Abstract 757: Genetic Association of the Serotonin Transporter and the Bone Morphogenetic Protein Receptor-2 in Pulmonary Arterial Hypertension
Background: Mutations in the bone morphogenetic protein receptor-2 (BMPR-2) gene have been found in patients with pulmonary arterial hypertension (PAH). However, the low disease penetrance suggests that other factors are necessary to manifest the disease. Recently, the 5-HT transporter (5-HTT) polymorphism has been also reported to associate with PAH, although this association has recently been challenged. Compared with the short (S) allele, the long (L) 5-HTT promoter allele is known to associate with increased 5-HTT transcription and more prevalent in PAH compared with control subjects. To investigate whether 5-HTT gene polymorphism affect clinical condition in PAH patients, we examined 5-HTT polymorphism and BMPR-2 mutations in patients with idiopathic (IPAH) and connective tissue disease-associated PAH (CPAH).
Methods and Results: Mutations in the 13 exons from the BMPR-2 gene and L and S allelic variant of the 5-HTT gene promoter in 12 IPAH and 10 CPAH patients were determined. Clinical severity was evaluated by pulmonary arterial pressure (PAP) by Doppler echocardiography and plasma BNP level. Twenty-three subjects were served as control (LS genotype 4%, SS genotype 96%). Distribution of the LL, LS and SS genotypes were 0, 36 and 64% in PAH. There was no significant difference in the distribution of the genotypes between IPAH and CPAH. Moreover, there was no significant difference in systolic PAP and BNP with the LS and SS genotypes either in IPAH (PAP: 83.8 mmHg vs 81.3 mmHg, BNP: 176.6 pg/ml vs 324.2 pg/ml) or CPAH (PAP: 77.0 mmHg vs 67.5 mmHg, BNP: 245.2 pg/ml vs 308.5 pg/ml). Although BMPR-2 mutation was not detected in patients with CPAH, 50% patients presented BMPR-2 mutation in IPAH. The distribution of LS and SS genotypes in IPAH patients were 67% and 33% with BMPR-2 mutation and 17% and 83% without mutation.
Conclusion: These data suggests that 5-HTT regulatory region polymorphism does not associate with clinical severity of PAH. BMPR-2 mutation was found only in IPAH, and the patients with BMPR-2 mutation associate with the LS genotype with high frequency. There might be a possible relationship between the BMPR-2 mutation and the L allelic variant of the 5-HTT gene in the genetic determinant of disease susceptibility.