We found no significant differences for any measured parameter according to the eNOS, 5-HTR2A and the 5-HTT polymorphisms, although there was a higher allelic frequency of the 5-HTT long variant in IPAH than in CTEPH and controls.
Compared with the short (S) allele, the long (L) SERT promoter allele is associated with increased SERT transcription and more severe pulmonary hypertension in a cohort of patients with chronic obstructive pulmonary disease, and was more prevalent in a cohort with idiopathic pulmonary arterial hypertension (IPAH), compared with control subjects.
One intrinsic abnormality of pulmonary artery smooth muscle cells (PA-SMCs) in human idiopathic pulmonary hypertension (iPH) is an exaggerated proliferative response to internalized serotonin (5-HT) caused by increased expression of the 5-HT transporter (5-HTT).
We found that homozygosity for the long variant of 5HTT was highly associated with idiopathic pulmonary hypertension in children, suggesting perhaps a more important role for 5HTT gene function in the pathogenesis of early onset disease.
Among these, the finding of an association between PPH and the L-allelic variant of the serotonin transporter (5-HTT) gene indicates that 5-HTT, which controls smooth muscle hyperplasia, probably contributes to susceptibility to PPH or is an important modifier of the PPH phenotype.
We conclude that 5-HTT activity plays a key role in the pathogenesis of PA-SMC proliferation in PPH and that a 5HTT polymorphism confers susceptibility to PPH.