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

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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.

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

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GTP Cyclohydrolase
Medical Genetics
Nitric Oxide
Catecholamines
Pressoreceptors
3' Untranslated Regions
Heart Rate
Neopterin
Plasmids
Cardiovascular Diseases
Joints
Hypertension
Kidney
Population

ASJC Scopus subject areas

  • Medicine(all)

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Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk. / Zhang, Lian; Rao, Fangwen; Zhang, Kuixing; Khandrika, Srikrishna; Das, Madhusudan; Vaingankar, Sucheta M.; Bao, Xuping; Rana, Brinda K.; Smith, Douglas W.; Wessel, Jennifer; Salem, Rany M.; Rodriguez-Flores, Juan L.; Mahata, Sushil K.; Schork, Nicholas J.; Ziegler, Michael G.; O'Connor, Daniel T.

In: Journal of Clinical Investigation, Vol. 117, No. 9, 04.09.2007, p. 2658-2671.

Research output: Contribution to journalArticle

Zhang, L, Rao, F, Zhang, K, Khandrika, S, Das, M, Vaingankar, SM, Bao, X, Rana, BK, Smith, DW, Wessel, J, Salem, RM, Rodriguez-Flores, JL, Mahata, SK, Schork, NJ, Ziegler, MG & O'Connor, DT 2007, 'Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk', Journal of Clinical Investigation, vol. 117, no. 9, pp. 2658-2671. https://doi.org/10.1172/JCI31093
Zhang, Lian ; Rao, Fangwen ; Zhang, Kuixing ; Khandrika, Srikrishna ; Das, Madhusudan ; Vaingankar, Sucheta M. ; Bao, Xuping ; Rana, Brinda K. ; Smith, Douglas W. ; Wessel, Jennifer ; Salem, Rany M. ; Rodriguez-Flores, Juan L. ; Mahata, Sushil K. ; Schork, Nicholas J. ; Ziegler, Michael G. ; O'Connor, Daniel T. / Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 9. pp. 2658-2671.
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AU - Khandrika, Srikrishna

AU - Das, Madhusudan

AU - Vaingankar, Sucheta M.

AU - Bao, Xuping

AU - Rana, Brinda K.

AU - Smith, Douglas W.

AU - Wessel, Jennifer

AU - Salem, Rany M.

AU - Rodriguez-Flores, Juan L.

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