OBJECTIVE: The postural tachycardia syndrome (POTS) has multiple symptoms, chief 
among which are tachycardia, weakness, and recurrent blackouts while standing. 
Previous research has implicated dysfunction of the norepinephrine transporter. 
A coding mutation in the norepinephrine transporter gene (SLC6A2) sequence has 
been reported in 1 family kindred only. The goal of the present study was to 
further characterize the role and regulation of the SLC6A2 gene in POTS.
METHODS AND RESULTS: Sympathetic nervous system responses to head-up tilt were 
examined by combining norepinephrine plasma kinetics measurements and muscle 
sympathetic nerve activity recordings in patients with POTS compared with that 
in controls. The SLC6A2 gene sequence was investigated in leukocytes from POTS 
patients and healthy controls using single nucleotide polymorphisms genotyping, 
bisulphite sequencing, and chromatin immunoprecipitation assays for histone 
modifications and binding of the transcriptional regulatory complex, methyl-CpG 
binding protein 2. The expression of norepinephrine transporter was lower in 
POTS patients compared with healthy volunteers. In the absence of altered SLC6A2 
gene sequence or promoter methylation, this reduced expression was directly 
correlated with chromatin modifications.
CONCLUSIONS: We propose that chromatin-modifying events associated with SLC6A2 
gene suppression may constitute a mechanism of POTS.