Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease.

Cerebral accumulation of beta-amyloid peptide (A beta) is a central event in the pathogenesis of Alzheimer's disease (AD). Endothelin-converting enzyme-1 (ECE-1) is a candidate A beta-degrading enzyme in brain, but its involvement in AD pathogenesis was never assessed. We first performed brain immunocytochemistry, using a monoclonal anti-ECE-1 antibody, and observed neuronal ECE-1 expression in various cortical regions of nondemented subjects. In the hippocampus, ECE-1 immunoreactivity showed a stereotypical pattern inversely correlated with susceptibility to A beta deposition, further suggesting a physiological role in A beta clearance. In order to undertake a genetic association study, we identified a functional genetic variant (ECE1B C-338A) located in a regulatory region of the ECE1 gene. We showed that the A allele is associated with increased transcriptional activity in promoter-reporter gene assays and with increased ECE-1 mRNA expression in human neocortex. In a case-control study involving 401 patients with late-onset AD and 461 aged controls, we found that homozygous carriers of the A allele had a reduced risk of AD (OR=0.47, 95% CI 0.25-0.88). This finding was strengthened by the analysis of two other genetic variants of the ECE1 gene, which showed that the genetic association is extended over at least 13 kilobases of the gene sequence. Our results suggest that ECE-1 expression in brain may be critical for cortical A beta clearance and offer new potential targets for therapeutic interventions in AD.

Effect of ACE inhibitors on angiographic restenosis after coronary stenting (PARIS): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The DD genotype for the angiotensin-I converting enzyme (ACE I) deletion allele (D) polymorphism is a possible genetic risk factor for restenosis after coronary stent implantation. We aimed to establish whether or not blockade of ACE with high doses of ACE inhibitors could reduce this risk of angiographic restenosis. METHODS: We characterised the ACE I/D polymorphism in 345 consecutive patients who were undergoing coronary stenting. 115 had the DD genotype. We assigned 91 of these 115 patients to quinapril 40 mg daily (n=46) or placebo (n=45). Treatment was started within 48 h after stent implantation and continued for 6 months. 79 patients complied with the protocol and underwent follow-up angiography after 6 months. FINDINGS: Our primary endpoint of late loss in minimum lumen diameter (a quantitative index of restenosis) was significantly higher in the quinapril group than in the controls (mean 1.11 mm [SD 0.70] vs 0.76 mm [0.60]; p=0.018). Secondary endpoints also showed consistent trends towards increased angiographic restenosis in the treatment group. INTERPRETATION: Contrary to our expectations, ACE inhibitor treatment did not reduce restenosis after coronary stent implantation in patients with DD genotype, but was associated with an exaggerated restenotic process when compared with administration of placebo.

The role of a triplet repeat sequence of the very low density lipoprotein receptor gene in plasma lipid and lipoprotein level variability in humans.

The biological role of the very low density lipoprotein receptor (VLDL-R) in humans is not yet elucidated. This cellular receptor binds apolipoprotein E (apoE)-containing lipoparticles and is mainly expressed in peripheral tissues. The VLDL-R gene contains a polymorphic triplet (CGG) repeat located 19 bp upstream of the initiation codon. We explored the allelic distribution of this repeat in 1384 subjects of European Caucasian origin, 609 of them surviving a myocardial infarction. Six alleles corresponding to 5, 6, 7, 8, 9, and 11 repeats were detected in this population. The alleles 5, 8, and 9 were the most frequent, with frequencies of 0.413, 0.275, and 0.292, respectively. No association was found between the VLDL-R polymorphism and myocardial infarction. In controls without lipid lowering treatment, a statistically significant interaction between VLDL-R genotype and apoE phenotype was found for plasma triglycerides (P < .04), suggesting a gene-gene interaction. There was also a main effect of the VLDL-R polymorphism on LpE:B and LpA-I. The VLDL-R 9 allele was associated with lower levels of plasma LpE:B (P < .05) and higher concentrations of plasma LpA-I (P < .01) than the other alleles. These results suggest that VLDL-R has a modest influence on circulating lipoproteins in humans.

The deletion allele of the angiotensin I converting enzyme gene as a genetic susceptibility factor for cognitive impairment.

Experimental evidences suggest an implication of the renin angiotensin system (RAS) as a potential determinant of cognitive functions. To explore this hypothesis, we compared the distribution of an insertion (I)/deletion (D) polymorphism of the gene coding for the angiotensin I converting enzyme (ACE), a key enzyme of the RAS, in 228 elderly with cognitive impairment to that of 255 controls. The ACE D allele frequency was higher in the group with cognitive impairment (0.594) than in controls (0.514) (P < 0.02). The ACE DD genotype carriers had an increased risk of cognitive impairment (OR = 1.60, 95% CI (1.04-2.36), P < 0.03), independent of other risk factors of cognitive impairment: age, gender and presence of the apolipoprotein E epsilon 4 allele. This association was stronger in men (OR = 3.25, 95% CI (1.40-7.58), P < 0.006). This result suggests a possible implication of the RAS in human brain and cognitive functions.