Adrenergic polymorphism and the human stress response

Fangwen Rao, Lian Zhang, Jennifer Wessel, Kuixing Zhang, Gen Wen, Brian P. Kennedy, Brinda K. Rana, Madhusudan Das, Juan L. Rodriguez-Flores, Douglas W. Smith, Peter E. Cadman, Rany M. Salem, Sushil K. Mahata, Nicholas J. Schork, Laurent Taupenot, Michael G. Ziegler, Daniel T. O'Connor

Research output: Chapter in Book/Report/Conference proceedingConference contribution

10 Citations (Scopus)

Abstract

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Does common genetic variation at human TH alter autonomic activity and predispose to cardiovascular disease? We undertook systematic polymorphism discovery at the TH locus, and then tested variants for contributions to sympathetic function and blood pressure. We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production and environmental (cold) stress responses. To evaluate hypertension, we genotyped subjects selected from the most extreme diastolic blood pressure percentiles in the population. Human TH promoter haplotype/reporter plasmids were transfected into chromaffin cells. Forty-nine single nucleotide polymorphisms (SNPs) and one tetranucleotide repeat were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned four common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable, as were stress-induced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine excretion, as well as blood pressure response to stress. TH promoter haplotype #2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. In hypertension, a case-control study (1266 subjects, 53% women) established the effect of C-824T in determination of blood pressure. We conclude that human catecholamine secretory traits are heritable, displaying joint genetic determination (pleiotropy) with autonomic activity and finally with blood pressure in the population. Catecholamine secretion is influenced by genetic variation in the adrenergic pathway encoding catecholamine synthesis, especially at the classically rate-limiting step, TH. The results suggest novel pathophysiological links between a key adrenergic locus, catecholamine metabolism, and blood pressure, and suggest new strategies to approach the mechanism, diagnosis, and treatment of systemic hypertension.

Original languageEnglish (US)
Title of host publicationAnnals of the New York Academy of Sciences
Pages282-296
Number of pages15
Volume1148
DOIs
StatePublished - Dec 2008
Externally publishedYes

Publication series

NameAnnals of the New York Academy of Sciences
Volume1148
ISSN (Print)00778923
ISSN (Electronic)17496632

Fingerprint

Blood pressure
Tyrosine 3-Monooxygenase
Polymorphism
Adrenergic Agents
Catecholamines
Blood Pressure
Hypertension
Haplotypes
Cold-Shock Response
Genetic Pleiotropy
Blood Pressure Determination
Chromaffin Cells
Biosynthesis
Linkage Disequilibrium
Metabolism
Microsatellite Repeats
Population
Single Nucleotide Polymorphism
Case-Control Studies
Norepinephrine

Keywords

  • (TCAT) polymorphism in the first TH intron
  • Blood pressure
  • Cold pressor test
  • Heart rate
  • Tyrosine hydroxylase

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Rao, F., Zhang, L., Wessel, J., Zhang, K., Wen, G., Kennedy, B. P., ... O'Connor, D. T. (2008). Adrenergic polymorphism and the human stress response. In Annals of the New York Academy of Sciences (Vol. 1148, pp. 282-296). (Annals of the New York Academy of Sciences; Vol. 1148). https://doi.org/10.1196/annals.1410.085

Adrenergic polymorphism and the human stress response. / Rao, Fangwen; Zhang, Lian; Wessel, Jennifer; Zhang, Kuixing; Wen, Gen; Kennedy, Brian P.; Rana, Brinda K.; Das, Madhusudan; Rodriguez-Flores, Juan L.; Smith, Douglas W.; Cadman, Peter E.; Salem, Rany M.; Mahata, Sushil K.; Schork, Nicholas J.; Taupenot, Laurent; Ziegler, Michael G.; O'Connor, Daniel T.

Annals of the New York Academy of Sciences. Vol. 1148 2008. p. 282-296 (Annals of the New York Academy of Sciences; Vol. 1148).

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Rao, F, Zhang, L, Wessel, J, Zhang, K, Wen, G, Kennedy, BP, Rana, BK, Das, M, Rodriguez-Flores, JL, Smith, DW, Cadman, PE, Salem, RM, Mahata, SK, Schork, NJ, Taupenot, L, Ziegler, MG & O'Connor, DT 2008, Adrenergic polymorphism and the human stress response. in Annals of the New York Academy of Sciences. vol. 1148, Annals of the New York Academy of Sciences, vol. 1148, pp. 282-296. https://doi.org/10.1196/annals.1410.085
Rao F, Zhang L, Wessel J, Zhang K, Wen G, Kennedy BP et al. Adrenergic polymorphism and the human stress response. In Annals of the New York Academy of Sciences. Vol. 1148. 2008. p. 282-296. (Annals of the New York Academy of Sciences). https://doi.org/10.1196/annals.1410.085
Rao, Fangwen ; Zhang, Lian ; Wessel, Jennifer ; Zhang, Kuixing ; Wen, Gen ; Kennedy, Brian P. ; Rana, Brinda K. ; Das, Madhusudan ; Rodriguez-Flores, Juan L. ; Smith, Douglas W. ; Cadman, Peter E. ; Salem, Rany M. ; Mahata, Sushil K. ; Schork, Nicholas J. ; Taupenot, Laurent ; Ziegler, Michael G. ; O'Connor, Daniel T. / Adrenergic polymorphism and the human stress response. Annals of the New York Academy of Sciences. Vol. 1148 2008. pp. 282-296 (Annals of the New York Academy of Sciences).
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