Genetic Association of the Serotonin Transporter in Pulmonary Arterial Hypertension

Abstract

Variation of the serotonin transporter gene appears unlikely to confer significant susceptibility to pulmonary arterial hypertension. This study emphasizes the need for adequately powered cohorts for association analyses to identify not only genetic determinants of disease susceptibility but also inherited modifiers for disease development.

Serotonin Transporter Polymorphisms in Patients With Portopulmonary Hypertension

“…Subsequent attempts to replicate these findings in larger, geographically distinct cohorts of PAH patients were unsuccessful. 15,16 Similarly, although plasma serotonin levels were increased in PAH patients in older studies, 27,28 they were not increased in a more recent study that included patients with PPHTN. 29 Possible explanations for these discrepant findings include population differences between studies, the existence of additional causal genetic variants in SERT, pathogenetic contributions from redundant mechanisms with serotonin signaling pathways, or type I error.…”

“…13,14 However, attempts to replicate the initial association between the long allele and PAH were unsuccessful in distinct populations of IPAH and familial PAH. 15,16 No data are available regarding patients with the many different forms of PAH associated with other conditions, such as PPHTN.…”

Mediators and modulators of pulmonary arterial hypertension

“…In the first study, no significant correlation was detected between alleles of the 5-HTT gene and PH (69). In the second report, the long (LL) transporter genotype correlated with an earlier age at diagnosis of FPAH than the SL or short (SS) allele (148).…”

“…Signaling by these receptors is mediated by the Smad protein family, which upon phosphorylation by the activated receptors, carries the TGF-␤ signals from the cell membrane receptors to target genes (74 -76, 89, 123). Dysfunction of the BMPRII protein is thought to result in impaired control of cellular proliferation, a cardinal feature of PAH (69,70,131,150).…”

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

“…Variants of the gene that encode SERT have been identified. The LL genotype is associated with increased cellular expression of SERT and therefore increased 5-HT uptake, but this does not convey increased susceptibility to PAH, although PAH patients with the LL genotype may present earlier than those without (Machado, Koehler, & Glissmeyer, 2006;Willers et al, 2006). These reports aside, the prevailing view is that pharmacological manipulation of 5-HT remains a worthwhile therapeutic pursuit.…”