Endothelial nitric oxide synthase and methylenetetrahydrofolate reductase gene polymorphisms are associated with endothelial dysfunction in young, healthy men.
BACKGROUND
The guanine to thymine polymorphism at position 894 of the eNOS gene (resulting in a change from glutamate to aspartate [Asp] at codon 298 [Asp298]) and the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (C677T) have been reported to be associated with atherosclerosis and cardiovascular disease. Endothelial dysfunction is considered to be the earliest stage of atherosclerosis.


OBJECTIVE
To examine whether common eNOS and MTHFR gene polymorphisms are associated with endothelial dysfunction in young, healthy men without overt cardiovascular disease.


METHODS
Flow-mediated, endothelium-dependent vasodilation (FMD) and glyceryl trinitrate-induced, endothelium-independent vasodilation (GTN) were measured using high-resolution ultrasound of the brachial artery in 53 young, healthy men assigned to eNOS and MTHFR genotypes.


RESULTS
Subjects with the eNOS Asp298 allele (n=15) showed significantly reduced FMD:GTN compared with those without this allele (n=38) (0.23+/-0.13 [mean +/- SD] versus 0.35+/-0.14, P=0.0072), whereas there was no significant difference in GTN between these two groups. Although subjects with the MTHFR T677 allele did not show significantly reduced levels of FMD:GTN, subjects with the eNOS Asp298 allele and who were carriers of the MTHFR T677 allele demonstrated markedly reduced levels of FMD:GTN compared with noncarriers (0.14+/-0.05 versus 0.28+/-0.13, P=0.04).


CONCLUSIONS
The data suggest that even in young men, the eNOS Asp298 allele may be involved in endothelial dysfunction before any overt vascular disease has occurred. Furthermore, a combination of the eNOS Asp298 and MTHFR T677 alleles may exaggerate endothelial dysfunction and may contribute to a comparatively earlier development of atherosclerosis.
Imamura
Akiko
A
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Okumura
Kenji
K
Matsui
Hideo
H
Mizuno
Tomofumi
T
Ogawa
Yasuhiro
Y
Imai
Hajime
H
Numaguchi
Yasushi
Y
Sakai
Kazuyoshi
K
Murohara
Toyoaki
T
D000328:Adult; D001161:Arteriosclerosis / Q000175:diagnosis / Q000235:genetics; D001483:Base Sequence; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000235:genetics; D004730:Endothelium, Vascular / Q000503:physiopathology*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008969:Molecular Sequence Data; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011336:Probability; D011446:Prospective Studies; D012016:Reference Values
C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D042965:Methylenetetrahydrofolate Reductase (NADPH2)