Glutamate-cysteine ligase polymorphism, hypertension, and male sex are associated with cardiovascular events. Biochemical and genetic characterization of Italian subpopulation.
BACKGROUND
Glutathione (GSH) is an important intravascular scavenger that protects endothelial cells from atherosclerosis. However, it is still unknown whether cardiovascular (CV) events are associated with metabolic and genetic factors, linked to GSH synthesis in an Italian subpopulation, and if a glutamate-cysteine ligase polymorphism within the catalytic subunit (GCLC) could affect blood and plasma GSH concentrations.


METHODS
One hundred subjects, with or without CV risk factors, were enrolled to evaluate plasma and erythrocyte redox status (GSH, homocysteine, cysteine, cysteinylglycine), antioxidant vitamins (alpha-tocopherol and ascorbate), malondialdehyde, a lipid peroxidation product, and the presence of the GCLC-129 C/T polymorphism; an experimental hyperhomocysteinemia after methionine-induced stimulation of transsulfuration pathway was performed in 91% of enrolled subjects. Clinical, biochemical, and genetic variables were correlated with the presence of CV events (myocardial infarction, transient ischemic attacks, and stroke).


RESULTS
By multiple logistic regression analysis, male sex (P = .027), hypertension (P = .001), and GCLC C/T genotype (P = .009) were the only variables associated with events. Plasma alpha-tocopherol content decreased postmethionine in the T allele subjects compared with wild type (P for time x group interaction = .001). Plasma-reduced GSH level was higher in C/T than in C/C genotype subjects at both time points (P for group = .03), whereas intracellular GSH concentration did not differ between the 2 genotype groups either at baseline or postmethionine.


CONCLUSIONS
GCLC T allele, together with hypertension and male sex, is associated with CV events in our study population. Moreover, after stimulation of transsulfuration, intracellular GSH content is preserved in T allele subjects, probably by increases in GSH turnover and export, and consumption of alpha-tocopherol.
CNR Clinical Physiology Institute-Milan, Cardiology Department, Niguarda Ca' Granda Hospital, Milan, Italy.
Jonica
J
Campolo
Silvana
S
Penco
Elena
E
Bianchi
Laura
L
Colombo
Marina
M
Parolini
Raffaele
R
Caruso
Valentina
V
Sedda
Maria Cristina
MC
Patrosso
Giuliana
G
Cighetti
Alessandro
A
Marocchi
Oberdan
O
Parodi
D000328:Adult; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000150:complications*; D002546:Ischemic Attack, Transient / Q000209:etiology* / Q000235:genetics; D007558:Italy; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology* / Q000235:genetics; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012737:Sex Factors; D020521:Stroke / Q000209:etiology* / Q000235:genetics
D005721:Glutamate-Cysteine Ligase