CLINICAL STUDY: POLYMORPHISMS AND CARDIOVASCULAR DISEASE
The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients
Gian Paolo Rossi, MD, FACC, FAHA*,*,
Stefano Taddei, MD ,
Agostino Virdis, MD,
Martina Cavallin, BiolD*,
Lorenzo Ghiadoni, MD,
Stefania Favilla, BiolD,
Daniele Versari,
Isabella Sudano, MD,
Achille C. Pessina, MD, PhD* and
Antonio Salvetti, MD
* Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Padova, Italy
Department of Internal Medicine, University of Pisa Pisa, Italy
Manuscript received March 20, 2002;
revised manuscript received May 16, 2002,
accepted June 7, 2002.
* Reprint requests and correspondence: Prof. Gian Paolo Rossi, Department of Clinical and Experimental Medicine, University Hospital, via Giustiniani, 2, 35126 Padova, Italy.
gianpaolo.rossi{at}unipd.it
OBJECTIVES: We sought to investigate whether two polymorphisms located in the promoter (T-786C) and exon 7 (Glu298Asp) of the endothelial nitric oxide (NO) synthase (eNOS) gene affected agonists-mediated NO release.
BACKGROUND: Endothelial dysfunction can be genetically determined. Therefore, we investigated whether two polymorphisms located in the eNOS gene affected agonists-mediated NO release.
METHODS: We compared endothelial-dependent and -independent vasodilation of the different eNOS genotypes in a cross-sectional study on 187 subjects, of whom 137 were uncomplicated essential hypertensive patients (PH) (49 ± 9 years, 151 ± 11/99 ± 5 mm Hg) and 50 healthy normotensive subjects (NT) (43 ± 16 years, 123 ± 10/78 ± 7 mm Hg). Endothelial-dependent and -independent vasodilation was assessed as the forearm blood flow response to incrementally increasing doses of acetylcholine (0.15, 0.45, 1.5, 4.5, 15 µg/100 ml/min) and sodium nitroprusside (1, 2, 4 µg/100 ml/min), respectively. Genotyping was performed with melting curve analysis (Lightcycler) of polymerase chain reaction products from acceptor (5' end-labeled with LCRed 640) and donor probes (3' end-labeled with fluorescein) specific for each polymorphism.
RESULTS: The genotype distribution of T-786C (CC = 21.9%, CT = 48.7%, TT = 29.4%) and Glu298Asp (GG = 39.0%, GT =51.9%, TT = 9.1%) was similar in PH and NT. A repeated measure analysis of variance showed a blunting of endothelium-dependent vasodilation in PH compared with NT (p < 0.001). A significant effect of the T-786C (p = 0.002) but not of the Glu298Asp (p = NS) eNOS polymorphism on endothelial-dependent vasodilation was found. However, we also detected a significant interaction between the T-786C and Glu298Asp polymorphism (p < 0.001). No effect on either polymorphism on endothelial-independent vasodilation was seen.
CONCLUSIONS: The T-786C promoter polymorphism and its interaction with exon 7 Glu298Asp affect endothelium-dependent vasodilation in mild-to-moderate PH patients and NT Caucasian subjects.
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Abbreviations and Acronyms
| | ACH | | acetylcholine | | ANOVA | | analysis of variance | | BP | | blood pressure | | DNA | | deoxyribonucleic acid | | EDV | | endothelium-dependent vasodilation | | EIV | | endothelium-independent vasodilation | | eNOS | | endothelial nitric oxide synthase | | FBF | | forearm blood flow | | NO | | nitric oxide | | NT | | normotensive | | PCR | | polymerase chain reaction | | PH | | primary (essential) hypertension | | SNP | | sodium nitroprusside |
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