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

Abstract

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 β-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.

Keywords: genetic polymorphism; genetic predisposition; signal transduction; syncope; vasovagal syncope.

Figure 1

Combinations of alleles, the carriage of which is associated with the risk of VVS: (A) predisposing combination COMT*G + NOS3*T and its alleles; (B) protective combination ADRA1A*A + ADORA2A*T and its alleles. Odds ratio values (dots) and confidence intervals of genetic variants (vertical segments) are presented graphically; p-values are denoted on the top. Black dots denote insignificant variants, red dots denote predisposing variants, and green dots denote protective variants.

Figure 2

ROC analysis of the effectiveness of the models performed for the identified genetic variants of individual risk of VVS and for a composite model. Efficacy of the classification of individuals using models based on the carriage of individual genetic markers (ADRA1A, ADRB1, ADORA2A, and COMT gene variants, circles) and a model allowing for carriage of variants in all four genes (composite genetic marker, triangles).