Functional allelic heterogeneity and pleiotropy of a repeat polymorphism in tyrosine hydroxylase: Prediction of catecholamines and response to stress in twins

Abstract

Tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, has a common repeat polymorphism, (TCAT)n. We asked whether variation at TH influenced the autonomic stress responses in a human twin study design. Autonomic traits displayed substantial heritability (h2), up to h2=56.8±7.5% (p<0.0001) for norepinephrine secretion, and h2=61±6% (p<0.001) for heart rate. Common (TCAT)n alleles, particularly (TCAT)6 and (TCAT)10i, influenced such traits (including catecholamine secretion, as well as basal and post-stress heart rate) in allele copy number dose-dependent fashion, though in directionally opposite ways, indicating functional allelic heterogeneity. Multivariate ANOVA documented genetic pleiotropy: joint effects of the (TCAT)10i allele to influence both biochemical (norepinephrine) and physiological (heart rate) traits. (TCAT)6 allele frequencies were lower in normotensive twins at genetic risk of hypertension, consistent with an effect to protect against later development of hypertension, and suggesting that the traits predicted by these variants in still-normotensive subjects are early, heritable, “intermediate phenotypes” in the pathogenetic scheme for later development of sustained hypertension. We conclude that common allelic variation within the TH locus exerts a heritable effect on autonomic control of the circulation, and that such variation may have implications in later development of cardiovascular disease. Clinical Pharmacology & Therapeutics (2005) 77, P6–P6; doi: 10.1016/j.clpt.2004.11.025