Genetic Association Study in Multigenerational Kindreds With Vasovagal Syncope

Abstract

Background: Several studies suggest that vasovagal syncope has a genetic origin, but this is unclear. We assessed whether plausible gene variants associate with vasovagal syncope. Methods: We studied 160 subjects in 9 kindreds comprising 82 fainters and 78 controls. The diagnosis was ascertained with the Calgary Syncope Score. Common genetic variants were genotyped for 12 genes for vascular signaling, potassium channels, the HTR1A (serotonin 5-HT1A receptor), SLC6A4 (serotonin reuptake transporter), and COMT (catecholamine O-methyltransferase). Sex-specific associations between genotypes and phenotypes were tested. Results: In 9 out of 12 variants, there was no significant association between genotype and phenotype. However, the HTR1A (−1019) G alleles associated with syncope in males, but not in females ( P =0.005). CC and GG males had 9% versus 77% likelihoods of syncope. The SLC6A4 promoter L alleles associated with decreased syncope in males but increased in females ( P =0.059). The LL and SS males had 25% and 47% syncope likelihoods, whereas females had 75% and 50% syncope likelihoods. The COMT c.472 A alleles associated with decreased syncope in males but increased in females ( P =0.017). The GG and AA males had 50% and 15% syncope likelihoods, whereas females had 52% and 73% syncope likelihoods. Conclusions: There is a sex-dependent effect of alleles of serotonin signaling and vasovagal syncope, supporting the serotonin hypothesis of the physiology of vasovagal syncope.

The Search for the Genes of Vasovagal Syncope

“…However, the control population was syncope patients with negative tilt responses, not unaffected controls. Furthermore, neither we (18) nor others (25, 31) detected an association of the ADRB1 1165G>C alleles with the clinical vasovagal phenotype when compared with unaffected control subjects.…”

“…Most candidate gene studies of vasovagal syncope compared patients with positive tilt tests to those with negative tilt tests; in essence, a surrogate biomarker. We took a complementary approach by directly testing the association of 12 candidate gene alleles with clinical vasovagal syncope in 7 kindreds (18). The advantages of this approach are that we are studying clinical presentations and not surrogate markers, and kindred studies reduce the background variability in both genetic and environmental influences.…”

Understanding vasovagal syncope: a role for sex and gender

“…A recent genetic association study in VVS took a slightly different approach. Instead of just looking at the overall cohort of 160 participants, the investigators probed 12 distinct candidate genes by sex [8]. There was no significant association for nine of the 12 candidate genes.…”

Syncope in Malaysian populations

“…Twin studies and small genome-wide association studies hint at genetic loci [8]. Candidate gene studies have identified adrenergic signalling pathways that correlate with tilt test outcomes, and a study [9] of seven kindreds identified three candidate genes associated with serotonin and dopamine signalling. Studies of vasovagal syncope, however, have focused on European heritage populations, either in Europe [10][11][12][13] or the Americas [6,9,[14][15][16].…”

“…Finally, are the same alleles associated with clinical vasovagal syncope in all the Malaysian populations as in European-Canadians? This is critical, because these three genes-the serotonin transporter, the serotonin 1A receptor, and catecholamine O-methyltransferase-have different effects on syncope likelihood in men and women [9]. Tan et al [4] carefully documented the incidence of syncope in several populations many thousands of years apart, and in doing so lay the groundwork for fundamentally important work in the future.…”