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

Lian Zhang, Fangwen Rao, Jennifer Wessel, Brian P. Kennedy, Brinda K. Rana, Laurent Taupenot, Elizabeth O. Lillie, Myles Cockburn, Nicholas J. Schork, Michael G. Ziegler, Daniel T. O'Connor

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

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 post-stress 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). Multi-variate 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.

Original languageEnglish (US)
Pages (from-to)277-291
Number of pages15
JournalPhysiological Genomics
Volume19
DOIs
StatePublished - Jan 1 2005
Externally publishedYes

Keywords

  • Blood pressure
  • Cold pressor test
  • Heart rate
  • Hypertension
  • Microsatellite

ASJC Scopus subject areas

  • Physiology
  • Genetics

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    Zhang, L., Rao, F., Wessel, J., Kennedy, B. P., Rana, B. K., Taupenot, L., Lillie, E. O., Cockburn, M., Schork, N. J., Ziegler, M. G., & O'Connor, D. T. (2005). Functional allelic heterogeneity and pleiotropy of a repeat polymorphism in tyrosine hydroxylase: Prediction of catecholamines and response to stress in twins. Physiological Genomics, 19, 277-291. https://doi.org/10.1152/physiolgenomics.00151.2004