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

¹ Departments of Medicine, University of California at San Diego, San Diego, California
² Psychiatry, University of California at San Diego, San Diego, California
³ Pharmacology, University of California at San Diego, San Diego, California
⁴ Polymorphism Research Laboratory, University of California at San Diego, San Diego, California
⁵ Center for Molecular Genetics, University of California at San Diego, San Diego, California
⁶ Veterans Affairs San Diego Healthcare System, San Diego, California
⁷ Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California

Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, has a common tetranucleotide repeat polymorphism, (TCAT)_n. We asked whether variation at (TCAT)_n may influence the autonomic nervous system and its response to environmental stress. To understand the role of heredity in such traits, we turned to a human twin study design. Both biochemical and physiological 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, predicted such traits (including catecholamine secretion, as well as basal and poststress heart rate) in allele copy number dose-dependent fashion, although in directionally opposite ways, indicating functional allelic heterogeneity. (TCAT)_n diploid genotypes (e.g., [TCAT]₆/[TCAT]_10i) predicted the same physiological traits but with increased explanatory power for trait variation (in contrast to allele copy number). Multivariate ANOVA documented genetic pleiotropy: joint effects of the (TCAT)_10i allele on 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 tyrosine hydroxylase locus exerts a powerful, heritable effect on autonomic control of the circulation and that such variation may have implications in later development of cardiovascular disease traits such as hypertension.

microsatellite; cold pressor test; blood pressure; heart rate; hypertension

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