title: 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.
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California 92093-0838, USA. frao@ucsd.edu
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.forename: Lian
authors.initials: L
authors.lastname: Zhang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wessel
authors.forename: Kuixing
authors.initials: K
authors.lastname: Zhang
authors.forename: Gen
authors.initials: G
authors.lastname: Wen
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kennedy
authors.forename: Brinda K
authors.initials: BK
authors.lastname: Rana
authors.forename: Madhusudan
authors.initials: M
authors.lastname: Das
authors.forename: Juan L
authors.initials: JL
authors.lastname: Rodriguez-Flores
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Smith
authors.forename: Peter E
authors.initials: PE
authors.lastname: Cadman
authors.forename: Rany M
authors.initials: RM
authors.lastname: Salem
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Laurent
authors.initials: L
authors.lastname: Taupenot
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ziegler
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology; D001794:Blood Pressure / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics*; D002395:Catecholamines / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology; D015810:Linkage Disequilibrium; D008875:Middle Aged; D016716:PC12 Cells; D010829:Physiological Phenomena / Q000235:genetics; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D051381:Rats; D013315:Stress, Psychological; D014427:Twins / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D002395:Catecholamines; D014446:Tyrosine 3-Monooxygenase