Abstract 10398: Haplotype on GTP-Cyclohydrolase I Gene, Reveals a Novel Role of Tetrahydrobiopterin as a Defense Mechanism Against Inflammation-Induced Endothelial Dysfunction in Human Atherosclerosis
Background: Tetrahydrobiopterin (BH4) plays a critical role in the maintenance of endothelial nitric oxide synthase (eNOS) coupling in human atherosclerosis. Genetic variability of GTP-cyclohydrolase I (GTPCHI), the rate-limiting enzyme for BH4 biosynthesis, modifies BH4 bioavailability and endothelial function in humans, but in experimental models its expression is induced by inflammatory stimulation. We used the presence of a rare functional haplotype on GTPCH I gene to investigate the role of BH4 in low-grade inflammation related with human atherosclerosis.
Methods: We genotyped 1182 patients with coronary artery disease for SNPs rs8007267G/A, rs3783641A/T and rs10483639C/G (X haplotype: A, T, G; O haplotype: any other combination), and identified 287 (24.3%) XO and 31 (2.6%) XX. We obtained blood samples and estimated flow-mediated dilation (FMD) in the brachial artery in 280 OO, 85 XO and 11 XX (Study 1). Then we called back 40 OO and 10 XX for Study 2, in which inflammation was induced by Salmonella Typhii vaccination and blood samples/FMD were evaluated as 0 and 8h. C-reactive protein (hsCRP), interleukin 6 (IL-6) and plasma tetrahydrobiopterin (BH4) were determined.
Results: In Study 1, carriage of the X haplotype was associated with reduced FMD (A) and plasma BH4 (B) only among patients at the highest tertile of hsCRP. Despite the similar elevation of IL-6 (C) and the stable hsCRP levels (D) 8h post vaccination in both genotypes, plasma BH4 was elevated at 8h only in OO (E), while the reduction of FMD was greater in XX than in OO (F).
Conclusions: The presence of a rare haplotype on GTPCH-I gene affects the response of plasma BH4 to chronic or acute inflammation. Inability to increase plasma BH4 in response to inflammation, is associated with significant impairment of endothelial function, suggesting that the increase of GTPCH-I expression and plasma BH4 may be a defense mechanism of the vascular wall against systemic low-grade inflammation in human atherosclerosis.
- © 2011 by American Heart Association, Inc.