Abstract 247: The Association of the Serotonin Transporter Polymorphism LL-Genotype with Non-Syndromic Mitral Valve Prolapse Requiring Surgery at a Younger Age

Background: Non-syndromic mitral valve prolapse (MVP) is a highly prevalent heart valve disease that is treated surgically when indicated by clinical deterioration. Serotonin (5HT)-related valvulopathies have been reported; however, 5HT has not been shown to be directly associated with MVP. A polymorphism (5-HTTLPR), with a 44-base micro-insertion/deletion in the promoter of the 5HT transporter (SERT) gene, is present in all human populations studied. 5-HTTLPR, with designated long (L) or short (S) alleles, has been reported to have an impact on SERT expression in non-cardiac valve studies. We hypothesized that MVP surgical patients may have an altered distribution of 5-HTTLPR, resulting in SERT expression levels associated with an increased risk of disease progression. Methods: 201 MVP surgical patients were recruited under an IRB approved protocol; DNA extraction followed by genomic fragment analysis was performed to determine allelic frequencies. qRT-PCR of SERT and related genes was carried out on RNA extracted from available MVP tissue (N=64). A RT2 Profiler microarray study for 84 genes associated with human dopamine and 5HT signaling was also performed (N=44). Results: MVP surgical patients had an overall frequency of LL-32%, LS-50%, and SS-18%. The frequency of 5-HTTLPR-LL was significantly increased in males under 55 years of age (N=19/41, 47.6%) ( p=0.04 ) compared to the rest of the population. Interestingly, the LL patients had the lowest SERT expression levels per qRT-PCR compared to LS and SS. A similar expression pattern was also noted for another 5HT transporter, vesicular monamine transporter-2 (VMAT2), with the lowest expression in the LL specimens. Expression of 5HT receptors 2A and 2B were comparable between genotypes in the MVP samples analyzed. Similarly, microarray studies demonstrated tight regulation of 5HT-associated genes, but with LS/SS patients expressing >2-fold more SERT than LL. Conclusion: 5-HTTLPR-LL is associated with MVP surgery at a younger age in men, with relatively lower expression of both SERT and VMAT2, suggesting a reduced capacity for transporter processing of 5HT. The 5-HTTLPR-LL genotype may constitute a novel risk factor useful for identifying MVP patients more likely to have rapid disease progression.