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

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

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 1

Polymorphism at GCH1: distribution across the gene.

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Polymorphism at GCH1: distribution across the gene. (A) ...
(A) Local genomic region. GCH1 resequencing strategy and identified variants. Sequences conserved between mouse and human GCH1 were visualized with VISTA (http://genome.lbl.gov/vista/index.shtml). Location of common (upper) and rare (lower) SNPs relative to exons and conserved noncoding sequences is indicated by position. Red lines represent nonsynonymous SNPs, while black rods represent synonymous SNPs. Nucleotides in red in the chimpanzee haplotype indicate the minor allele in the human sequence. Computationally reconstructed haplotypes are indicated, along with their relative frequencies in ethnogeographic groups within our sample population. Nucleotide deletions in haplotype sequences are indicated by an asterisk. n = 42 variants were discovered; n = 13 were common (≥5%), while n = 29 were rare (<5%). (B) Functional domains and coding region SNPs. The distribution of variants across GCH1 exons and functional protein domains is illustrated. ATG, translational start codon; Cap, transcriptional initiation site; ORF, open reading frame.