GTP Cyclohydrolase I Gene Polymorphisms Are Associated with Endothelial Dysfunction and Oxidative Stress in Patients with Type 2 Diabetes Mellitus

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Nov 5

PMID 25369080

Citations 7

Authors

Pawel P Wolkow

Wladyslaw Kosiniak-Kamysz

Grzegorz Osmenda

Grzegorz Wilk

Beata Bujak-Gizycka

Adam Ignacak

Mihir Kanitkar

Malgorzata Walus-Miarka

David G Harrison

Ryszard Korbut

Maciej T Malecki

Tomasz J Guzik

Affiliations

Soon will be listed here.

Abstract

Background: The genetic background of atherosclerosis in type 2 diabetes mellitus (T2DM) is complex and poorly understood. Studying genetic components of intermediate phenotypes, such as endothelial dysfunction and oxidative stress, may aid in identifying novel genetic components for atherosclerosis in diabetic patients.

Methods: Five polymorphisms forming two haplotype blocks within the GTP cyclohydrolase 1 gene, encoding a rate limiting enzyme in tetrahydrobiopterin synthesis, were studied in the context of flow and nitroglycerin mediated dilation (FMD and NMD), intima-media thickness (IMT), and plasma concentrations of von Willebrand factor (vWF) and malondialdehyde (MDA).

Results: Rs841 was associated with FMD (p = 0.01), while polymorphisms Rs10483639, Rs841, Rs3783641 (which form a single haplotype) were associated with both MDA (p = 0.012, p = 0.0015 and p = 0.003, respectively) and vWF concentrations (p = 0.016, p = 0.03 and p = 0.045, respectively). In addition, polymorphism Rs8007267 was also associated with MDA (p = 0.006). Haplotype analysis confirmed the association of both haplotypes with studied variables.

Conclusions: Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients.

Citing Articles

Marginal BH4 deficiencies, iNOS, and self-perpetuating oxidative stress in post-acute sequelae of Covid-19.

Villaume W Med Hypotheses. 2022; 163:110842.

PMID: 35431403 PMC: 9006446. DOI: 10.1016/j.mehy.2022.110842.

GCH1 (rs841) polymorphism in the nitric oxide-forming pathway has protective effects on obstructive sleep apnea.

Sheikhi Kouhsar S, Bigdeli M, Shakiba Y, Sadeghniiat K Sci Rep. 2019; 9(1):18664.

PMID: 31819149 PMC: 6901474. DOI: 10.1038/s41598-019-55244-1.

GCH1 haplotypes and cardiovascular risk in HIV.

Slaven J, Haas D, Liu Z, Stein J, Brown T, Gupta S AIDS. 2019; 33(10):1669-1671.

PMID: 31082861 PMC: 6700724. DOI: 10.1097/QAD.0000000000002263.

Genome-wide association study identifies QTLs for displacement of abomasum in Chinese Holstein cattle1.

Huang H, Cao J, Guo G, Li X, Wang Y, Yu Y J Anim Sci. 2019; 97(3):1133-1142.

PMID: 30715382 PMC: 6396242. DOI: 10.1093/jas/skz031.

Genetic Regulation of Endothelial Vasomotor Function.

Kim S, Massett M Front Physiol. 2016; 7:571.

PMID: 27932996 PMC: 5122706. DOI: 10.3389/fphys.2016.00571.

References

Guzik T, Sadowski J, Kapelak B, Jopek A, Rudzinski P, Pillai R . Systemic regulation of vascular NAD(P)H oxidase activity and nox isoform expression in human arteries and veins. Arterioscler Thromb Vasc Biol. 2004; 24(9):1614-20. DOI: 10.1161/01.ATV.0000139011.94634.9d. View

Gesierich A, Niroomand F, Tiefenbacher C . Role of human GTP cyclohydrolase I and its regulatory protein in tetrahydrobiopterin metabolism. Basic Res Cardiol. 2003; 98(2):69-75. DOI: 10.1007/s00395-003-0394-y. View

Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V . Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012; 380(9859):2095-128. PMC: 10790329. DOI: 10.1016/S0140-6736(12)61728-0. View

Wilk G, Osmenda G, Matusik P, Nowakowski D, Jasiewicz-Honkisz B, Ignacak A . Endothelial function assessment in atherosclerosis: comparison of brachial artery flow‑mediated vasodilation and peripheral arterial tonometry. Pol Arch Med Wewn. 2013; 123(9):443-52. DOI: 10.20452/pamw.1879. View

Hirata M, Yoshikawa Y, Nagafuchi Y, Toyoshima H, Watanabe T . Role of macrophages in atherosclerosis. Sequential observations of cholesterol-induced rabbit aortic lesion by the immunoperoxidase technique using monoclonal antimacrophage antibody. Lab Invest. 1985; 53(1):80-90. View

Sim A, Salonikas C, Naidoo D, Wilcken D . Improved method for plasma malondialdehyde measurement by high-performance liquid chromatography using methyl malondialdehyde as an internal standard. J Chromatogr B Analyt Technol Biomed Life Sci. 2003; 785(2):337-44. DOI: 10.1016/s1570-0232(02)00956-x. View

Antoniades C, Shirodaria C, Van Assche T, Cunnington C, Tegeder I, Lotsch J . GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function. J Am Coll Cardiol. 2008; 52(2):158-65. PMC: 2699614. DOI: 10.1016/j.jacc.2007.12.062. View

Kim H, Dionne R . Lack of influence of GTP cyclohydrolase gene (GCH1) variations on pain sensitivity in humans. Mol Pain. 2007; 3:6. PMC: 1821314. DOI: 10.1186/1744-8069-3-6. View

Werns S, Walton J, HSIA H, Nabel E, Sanz M, Pitt B . Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation. 1989; 79(2):287-91. DOI: 10.1161/01.cir.79.2.287. View

10.

Tegeder I, Costigan M, Griffin R, Abele A, Belfer I, Schmidt H . GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. 2006; 12(11):1269-77. DOI: 10.1038/nm1490. View

11.

Steinberger D, Weber Y, Korinthenberg R, Deuschl G, Benecke R, Martinius J . High penetrance and pronounced variation in expressivity of GCH1 mutations in five families with dopa-responsive dystonia. Ann Neurol. 1998; 43(5):634-9. DOI: 10.1002/ana.410430512. View

12.

Gotschy A, Bauer E, Schrodt C, Lykowsky G, Ye Y, Rommel E . Local arterial stiffening assessed by MRI precedes atherosclerotic plaque formation. Circ Cardiovasc Imaging. 2013; 6(6):916-23. DOI: 10.1161/CIRCIMAGING.113.000611. View

13.

Lotsch J, Belfer I, Kirchhof A, Mishra B, Max M, Doehring A . Reliable screening for a pain-protective haplotype in the GTP cyclohydrolase 1 gene (GCH1) through the use of 3 or fewer single nucleotide polymorphisms. Clin Chem. 2007; 53(6):1010-5. DOI: 10.1373/clinchem.2006.082883. View

14.

Guzik B, Sagan A, Ludew D, Mrowiecki W, Chwala M, Bujak-Gizycka B . Mechanisms of oxidative stress in human aortic aneurysms--association with clinical risk factors for atherosclerosis and disease severity. Int J Cardiol. 2013; 168(3):2389-96. PMC: 3819986. DOI: 10.1016/j.ijcard.2013.01.278. View

15.

Peltonen L, Altshuler D, de Bakker P, Deloukas P, Gabriel S, Gwilliam R . Integrating common and rare genetic variation in diverse human populations. Nature. 2010; 467(7311):52-8. PMC: 3173859. DOI: 10.1038/nature09298. View

16.

Petrelli A, Di Fenza R, Carvello M, Gatti F, Secchi A, Fiorina P . Strategies to reverse endothelial progenitor cell dysfunction in diabetes. Exp Diabetes Res. 2012; 2012:471823. PMC: 3296202. DOI: 10.1155/2012/471823. View

17.

Kietadisorn R, Juni R, Moens A . Tackling endothelial dysfunction by modulating NOS uncoupling: new insights into its pathogenesis and therapeutic possibilities. Am J Physiol Endocrinol Metab. 2011; 302(5):E481-95. DOI: 10.1152/ajpendo.00540.2011. View

18.

Thony B, Blau N . Mutations in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes. Hum Mutat. 1997; 10(1):11-20. DOI: 10.1002/(SICI)1098-1004(1997)10:1<11::AID-HUMU2>3.0.CO;2-P. View

19.

Doehring A, Antoniades C, Channon K, Tegeder I, Lotsch J . Clinical genetics of functionally mild non-coding GTP cyclohydrolase 1 (GCH1) polymorphisms modulating pain and cardiovascular risk. Mutat Res. 2008; 659(3):195-201. DOI: 10.1016/j.mrrev.2008.04.007. View

20.

Liao Y, Zeng T, Chen L, Li Y, Yu F, Hu L . Association of a functional polymorphism (C59038T) in GTP cyclohydrolase 1 gene and Type 2 diabetic macrovascular disease in the Chinese population. J Diabetes Complications. 2009; 24(5):313-9. DOI: 10.1016/j.jdiacomp.2009.04.003. View