrees of vasovagal syncope, and statistical analyses of the impact of family history on the likelihood of an individual fainting that suggest an autosomal dominant transmission with incomplete penetrance. There is also evidence of sex-specific penetrance. Early candidate gene studies point towards involvement of sympathetic signal transduction in the physiologic cascade. SUMMARY: Several epidemiologic characteristics of vasovagal syncope suggest that it may have a genetic origin.

Genetic aspects of vasovagal syncope: a systematic review of current evidence.

Knowledge on the aetiology of vasovagal syncope (VVS) is of great importance to optimize its diagnostic and therapeutic options. To unravel the largely unknown pathophysiology, studies on genetic aspects of VVS can be of use. This systematic review on all available literature aims to provide an overview of the current knowledge of VVS genetics. The MEDLINE and EMBASE database were systematically searched for all studies discussing genetic factors as a cause of VVS. Hereditary aspects of VVS were studied in 19 studies. Six studies determined a positive family history in, respectively, 19-90% of the VVS patients. These numbers, however, are not higher than the cumulative incidence of VVS in the general population (35-39%). Four studies examined potential genetic polymorphisms associated with VVS. Only a Gly389 allele was more frequently present in VVS patients with a positive HUT test, although the significance level was set much higher than usual in genetic studies, and this result has not been replicated so far. Knowledge on genetic aspects of VVS could be very useful in clinical practice and research, but the current evidence that it has a genetic basis is not very strong.