Association of the Glu298Asp polymorphism in the endothelial nitric oxide synthase gene with essential hypertension resistant to conventional therapy.
Endothelial nitric oxide synthase (eNOS) produces nitric oxide (NO) which, after diffusing into vascular smooth muscle cells, activates guanylate cyclase leading to vasodilatation. A polymorphism (894G to T) in exon 7 of the eNOS gene causes the conversion of Glu to Asp in position 298. The recently described crystal structure of the heme domain of eNOS protein shows that Glu298 is fully solvent accessible and distant from regions integral to enzyme function. Searching for phenotypic expression of eNOS gene variants, we genotyped a group of patients with essential hypertension (H, n = 119) for the Glu298Asp polymorphism and compared them with age- and sex-matched healthy normals (N, n = 85). To specify phenotypic expression further, the hypertensive patients were subdivided into one group that responded well to regular antihypertensive therapy (CH, n = 45) and one group that was resistant to the therapy (RH, n = 74). Patients with BP higher than 140/90 mmHg when on adequate lifestyle modification and triple-combination therapy (including diuretics) were considered resistant. In RH and H groups, a significantly higher frequency of T alleles (P = 0.022 and P = 0.046, respectively) was found compared to normotonics (N). In well-controlled hypertonics, the same tendency was found, but did not reach statistical significance. The Glu298Asp polymorphism may contribute to the complex pathogenesis of essential hypertension and may be a factor in the resistance of these patients to conventional antihypertensive therapy. The presence of this allele may thus be predictive of the patients' therapeutic response.
Jáchymová
M
M
Department of Medicine II, Charles University, Prague, 2, Czech Republic.
Horký
K
K
Bultas
J
J
Kozich
V
V
Jindra
A
A
Peleska
J
J
Martásek
P
P
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000483:Alleles; D019943:Amino Acid Substitution; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D004232:Diuretics / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics; D004359:Drug Therapy, Combination; D005787:Gene Frequency; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics*; D008019:Life Style; D008875:Middle Aged; D008958:Models, Molecular; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D010641:Phenotype; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests
D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D004232:Diuretics; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III