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Background: Endothelin-1 (EDN1) has been involved in the development of airway obstruction and inflammation in asthma. Several polymorphisms have been identified among the genes encoding for preproET1, an inactive precursor of ET-1, and for ETA (EDNRA) and ETB (EDNRB), the two receptors for EDN1. In the present work, we hypothesised that molecular variation in these genes could be a major determinant of the degree of bronchial obstruction. The purpose of this study was to investigate whether the genetic polymorphisms of preproET-1, EDNRA and EDNRB genes were associated with the degree of airway obstruction, assessed by FEV1., Methods: Polymorphisms of preproET-1, EDNRA and EDNRB were first studied in a population of adult asthmatic patients. Results were confirmed in a large population of adults from the general population from the ECRHS II study., Results: In our population of adult asthmatic patients, the EDNRB-30G>A (Leu277Leu) polymorphism (GG genotype) is strongly associated with a low FEV1 and with a higher percentage of patients with FEV1 < 80% of predicted value. No relationship was found between pulmonary function and EDNRA-1363C>T (His323His) or preproET-1-595G>T (Lys198Asp) polymorphism. In the adult population from the ECRHS II, we found a similar association between GG genotype and a low FEV1 or a higher percentage of subjects with FEV1 < 80% predicted, especially in the subgroups of asthmatics subjects (OR = 4.31 (95%CI 1.03 - 18.04)) and smokers (OR = 7.42 (95%CI 1.69 - 32.6))., Conclusion: the EDNRB-30G>A polymorphism could be a determinant of airway obstruction in humans with predisposing factors such as tobacco smoke exposure or asthma.

Objective: Platelet adhesion to the subendothelial tissue via the collagen receptor alpha2beta1 is a crucial event in vascular biology. Although evidence has been provided that the number of platelets alpha2beta1 copies is genetically determined, the molecular change primary responsible has not been yet elucidated. The aim of our present study was to investigate the effect of combined polymorphisms within both regulatory (-52C/T and -92C/G) and coding regions (807C/T and 1648A/G) of the alpha2 subunit gene on human platelets alpha2beta1 receptor density and/or susceptibility to coronary artery disease (CAD)., Methods and Results: Among 254 cardiac surgery patients, no evidence was found for an association between the alpha2 subunit gene polymorphisms and CAD. In contrast, in a subgroup of 113 patients, we observed a significant association between all polymorphisms except -52C/T and alpha2beta1 receptor level. Furthermore, when 3 groups of patients were defined according to the tertiles of platelets alpha2beta1 copies, the -92C/807T haplotype was more frequent in the group of patients with high alpha2beta1 receptor level., Conclusions: These results suggest that an individual effect of each polymorphism located either in the coding or promoter sequence of the alpha2 gene may act in combination to modulate variations in platelets alpha2beta1 receptor density.

Background: Differences in vascular reactivity to phenylephrine (PE) responsiveness have been largely evidenced in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Because nitric oxide (NO) strongly affects modulation of the vascular tone in response to vasopressor agents, we hypothesized that the G894T polymorphism of the endothelial NO synthase gene (eNOS) could be related to changes in the pressor response to PE., Methods and Results: The protocol was performed in 68 patients undergoing coronary artery bypass grafting (n=33) or valve surgery (n=35) in whom mean arterial pressure decreased below 65 mm Hg during normothermic CPB. Under constant and nonpulsatile pump flow conditions (2 to 2.4 L. min-1. m-2), a PE dose-response curve was generated by the cumulative injection of individual doses of PE (25 to 500 micrograms). The G894T polymorphism of the eNOS gene was determined, and 3 groups were defined according to genotype (TT, GT, and GG). Groups were similar with regard to perioperative characteristics. The PE dose-dependent response was significantly higher in the allele 894T carriers (TT and GT) than in the homozygote GG group (P=0.02), independently of possible confounding variables., Conclusions: These results evidenced an enhanced responsiveness to alpha-adrenergic stimulation in patients with the 894T allele in the eNOS gene.

A gene polymorphism of the angiotensin II (AII) type 1 receptor has been described previously (A to C transversion at position 1166). Besides the epidemiological studies needed to determine a possible relationship between the polymorphism and some cardiovascular diseases, no study has been conducted to determine the impact of the polymorphism on vascular functions. At subthreshold concentrations, within the physiological range, AII potentiates alpha-adrenergic-dependent vascular tone. We investigated phenylephrine-induced tone and its amplification by AII (10 pmol/l) in human internal mammary artery rings mounted in organ baths. We performed concentration-response curves to phenylephrine (0.1-100 micromol/l) before and after pretreatment with AII (10 pmol/l). Patients had the genotype AA (n = 20) or the A to C transversion (AC/CC, n = 30). Contractions to phenylephrine (0.1-100 micromol/l) were significantly higher in rings from AC/CC than from AA patients (maximum response: 1.47+/-0.07 vs. 1.22+/-0.06 mN/mg, p < 0.001). AII (10 pmol/l) induced a significant potentiation of phenylephrine-induced contraction (e.g. 58.9% increase in tone with 1 micromol/l phenylephrine, p < 0.001) which was significantly lower in the AC/CC than in the AA group (46+/-9 vs. 66+/-7% with 1 micromol/l phenylephrine, p < 0.01). Contractions to AII (1 or 100 nmol/l) were not significantly affected by the genotype. Although the study was performed in arteries from patients with a coronary artery disease, these changes in vascular reactivity might be of interest in the understanding of the relationship between a possible higher probability of cardiovascular disorder and the genetic polymorphism of the AII type 1 receptor.

Background: An insertion-deletion polymorphism of the angiotensin-converting enzyme (ACE) gene has been shown to be associated with levels of ACE. Because ACE is heavily expressed in the lungs and plays a key role in the metabolism of angiotensin II and bradykinin, which are potentially involved in the pathogenesis of asthma, we tested the hypothesis of an association between the polymorphism of the ACE gene and asthma., Methods: Seventy-nine patients with asthma, 54 healthy subjects, and 33 patients with nonasthmatic lung disease were studied. Pulmonary function tests were performed in patients with asthma, and the ACE genotypes were determined in all subjects by the polymerase chain reaction., Results: The ACE genotype distribution was similar in healthy subjects and in patients without asthma. By contrast, the population of patients with asthma was characterized by a higher prevalence of the DD genotype of ACE (odds ratio, 2.09; 95% confidence interval, 1.05 to 4.16; p = 0.023). No difference in pulmonary function test results was detected in asthmatic patients according to the distribution of ACE genotypes., Conclusion: This study reports an association between the DD genotype of ACE and asthma, which is not related to the degree of airway obstruction. These results need to be confirmed by a larger case-control study.