The GLU298ASP variant of nitric oxide synthase interacts with asymmetric dimethyl arginine in determining cardiovascular mortality in patients with end-stage renal disease.
OBJECTIVE
Impaired nitric oxide generation and accumulation of the endogenous inhibitor of nitric oxide synthase (NOS), asymmetric dimethylarginine (ADMA), have been identified as strong predictors of cardiovascular outcomes in patients with end-stage renal disease (ESRD). We evaluated the role of endothelial NOS (eNOS) gene polymorphisms and its interaction with plasma ADMA in the high cardiovascular complications rate of these patients.


METHODS
The relationship between the Glu298Asp variant of eNOS and all-cause and cardiovascular mortality was assessed in a cohort study including 261 ESRD patients that were followed up for an average of 42 months.


RESULTS
During the follow-up period, 138 patients died, 81 of them (i.e. 59% of total deaths) of cardiovascular causes. On univariate Cox's regression analysis, eNOS genotype tended to be related to all-cause death but failed to reach formal statistical significance (P for trend=0.11). However, eNOS genotype showed a significant association with cardiovascular mortality in statistical models, including traditional risk factors and factors peculiar to ESRD, and became even stronger when plasma ADMA was forced into the Cox model (P=0.006). Furthermore, the risk of cardiovascular death was maximum in heterozygotes and homozygotes patients carrying the risk allele and in those having high ADMA levels (hazard ratio=2.71, 95% confidence interval 1.38-5.35, P=0.004) compared to those having just one of these two risk factors.


CONCLUSIONS
The T allele of the Glu298Asp polymorphism predicts cardiovascular mortality and interacts with plasma ADMA in determining this outcome in dialysis patients.
Testa
Alessandra
A
CNR-IBIM, National Research Council-Institute of Biomedicine, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Reggio Calabria and Department of Internal Medicine, Catania University, Catania, Italy.
Spoto
Belinda
B
Tripepi
Giovanni
G
Mallamaci
Francesca
F
Malatino
Lorenzo
L
Fatuzzo
Pasquale
P
Maas
Renke
R
Boeger
Rainer
R
Zoccali
Carmine
C
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics*; D000704:Analysis of Variance; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D001224:Aspartic Acid / Q000235:genetics; D002318:Cardiovascular Diseases / Q000150:complications / Q000401:mortality*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000235:genetics*; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D015996:Survival Rate
D001224:Aspartic Acid; D018698:Glutamic Acid; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase