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.

Exploring epistatic relationships of NO biosynthesis pathway genes in susceptibility to CHD

“…The C+640T polymorphism in the 3'-UTR of the p22 phox gene might modulate the activity and regulation of the NADH/NADPH oxidase, which may lead to a decrease in oxidative stress in the vasculature. Likewise, the common polymorphism G+243A in the 3'-UTR of GCH1 has been shown to predict NO excretion [27] . We also detected two-way SNP-SNP interactions among these candidate genes: iNOS Leu608Ser (rs2297518) with either CYBA C+640T (rs1049255) or GCH1 G+243A (rs841).…”

“…With regard to the regulation of the NO biosynthesis pathway, we selected seven single-nucleotide polymorphisms (SNPs) based on previous evidence of potential functionality, validated allele frequency, and sequence-proven allelic variation: Leu608Ser (rs2297518) in iNOS [18,19] , G-84A (rs41279104) in the promoter region of nNOS [20] , Glu298Asp (rs1799983) and T-786C (rs2020744) in the promoter region of eNOS [9-11, 21, 22] , Tyr72His (rs4673) and C+640T (rs1049255) in the 3'-untranslated region (UTR) of the cytochrome b-245, alpha polypeptide gene (CYBA) [23][24][25][26] , which encodes the p22 phox subunit of the NADPH oxidase, and G+243A (rs841) in the 3'-UTR of the GTP cyclohydrolase 1 gene (GCH1) [27] .…”

Polymorphisms of genes in nitric oxide-forming pathway associated with ischemic stroke in Chinese Han population

“…Low brain levels of BH4 have been shown in the mouse model for dominantly inherited GCH1 deficiency [29] . Recent evidence suggests that one SNP (rs841), located in the 3'-UTR of the GCH1 gene, is also associated with reduced biopterin-dependent effects [17] . The CYBA gene, located on the long arm of chromosome 16 at position 24, encodes human p22phox, which is an essential subunit for the functionality of the NADPH oxidase [30] .…”

“…Several potential functional polymorphisms in the nitric oxide-forming pathway have recently been discovered, including (1) Leu608Ser (rs2297518) in inducible [iNOS] [7] , (2, 3) Glu298Asp (rs1799983) and T-786C (rs2070744) in the promoter region of endothelial [eNOS] [8][9][10][11][12] , (4,5) Tyr72His (rs4673) and C+640T (rs1049255) in the 3'-untranslated region (UTR) of the cytochrome b-245, alpha polypeptide gene (CYBA) [13][14][15][16] , which encodes the p22phox subunit of the NADPH oxidase, and (6) G+243A (rs841) in the 3'-UTR of the GTP cyclohydrolase 1 gene (GCH1) [17] . With special attention to the biological process of cerebral ischemia regulation, we investigated whether polymorphisms in these genes implicated in the pathway of NO formation are associated with IS in a large cohort in the Chinese Han population.…”

Hereditary Determinants of Human Hypertension

“…Such intermediate phenotypes may be influenced earlier and more proximately by the genome than are ultimate disease/clinical traits such as hypertension, and therefore may assist in discovery of hypertension-predisposition loci. 2,3 Intermediate traits in physical, physiological/hemodynamic, 4 autonomic/sympathetic, 5-8 metabolic, 9 inflammatory, 9 oxidative, 5 endothelial, 10,11 and renal 12 pathways displayed significant heritability, typically exceeding that reported for blood pressure itself (eg, Figure 1). With the rapid advance of genome technologies, informed systematic phenotyping of sufficiently large numbers of subjects for genetic studies may now be the rate-limiting step in permitting substantive future advances in complex trait genetics.…”