A screen of candidate genes and influence of β₂-adrenergic receptor genotypes in postural tachycardia syndrome

Objective: To screen candidate genes, encoding β₂- adrenergic receptor (β₂AR), α_2C-adrenergic receptor (α_2CAR), norepinephrine transporter (NET), and mitochondrial complex I (COI), for common single nucleotide polymorphisms (SNPs) in patients with postural tachycardia syndrome (POTS); alterations could potentially cause or aggravate orthostatic tachycardia and to relate β₂AR SNPs, known to effect venomotor tone, to heart rate (HR) and blood pressure measurements during 10-min head-up tilt. Methods: (a) DNA extraction from leukocytes of 29 patients with POTS; (b) Denaturing high performance liquid chromatography analysis to screen for the 12-bp deletion (Del322-325) in α_2CAR and for the alanine to proline mutation at amino acid 457 (Ala457Pro) in NET; (c) Systematic direct sequence analysis to screen for SNPs in β₂AR, NET, and COI. Results: Three common polymorphisms were abundant in at least one allele in β₂AR resulting in a cysteine to arginine in the 5′ promoter region (72% of patients), an arginine to glycine at amino acid-16 (Gly16; 86%), and a glutamine to glutamic acid at amino acid-27 (Glu27; 66%), a frequency that was no different to the normal Caucasian population. Orthostatic HR was significantly greater in patients with Glu27. Diastolic blood pressure (DBP) was significantly lower in a subset of patients with Gly16 whose HR were ≥120 beats/min with head-up tilt. All patients did not show the Ala457Pro mutation of NET; all sequence variants detected in α_2CAR, NET, and COI were not considered causally related to POTS. Conclusions: Of the candidate genes screened, none harbored a SNP considered to be causally related to POTS. There was significant association of HR and DBP with SNPs of the gene encoding β₂AR; Gly16 or Glu27 could aggravate orthostatic tachycardia by excessive venous pooling.