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

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

Research output: Contribution to journalArticle

69 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2658-2671
Number of pages14
JournalJournal of Clinical Investigation
Volume117
Issue number9
DOIs
StatePublished - Sep 4 2007

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk'. Together they form a unique fingerprint.

  • Cite this

    Zhang, L., Rao, F., Zhang, K., Khandrika, S., Das, M., Vaingankar, S. M., Bao, X., Rana, B. K., Smith, D. W., Wessel, J., Salem, R. M., Rodriguez-Flores, J. L., Mahata, S. K., Schork, N. J., Ziegler, M. G., & O'Connor, D. T. (2007). Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk. Journal of Clinical Investigation, 117(9), 2658-2671. https://doi.org/10.1172/JCI31093