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(Circulation. 2007;116:993-1006.)
© 2007 American Heart Association, Inc.

Genetics

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, MM^*; Lian Zhang, MD^*; Jennifer Wessel, PhD; Kuixing Zhang, MD, PhD; Gen Wen, MD, PhD; Brian P. Kennedy, PhD; Brinda K. Rana, PhD; Madhusudan Das, PhD; Juan L. Rodriguez-Flores, MS; Douglas W. Smith, PhD; Peter E. Cadman, MD; Rany M. Salem, MPH; Sushil K. Mahata, PhD; Nicholas J. Schork, PhD; Laurent Taupenot, PhD; Michael G. Ziegler, MD; Daniel T. O’Connor, MD

From the Departments of Medicine (F.R., L.Z., K.Z., G.W., B.P.K., M.D., J.L.R.-F., P.E.C., R.M.S., S.K.M., L.T., M.G.Z., D.T.O.), Pharmacology (D.T.O.), Psychiatry (J.W., B.K.R., N.J.R.), and Biology (D.W.S.) and the Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, and the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif.

Correspondence to Daniel T. O’Connor, MD, Michael G. Ziegler, MD, or Laurent Taupenot, PhD, Department of Medicine and CHGG, UCSD School of Medicine, 9500 Gilman Dr, La Jolla, CA 92093–0838. E-mail doconnor{at}ucsd.edu, mziegler@ucsd.edu, or ltaupenot@ucsd.edu

Received January 18, 2007; accepted May 8, 2007.

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 (h²), 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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