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Adrenergic polymorphism and the human stress response.

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.

journal_name

Ann N Y Acad Sci

journal_title

Annals of the New York Academy of Sciences

authors

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

doi

10.1196/annals.1410.085

subject

Has Abstract

pub_date

2008-12-01 00:00:00

pages

282-96

eissn

0077-8923

issn

1749-6632

pii

NYAS1148085

journal_volume

1148

pub_type

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Adrenergic polymorphism and the human stress response.