Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis: Discovery of common human genetic variants governing transcription, autonomic activity, and blood pressure in vivo

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: Contribution to journalArticle

71 Citations (Scopus)

Abstract

BACKGROUND - 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. METHODS AND RESULTS - We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production, reflex control of the circulation, 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 were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned 4 common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable (h), as were stress-induced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine excretion and for blood pressure response to stress. TH promoter haplotype 2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. Coalescent simulations suggest that TH haplotype 2 likely arose ≈380 000 years ago. In hypertension, 2 independent case-control studies (1266 subjects with 53% women and 927 subjects with 24% women) replicated the effect of C-824T in the determination of blood pressure. CONCLUSIONS - 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)
Pages (from-to)993-1006
Number of pages14
JournalCirculation
Volume116
Issue number9
DOIs
StatePublished - Aug 2007
Externally publishedYes

Fingerprint

Medical Genetics
Tyrosine 3-Monooxygenase
Catecholamines
Blood Pressure
Enzymes
Haplotypes
Hypertension
Adrenergic Agents
Cold-Shock Response
Genetic Pleiotropy
Blood Pressure Determination
Chromaffin Cells
Linkage Disequilibrium
Population
Single Nucleotide Polymorphism
Reflex
Case-Control Studies
Norepinephrine
Plasmids
Cardiovascular Diseases

Keywords

  • Catecholamines
  • Genetics
  • Nervous system, autonomic
  • Nervous system, sympathetic
  • Norepinephrine

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis : Discovery of common human genetic variants governing transcription, autonomic activity, and blood pressure in vivo. / 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.

In: Circulation, Vol. 116, No. 9, 08.2007, p. 993-1006.

Research output: Contribution to journalArticle

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 2007, 'Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis: Discovery of common human genetic variants governing transcription, autonomic activity, and blood pressure in vivo', Circulation, vol. 116, no. 9, pp. 993-1006. https://doi.org/10.1161/CIRCULATIONAHA.106.682302
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. / Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis : Discovery of common human genetic variants governing transcription, autonomic activity, and blood pressure in vivo. In: Circulation. 2007 ; Vol. 116, No. 9. pp. 993-1006.
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abstract = "BACKGROUND - 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. METHODS AND RESULTS - We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production, reflex control of the circulation, 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 were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned 4 common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable (h), as were stress-induced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine excretion and for blood pressure response to stress. TH promoter haplotype 2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. Coalescent simulations suggest that TH haplotype 2 likely arose ≈380 000 years ago. In hypertension, 2 independent case-control studies (1266 subjects with 53{\%} women and 927 subjects with 24{\%} women) replicated the effect of C-824T in the determination of blood pressure. CONCLUSIONS - 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.",
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T1 - Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis

T2 - Discovery of common human genetic variants governing transcription, autonomic activity, and blood pressure in vivo

AU - Rao, Fangwen

AU - Zhang, Lian

AU - Wessel, Jennifer

AU - Zhang, Kuixing

AU - Wen, Gen

AU - Kennedy, Brian P.

AU - Rana, Brinda K.

AU - Das, Madhusudan

AU - Rodriguez-Flores, Juan L.

AU - Smith, Douglas W.

AU - Cadman, Peter E.

AU - Salem, Rany M.

AU - Mahata, Sushil K.

AU - Schork, Nicholas J.

AU - Taupenot, Laurent

AU - Ziegler, Michael G.

AU - O'Connor, Daniel T.

PY - 2007/8

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N2 - BACKGROUND - 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. METHODS AND RESULTS - We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production, reflex control of the circulation, 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 were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned 4 common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable (h), as were stress-induced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine excretion and for blood pressure response to stress. TH promoter haplotype 2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. Coalescent simulations suggest that TH haplotype 2 likely arose ≈380 000 years ago. In hypertension, 2 independent case-control studies (1266 subjects with 53% women and 927 subjects with 24% women) replicated the effect of C-824T in the determination of blood pressure. CONCLUSIONS - 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.

AB - BACKGROUND - 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. METHODS AND RESULTS - We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production, reflex control of the circulation, 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 were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned 4 common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable (h), as were stress-induced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine excretion and for blood pressure response to stress. TH promoter haplotype 2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. Coalescent simulations suggest that TH haplotype 2 likely arose ≈380 000 years ago. In hypertension, 2 independent case-control studies (1266 subjects with 53% women and 927 subjects with 24% women) replicated the effect of C-824T in the determination of blood pressure. CONCLUSIONS - 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.

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KW - Genetics

KW - Nervous system, autonomic

KW - Nervous system, sympathetic

KW - Norepinephrine

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