Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several clinical, epidemiological, and pathological observations suggest that vascular risk factors are associated with cognitive performances. The renin-angiotensin system components, major determinants of the cardiovascular system, are expressed in the brain. To estimate their potential impact on cognitive performances, we studied the association between cognitive functioning and an insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene. In a sample of 1168 highly performing subjects (59-71 years), DD homozygotes had the lowest cognitive scores as evaluated by the Mini-Mental State Examination. Cognitive decline at 4-year follow-up (defined as the loss of at least 3 points in Mini-Mental State Examination score) was more prevalent in these subjects, the odds ratio being equal to 1.53 (95% CI: 1.04-2.24) with subjects ID as reference class. Moreover, the combined effect of the presence of at least one APOE epsilon4 allele and ACE DD homozygosity was a risk factor for cognitive decline. This report reinforces the hypothesis of an influence of cardiovascular risk factors on cognitive performances.
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PMID:Effect of the angiotensin I-converting enzyme I/D polymorphism on cognitive decline. The EVA Study Group. 1079 51

A recent study suggested that the insertion (I) allele in intron 16 of the angiotensin converting enzyme gene (ACE) is associated with Alzheimer's disease (AD) risk. In our series of 239 necropsy confirmed late onset AD cases and 342 elderly non-demented controls aged >73 years, we found significantly different ACE genotype distributions in the case and control groups (p=0.007). Homozygotes for both the I and D alleles were associated with a higher risk compared to DI heterozygotes. While the APOE epsilon4 allele was strongly associated with AD risk in our series, we found no evidence for an interaction between the APOE and ACE loci. In addition, no interactions were observed between ACE and gender or age at death of the AD cases. A meta-analysis of all published reports (12 case-control series in total) suggested that both the II and ID ACE genotypes are associated with increased AD risk (odds ratio (OR) for II v DD 1.36, 95% confidence interval (CI)=1.13-1.63, OR for DI v DD 1.33, 95% CI=1.14-1.53, p=0.0002).
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PMID:The ACE gene and Alzheimer's disease susceptibility. 1097 62

Association study is the method of choice to identify genes involved in complex processes that result from the interaction of environmental and genetic factors. However, because of biases that increase the risk of false positive reports, preliminary positive conclusions have to be reproduced on other populations to be validated as firm conclusions. In 1994, certain alleles of two genes, APOE (Apolipoprotein E) and ACE (angiotensin converting enzyme), were reported to be more frequent in French centenarians, suggesting an association with such a complex polyfactorial process as longevity. Enlargement of the French centenarian cohort allows a new assessment of this hypothesis on 563 centenarians. In contrast to APOE, the ACE association was not confirmed. Retrospective analysis of the initial study revealed discrepancies that may in part explain this observation. Risk of reporting false positive associations is discussed and recommendations to set up a rigorous experimental design are proposed.
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PMID:A study of French centenarians: are ACE and APOE associated with longevity? 1128 44

A multilocus assay was used to genotype up to 27 variable sites in 15 genes in French and Italian, presumed to be healthy populations (n=1480, n=162, respectively). These genes are involved in lipid metabolism (APOE, APOB, APOC3, CETP, LPL, PON), homocysteine metabolism (CBS, MTHFR), blood viscosity (Fibrinogen, FV), platelet aggregation (GpIIIa), leukocyte adhesion (SELE), and renin-angiotensin system (AT1R, ACE, AGT). Allele frequencies for all the markers were compared between the two populations. Five allele frequencies differed between the two European countries: APOB 71Ile (p < 0.001), SELE 98T (p < 0.001), SELE 128Arg (p < or = 0.01), APOE E4 (p < or = 0.01) and MTHFR 677T (p < or = 0.01), suggesting the existence of a north-south gradient in European allele frequencies. The other allele frequencies : APOC3 -482T, -455C, 1100T, 3175G, 3206G; LPL -93G, 9Asn, 291Ser; CETP 405Val; PON 192Arg; ACE Del; AGT 235Thr; AT1R 1166C; CBS 278Thr, GpIIIa P1A2; Fibrinogen -455A, FV 506Gln and SELE 554Phe, were similar between the two populations. They were also similar to those observed in other European countries.
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PMID:Candidate gene polymorphisms in cardiovascular disease: a comparative study of frequencies between a French and an Italian population. 1134 49

A population genetic study was carried out with the APOE, APOB and ACE loci in 17 Colombian human populations. Ten of them were Amerindian communities coming from the northeastern part of Colombia, Pacific region, Eastern Plains and Amazonia. Six were black populations from Providence Island, Caribbean and Pacific coasts. Finally, the Mestizo population of Bogota was studied as well. The APOE and ACE loci were in Hardy-Weinberg equilibrium, whereas the APOB locus was not studied in all populations. The genetic heterogeneity was substantially greater among the Amerindian populations (G(ST) = 0.059) than in the Afrocolombian populations (G(ST) = 0.009). Also the gene flow population pair estimates were so much higher among the Afrocolombian populations (Nm = 49.08 +/- 43.07) than among Amerindian populations (Nm = 9.66 +/- 18.04). Different phylogenetic and multivariant analyses showed that the Amerindian populations analyzed were clustered in three different arrays: one constituted by the Colombian northeastern and Pacific populations, the second one by the two Amazon populations (Coreguaje and Nukak) and the last one by the Yuco (the unique Caribbe-speaking population among those studied). The latter population was highly divergent from a genetic point of view from the remainder Amerindian populations studied. By using the Mantel test, the existence of a positive and significant correlation between the genetic and geographical distances found among Amerindian populations was demonstrated. This fact was not observed among the Afrocolombian populations. Nevertheless, an isolation-by-distance Slatkin analysis test did not show a significant clear structure of this special pattern among the Indian tribes studied.
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PMID:Population genetic analysis of the genes APOE, APOB(3'VNTR) and ACE in some black and Amerindian communities from Colombia. 1135 65

The contribution of 17 polymorphisms within 13 candidate genes on lipid trait variability was investigated by a multiplex assay in 772 men and 780 women coming for a health checkup examination. The studied genes were APOE, APOB, APOC3, CETP, LPL, PON, MTHFR, FGB, GpIIIa, SELE, ACE, and AGT. We found that APOB-Thr71Ile, APOE-(112/158), APOC3-1100C/T, and SELE-98G/T polymorphisms had a significant effect on lipid traits (P < or = 0.001 to P < or = 0.01). Genetic effects accounted for 3.5-5.7% of variation in apolipoprotein B (apoB)-related traits among men, and for 5.7-9.0% among women. The contribution of APOE polymorphism on apoB-related traits variability was two to three times more important in women than in men. We found suggestive evidence for interactive effects between genetics and age, smoking status, and oral contraceptives. Increase of LDL-cholesterol and apoB concentrations with age was stronger among the epsilon4 carriers in women, and apolipoprotein A-I (apoA-I) concentration decreased with age in epsilon4 male carriers. The effect of epsilon2 allele on LDL-cholesterol was more important in the oral contraceptive users. In nonsmokers only, the APOC3-1100C allele in women was related to lower apoB-related traits concentrations, and in men to higher apoA-I and HDL-cholesterol concentrations. In conclusion, this work, in addition to the reinforcement of the already known associations between APOB, APOE, and APOC3 genes and lipids, leads to new perspectives in the complex relationships among genes and environmental factors. The newly observed relationships between E-selectine gene and lipid concentrations support the hypotheses of multiple metabolic pathways contributing to the complexity of lipids variability.
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PMID:Genetic influences on lipid metabolism trait variability within the Stanislas Cohort. 1171 57

Alzheimer's disease (AD) is a complex disorder associated with multiple genetic defects either mutational or of susceptibility. Information available on AD genetics does not explain in full the etiopathogenesis of AD, suggesting that environmental factors and/or epigenetic phenomena may also contribute to AD pathology and phenotypic expression of dementia. The genomics of AD is still in its infancy, but is helping to understand novel aspects of the disease including genetic epidemiology, multifactorial risk factors, pathogenic mechanisms associated with genetic networks and genetically-regulated metabolic cascades. AD genomics is also helping to develop new strategies in pharmacogenomic research and prevention. Functional genomics, proteomics, pharmacogenomics, high-throughput methods, combinatorial chemistry and modern bioinformatics will greatly contribute to accelerate drug development for AD and other complex disorders. Main genes involved in AD include mutational loci (APP, PS1, PS2, TAU) and multiple susceptibility loci (APOE, A2M, AACT, LRP1, IL1A, TNF, ACE, BACE, BCHE, CST3, MTHFR, GSK3B, NOS) distributed across the human genome. Genomic associations integrate bigenic, trigenic, tetragenic or polygenic matrix models to investigate the genomic organization of AD in comparison to the control population. Similar genetic models are used in pharmacogenomics to elucidate genotype-specific responses of AD patients to a particular drug or combination of drugs. Using APOE-related monogenic models it has been demonstrated that the therapeutic response to drugs in AD is genotype-specific. A multifactorial therapy combining 3 different drugs yielded positive results during the 6-12 months in approximately 60% of the patients. With this therapeutic strategy, APOE-4/4 carriers were the worst responders, and patients with the APOE-3/4 genotype were the best responders. In bigenic and trigenic models it was possible to differentiate the influencial effect of PS1 and PS2 polymorphic variants on mental performance in response to multifactorial therapy. The application of functional genomics to AD can be a suitable strategy for harmonization in molecular diagnosis and drug clinical trials. Furthermore, the pharmacogenomics of AD may contribute in the future to optimise drug development and therapeutics, increasing efficacy and safety, and reducing side-effects and unnecessary costs.
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PMID:Pharmacogenomics in Alzheimer's disease. 1236 58

Alzheimer's disease (AD) is a genetically complex disorder associated with multiple genetic defects either mutational or of susceptibility. Current AD genetics does not explain in full the etiopathogenesis of AD, suggesting that environmental factors and/or epigenetic phenomena may also contribute to AD pathology and phenotypic expression of dementia. The genomics of AD is still in its infancy, but is helping us to understand novel aspects of the disease including genetic epidemiology, multifactorial risk factors, pathogenic mechanisms associated with genetic networks and genetically-regulated metabolic cascades. AD genomics is also fostering new strategies in pharmacogenomic research and prevention. Functional genomics, proteomics, pharmacogenomics, high-throughput methods, combinatorial chemistry and modern bioinformatics will greatly contribute to accelerating drug development for AD and other complex disorders. The multifactorial genetic dysfunction in AD includes mutational loci (APP, PS1, PS2) and diverse susceptibility loci (APOE, A2M, AACT, LRP1, IL1A, TNF, ACE, BACE, BCHE, CST3, MTHFR, GSK3B, NOS3) distributed across the human genome, probably converging in common pathogenic mechanisms that lead to premature neuronal death. Genomic associations integrate polygenic matrix models to elucidate the genomic organization of AD in comparison to the control population. Using APOE-related monogenic models it has been demonstrated that the therapeutic response to drugs (e.g., cholinesterase inhibitors, non-cholinergic compounds) in AD is genotype-specific. A multifactorial therapy combining three different drugs yielded positive results during 6-12 months in approximately 60% of the patients. With this therapeutic strategy, APOE-4/4 carriers were the worst responders and patients with the APOE-3/4 genotype were the best responders. Other polymorphic variants (PS1, PS2) also influence the therapeutic response to different drugs in AD patients, suggesting that the final pharmacological outcome is the result of multiple genomic interactions, including AD-related genes and genes associated with drug metabolism, disposition, and elimination. The pharmacogenomics of AD may contribute in the future to optimise drug development and therapeutics, increasing efficacy and safety, and reducing side-effects and unnecessary costs.
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PMID:Pharmacogenomics for the treatment of dementia. 1245 80

Numerous genes have been implicated in Alzheimer's disease (AD), but, with the exception of a demonstrated association with the epsilon 4 allele of APOE, findings have not been consistently replicated across populations. One of the most widely studied is the gene for angiotensin I converting enzyme (ACE ). A meta-analysis of published data on a common Alu indel polymorphism in ACE was performed which indicated highly significant association of the insertion allele with AD (OR 1.30; 95% CI 1.19 - 1.41; P=4 x 10(-8)). To further explore the influence of ACE on AD, several single-nucleotide polymorphisms (SNPs) were genotyped in five independent populations represented by over 3100 individuals. Analyses based upon single markers and haplotypes revealed strong evidence of association in case-control models and also in a model examining the influence of variation in ACE upon cerebrospinal fluid levels of amyloid beta42 peptide (Abeta42). The most significant evidence for association with AD was found for an SNP, A-262T, located in the ACE promoter (OR 1.64; 95% CI 1.33 -1.94; P=2 x 10(-5)). Estimates of population attributable risk for the common allele of this SNP suggest that it, or an allele in tight linkage disequilibrium (LD) with it, may contribute to as much as 35% of AD in the general population. Results support a model whereby decreased ACE activity may influence AD susceptibility by a mechanism involving beta-amyloid metabolism.
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PMID:Haplotypes extending across ACE are associated with Alzheimer's disease. 1266 9

A screening of 22 DNA polymorphisms has been performed in western Mediterranean populations (Iberian Peninsula, Morocco, and Central Mediterranean Islands). The analyzed markers correspond to polymorphic sites in several candidate genes for cardiovascular disease including apolipopoteins and their receptors (APOA1, APOB, APOE, APOC1, APOC2, LPA, and LDLR), genes implied in the hemostasis regulation (Factor VII, alpha and beta-fibrinogen, alpha and beta platelet-integrin, tissue plasminogen activator, and plasminogen activator inhibitor-1), and the angiotensin converting enzyme gene. The results are presented of a partial analysis carried out in following population samples: 6 from the Iberian Peninsula, 2 from Morocco, and 3 from Central Islands. The degree of inter-population diversity was significant and consistent with data from other kind of genetic polymorphisms. The apportionment of the allele frequency variance supported a geographic structure into three main regions: Central Mediterranean Islands, the Iberia Peninsula and North Africa. The genetic distance pattern is compatible with a south-to-north North African influence in the Iberian Peninsula and a remarkable gene flow from sub-Saharan Africa into Morocco. Epidemiologically, North Africa is characterized by high frequencies of LPA PNR alleles with high number of repeats (protective for cardiovascular risk) and high frequencies of the APOE*E4 allele (risk factor) as compared with European populations.
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PMID:Molecular variation at functional genes and the history of human populations--data on candidate genes for cardiovascular risk in the Mediterranean. 1474 39


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