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Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk
Lian Zhang, … , Michael G. Ziegler, Daniel T. O’Connor
Lian Zhang, … , Michael G. Ziegler, Daniel T. O’Connor
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2658-2671. https://doi.org/10.1172/JCI31093.
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Research Article Genetics Article has an altmetric score of 3

Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk

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Abstract

GTP cyclohydrolase 1 (GCH1) is rate limiting in the provision of the cofactor tetrahydrobiopterin for biosynthesis of catecholamines and NO. We asked whether common genetic variation at GCH1 alters transmitter synthesis and predisposes to disease. Here we undertook a systematic search for polymorphisms in GCH1, then tested variants’ contributions to NO and catecholamine release as well as autonomic function in twin pairs. Renal NO and neopterin excretions were significantly heritable, as were baroreceptor coupling (heart rate response to BP fluctuation) and pulse interval (1/heart rate). Common GCH1 variant C+243T in the 3′-untranslated region (3′-UTRs) predicted NO excretion, as well as autonomic traits: baroreceptor coupling, maximum pulse interval, and pulse interval variability, though not catecholamine secretion. In individuals with the most extreme BP values in the population, C+243T affected both diastolic and systolic BP, principally in females. In functional studies, C+243T decreased reporter expression in transfected 3′-UTRs plasmids. We conclude that human NO secretion traits are heritable, displaying joint genetic determination with autonomic activity by functional polymorphism at GCH1. Our results document novel pathophysiological links between a key biosynthetic locus and NO metabolism and suggest new strategies for approaching the mechanism, diagnosis, and treatment of risk predictors for cardiovascular diseases such as hypertension.

Authors

Lian Zhang, Fangwen Rao, Kuixing Zhang, Srikrishna Khandrika, Madhusudan Das, Sucheta M. Vaingankar, Xuping Bao, Brinda K. Rana, Douglas W. Smith, Jennifer Wessel, Rany M. Salem, Juan L. Rodriguez-Flores, Sushil K. Mahata, Nicholas J. Schork, Michael G. Ziegler, Daniel T. O’Connor

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Figure 8

Intermediate phenotypes.

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Intermediate phenotypes.
In the “intermediate phenotype” schema, biochem...
In the “intermediate phenotype” schema, biochemical traits (such as NO production) are postulated to be determined earlier and more proximately by genotype (such as GCH1 3′-UTRs C+243T) than are physiological traits (such as heart rate variability and resting heart rate) and, ultimately, late-penetrance disease (such as cardiovascular disease, hypertension, or sudden death). Here the concept is illustrated by the findings at GCH1 in the current study: the GCH1 3′-UTRs variant C+243T initially alters NO production, subsequently influencing baroreceptor coupling and heart variability, later minimum resting heart rate, and finally basal BP in the population.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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