Abstract 5455: A Novel Haplotype on GCH1 Gene, Encoding GTP Cyclohydrolase 1, Regulates Vascular Biopterin Synthesis, eNOS Coupling and Vascular Redox in Human Vessels
Background: GTP cyclohydrolase (GTPCH) is a key enzyme in biopterins synthesis, while tetrahydrobiopterin (BH4) is a regulator of eNOS coupling in vascular endothelium. A novel haplotype in GCH1 gene, combining dbSNPs: rs8007267G/A, rs3783641A/T and rs10483639C/G, affects GTPCH activity and biopterins levels in inflammatory cells. We examined the effect of this haplotype on vascular biopterins, eNOS coupling and redox state in human vessels from patients with coronary atherosclerosis.
Methods: Samples of saphenous veins (SV) were obtained from 347 patients undergoing CABG. Vasorelaxations of SV to acetylcholine (ACh) and vascular O2- (± eNOS inhibitor LNAME) were determined. Biopterins were measured by HPLC. The haplotypes were defined as X (rs8007267A+ rs3783641T+ rs10483639G) or O (all other haplotypes).
Results: The haplotype distribution was OO:245(71%), OX:95(27%) and XX:7(2%). Carriers of the X haplotype had lower plasma (Fig. a⇓) and vascular (Fig. b⇓) BH4. The X haplotype was associated with higher vascular O2- (XX+XO: 2.97±0.44 vs OO:1.90±0.10 RLU/Sec/mg, p<0.01), greater LNAME-inhibitable O2- (Fig. c⇓) suggesting eNOS uncoupling) and lower NO bioavailability (Fig. d⇓) in human vessels. The X haplotype was also associated with higher plasma ox-LDL (51.0±2.2 in XX+XO vs 44.2±1.4 U/L in OO p<0.05) and lower BH4:total biopterins ratio (43.1±3.2 in XX+XO vs 51.7±2.1% in OO, p<0.05).
Conclusions: This novel haplotype on GCH1 gene regulates biopterins biosynthesis in both plasma and vascular endothelium. This haplotype also regulates eNOS coupling, O2- production and NO bioavailability in human vessels, and may play a role in atherogenesis.