Functional adrenergic receptor polymorphisms and idiopathic orthostatic intolerance

Objectives: Idiopathic orthostatic intolerance (IOI) is a common disorder that is characterized by chronic orthostatic symptoms and substantial increases in heart rate and plasma norepinephrine concentrations that are disproportionately high while standing. Several features of the syndrome, including the tachycardia, tremulousness, and exaggerated norepinephrine have been considered potentially due to hypoactive or hyperactive states of adrenergic receptors of the sympathetic nervous system. The aim of this study was therefore to ascertain whether genotypes at eight polymorphic loci within five relevant adrenergic receptor genes (α_2A, α_2B, α_2C, β₁ and β₂) influence the risk for IOI. Methods: We studied 80 young men in military service (20 patients with IOI and 60 age-matched controls). All participants underwent a tilt table test including monitoring of blood pressure, heart rate and plasma catecholamines, in the supine position and during 30 min of standing. Genotyping at the eight loci (α_2ALys251, α_2BDel301-303, α_2CDel322-325, β₁Gly49, β₁Arg389, β₂Arg16, β₂Glu27, β₂Ile164) was performed in all participants. Chi-square tests of independence were used to test for associations between IOI and genotype. In addition, an association of the polymorphisms with haemodynamic variables (heart rate, supine and upright blood pressure) was ascertained using one-way variance analysis. Results: For the β₁Gly49 polymorphism we found a decrease in the risk of IOI among persons who were homozygous (odds ratio, 0.88; 95% confidence interval, 0.81–0.97). In addition, we found an association between β₁Gly49 and decreased heart rate in the upright position, regardless of IOI diagnosis. There were no associations with the other studied polymorphisms and IOI. Conclusions: Our current results suggest that the β₁Gly49 polymorphism is protective for IOI. This is likely one of several common genetic loci that may represent modifiers of IOI phenotypes.