Polymorphism in glutamate-cysteine ligase modifier subunit gene is associated with impairment of nitric oxide-mediated coronary vasomotor function.
BACKGROUND
The minor -588T allele of polymorphism -588C/T of a modifier subunit gene in glutamate-cysteine ligase (GCLM), a rate-limiting enzyme for glutathione (GSH) synthesis, was associated with lower plasma GSH levels and was a risk factor for myocardial infarction.


RESULTS
We examined effects of the -588C/T polymorphism on coronary arterial diameter and blood flow responses to intracoronary infusion of acetylcholine in 157 consecutive subjects who had normal coronary angiograms. In multivariate linear regression analysis with covariates including traditional risk factors, the minor -588T allele had an independent association with impaired dilation or enhanced constriction of epicardial coronary arteries in response to acetylcholine, and it was independently associated with blunted increase in coronary flow response to acetylcholine. In a subgroup of 59 consecutive subjects, constrictor responses of epicardial coronary diameter to intracoronary infusion of NG-monomethyl-l-arginine, reflecting the presence of coronary nitric oxide (NO) bioactivity, had an inverse and independent association with the -588T allele in multivariate analysis.


CONCLUSIONS
The -588T polymorphism of the GCLM gene causes a decrease in endothelial NO bioactivity, leading to impairment of endothelium-dependent vasomotor function in large and resistance coronary arteries. The GCL-GSH-NO axis may play a role in the defense system against coronary artery disease.
Nakamura
Shin-ichi
S
2nd Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Nakakoma-gun, Yamanashi, 409-3898 Japan.
Sugiyama
Seigo
S
Fujioka
Daisuke
D
Kawabata
Ken-ichi
K
Ogawa
Hisao
H
Kugiyama
Kiyotaka
K
D024506:5' Flanking Region / Q000235:genetics; D000109:Acetylcholine / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000187:drug effects; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000209:etiology; D003326:Coronary Circulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D006801:Humans; D007564:Japan; D015999:Multivariate Analysis; D009569:Nitric Oxide / Q000378:metabolism*; D011110:Polymorphism, Genetic; D021122:Protein Subunits / Q000235:genetics; D012307:Risk Factors; D014654:Vascular Patency / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D021122:Protein Subunits; D014665:Vasodilator Agents; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D005721:Glutamate-Cysteine Ligase; D000109:Acetylcholine