Published ahead of print on December 9, 2005, doi:10.1164/rccm.200509-1361OC Am. J. Respir. Crit. Care Med., Volume 173, Number 7, April 2006, 798-802 A more recent version of this article appeared on April 1, 2006
Submitted on September 1, 2005 Serotonin Transporter Polymorphisms in Familial and Idiopathic Pulmonary Arterial HypertensionElisabeth D Willers1*,1 Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA, 2 Department of Pediatrics, Division of Genetics, Vanderbilt University School of Medicine, Nashville, TN, USA, 3 Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI, USA, 4 Hopital Antoine Beclere, Universite Paris-Sud, Clamart, France, 5 Columbia University College of Physicians and Surgeons, New York, NY, USA * To whom correspondence should be addressed. E-mail: elisabeth.willers{at}vanderbilt.edu.
Rationale: Serotonin is a pulmonary vasoconstrictor and smooth muscle cell mitogen. The serotonin transporter (SERT) is abundant in pulmonary vascular smooth muscle. Compared to the short (S) allele, the long (L) SERT promoter allele is associated with increased SERT transcription, more severe pulmonary hypertension in a cohort of chronic obstructive pulmonary disease patients, and was more prevalent in a cohort with idiopathic pulmonary arterial hypertension (IPAH), compared to controls. Objective: We hypothesized that the SERT L allele would associate with an earlier age at diagnosis and/or shorter survival interval in pulmonary arterial hypertension (PAH) than the S allele. Methods: SERT promoters from 166 familial PAH (FPAH), 83 IPAH, and 125 control subjects were sequenced. 127 of the FPAH patients had a known mutation in bone morphogenetic protein receptor 2 (BMPR2). Results: The mean age at diagnosis was 35.8 years in FPAH and 41.1 in IPAH (p=0.02). There were no significant differences in distribution of the LL, LS, or SS genotypes in IPAH, FPAH, or unaffected BMPR2 mutation carriers. In FPAH, the LL genotype was associated with an earlier age at diagnosis (p<0.02). Conclusions: In IPAH, these SERT genotypes do not correlate with age at diagnosis or survival interval. In FPAH, the LL genotype correlates with an earlier age at diagnosis than SL or SS, although survival among the groups was similar. The correlation of SERT promoter polymorphism with age at diagnosis in FPAH suggests a possible relationship between the SERT and BMPR2. Key words: PPH, IPAH, FPAH, SERT, 5-HTT
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