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Biomedical subjects

N Helbecque

Publications and source records attributed to N Helbecque.

At least 19 recordsLinked to original sources
PubMed2005

Hypoadiponectinaemia and high risk of type 2 diabetes are associated with adiponectin-encoding (ACDC) gene promoter variants in morbid obesity: evidence for a role of ACDC in diabesity.

AIMS/HYPOTHESIS: Morbid obesity (BMI>40 kg/m(2)) affecting 0.5-5% of the adult population worldwide is a major risk factor for type 2 diabetes. We aimed to elucidate the genetic bases of diabetes associated with obesity (diabesity), and to analyse the impact of corpulence on the effects of diabetes susceptibility genes. METHODS: We genotyped known single nucleotide polymorphisms (SNPs) in the adiponectin-encoding adipocyte C1q and collagen-domain-containing (ACDC) gene (-11,391G>A, -11,377C>G, +45T>G and +276G>T), the peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala SNP and ACDC exon 3 variants in 703 French morbidly obese subjects (BMI 47.6+/-7.4 kg/m(2)), 808 non-obese subjects (BMI<30 kg/m(2)) and 493 obese subjects (30< or =BMI<40 kg/m(2)). RESULTS: Two 5'-ACDC SNPs -11,391G>A, -11,377C>G were associated with adiponectin levels (p=0.0003, p=0.008) and defined a "low-level" haplotype associated with decreased adiponectin levels (p=0.0002) and insulin sensitivity (p=0.01) and with a risk of type 2 diabetes that was twice as high (p=0.002). In contrast, the prevalence of the PPARG Pro12Ala was identical in diabetic and normoglycaemic morbidly obese subjects. The PPARG Pro12 allele only displayed a trend of association with type 2 diabetes in the non-obese group. ACDC exon 3 variants were associated with type 2 diabetes in the non-obese group only (odds ratio 7.85, p<0.0001). In contrast, the 5'-ACDC "low-level" haplotype was associated with type 2 diabetes in obese and morbidly obese subjects (odds ratio 1.73 and 1.92) but not in non-obese individuals. CONCLUSIONS/INTERPRETATION: These data clarify the contribution of the 5'-ACDC SNPs to the risk of diabesity. Their interaction with corpulence suggests for the first time a different genetic profile of type 2 diabetes in morbidly obese patients compared with in less obese individuals.

Adiponectin↗
PubMed2005

Effect of common polymorphisms in the HNF4alpha promoter on susceptibility to type 2 diabetes in the French Caucasian population.

AIMS/HYPOTHESIS: The gene encoding HNF-4alpha, an orphan nuclear receptor playing critical roles in embryogenesis and metabolism by regulating gene expression in pancreatic beta cells, liver, and other tissues, is localised to chromosome 20q13, where linkage to type 2 diabetes has been shown in multiple studies. As two reports have independently demonstrated a convincing association with variants adjacent to the HNF-4alpha P2 promoter in Finnish and Ashkenazi Jewish populations, we evaluated their contribution to diabetes risk in the French Caucasian population. METHODS: Genotypes for four haplotype tag SNPs were analysed for association with diabetes in a case-control study of 744 unrelated type 2 diabetic patients and 686 normoglycaemic subjects, and for linkage in 148 diabetic families in whom significant linkage to the HNF4alpha region had been shown. RESULTS: The association seen in the Finnish and Ashkenazi studies for SNPs rs2144908 and rs1884614 located within a haplotype block encompassing the beta cell promoter P2 of HNF-4alpha was not replicated in our study; in French Caucasians the minor allele prevalence was increased in control subjects [odds ratio (OR) 0.80, uncorrected p=0.022 for rs2144908; OR 0.82 uncorrected p=0.058 for rs1884614]. Furthermore, none of the SNPs tested in the French familial sample was associated with diabetes, nor do they appear to contribute to the linkage. CONCLUSIONS/INTERPRETATION: None of the previously associated SNPs confer an increased risk for diabetes in French Caucasians. A large meta-analysis of association studies will determine whether there is a consistent association between particular SNPs upstream of HNF-4alpha and type 2 diabetes in several ethnic groups.

Case-Control Studies↗
PubMed2004

Overall alcohol intake, beer, wine, and systemic markers of inflammation in western Europe: results from three MONICA samples (Augsburg, Glasgow, Lille).

AIM: Anti-inflammatory effects of moderate alcohol consumption have been proposed to explain why moderate alcohol intake lowers coronary heart disease risk. We investigated the relationship between overall alcohol, beer or wine consumption and markers of systemic inflammation in three different geographical areas in Europe. METHODS AND RESULTS: Cross-sectional samples, each representative of the general population from Germany, Scotland, and France (MONICA Augsburg 1994/95, 2275 men and 2186 women, 25-74 years; Glasgow MONICA 1994/95, 561/616, 25-74 years, and MONICA Lille 1994/95, 581/574, 35-64 years) were studied. Alcohol intake was assessed by standardized interview. Adjusted means of C-reactive protein (CRP), fibrinogen, white blood cell (WBC) count, plasma viscosity (PV), and albumin were calculated among categories of alcohol intake, and separately for beer or wine consumption, by multiple linear regression. Self-reported moderate daily alcohol intake up to 40 g was associated with lower concentrations of CRP, fibrinogen, PV and WBC count, compared to non-drinking and heavy drinking, even after adjustment for various potential confounders. CONCLUSIONS: Moderate consumption of either wine or beer is associated with lower levels of systemic inflammatory markers in three different European areas, suggesting that ethanol itself might be largely responsible for the potential anti-inflammatory effects of these beverages.

Adult↗
PubMed2004

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.

Adult↗
PubMed2003

Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease.

Islet-brain1 (IB1) or c-Jun NH2 terminal kinase interacting protein-1 (JIP-1), the product of the MAPK8IP1 gene, functions as a neuronal scaffold protein to allow signalling specificity. IB1/JIP-1 interacts with many cellular components including the reelin receptor ApoER2, the low-density lipoprotein receptor-related protein (LRP), kinesin and the Alzheimer's amyloid precursor protein. Coexpression of IB1/JIP-1 with other components of the c-Jun NH2 terminal-kinase (JNK) pathway activates the JNK activity; conversely, selective disruption of IB1/JIP-1 in mice reduces the stress-induced apoptosis of neuronal cells. We therefore hypothesized that IB1/JIP-1 is a risk factor for Alzheimer's disease (AD). By immunocytochemistry, we first colocalized the presence of IB1/JIP-1 with JNK and phosphorylated tau in neurofibrillary tangles. We next identified a -499A>G polymorphism in the 5' regulatory region of the MAPK8IP1 gene. In two separate French populations the -499A>G polymorphism of MAPK8IP1 was not associated with an increased risk to AD. However, when stratified on the +766C>T polymorphism of exon 3 of the LRP gene, the IB1/JIP-1 polymorphism was strongly associated with AD in subjects bearing the CC genotype in the LRP gene. The functional consequences of the -499A>G polymorphism of MAPK8IP1 was investigated in vitro. In neuronal cells, the G allele increased transcriptional activity and was associated with an enhanced binding activity. Taken together, these data indicate that the increased transcriptional activity in the presence of the G allele of MAPK8IP1 is a risk factor to the onset of in patients bearing the CC genotype of the LRP gene.

Adaptor Proteins, Signal Transducing↗
PubMed2001

The angiotensin I converting enzyme gene as a susceptibility factor for dementia.

The frequency of a genetic susceptibility vascular factor, the deletion (D) allele of the angiotensin I converting enzyme gene (ACE), coding for a key enzyme of the renin angiotensin system, was characterized in two independent case--control studies. The results of the current study suggest that bearing at least one ACE D allele is a risk factor to develop dementia for subjects older than 74 years. This observation reinforces the hypothesis of a major implication of vascular risk factors in the occurrence of all types of dementia.

Aged↗
PubMed2001

Impact of sulfonylurea receptor 1 genetic variability on non-insulin-dependent diabetes mellitus prevalence and treatment: a population study.

The high affinity sulfonylurea receptor 1 (SUR1) is involved in the metabolism of glucose in pancreatic beta-cells. We investigated the impact of the SUR1 intron 16-3t-->c polymorphism on non-insulin-dependent diabetes mellitus (NIDDM) prevalence in a large representative sample of French men and women, 35-64 years old, and explored potential relationships between the SUR1 intron 16 -t-->c polymorphism and sulfonylurea therapy efficiency. This study took place in Lille (northern), Strasbourg (eastern), and Toulouse (southern France). One hundred and twenty-two subjects with NIDDM were registered. We stratified NIDDM subjects according to their medical treatment: sulfonylureas (n = 70) versus other treatments (n = 50). From the three populations, a control group was selected (n = 1,250). Subjects carrying the cc intron 16 genotype had an increased risk of NIDDM [odds ratio (OR) = 1.76, 95% confidence interval (CI) 1.10-2.80; P = 0.017]. Subjects bearing at least one -3c allele and treated with sulfonylurea agents had fasting plasma triglyceride concentrations 35% lower than subjects that were tt homozygous (P = 0.026), whereas no difference could be detected between genotypes in NIDDM subjects treated with other treatments. The SUR1 intron 16 -3t-->c polymorphism was associated with an increased susceptibility to NIDDM in this population study, and seems to modulate the sulfonylurea therapy efficiency on hypertriglyceridemia reduction. This observation may help to better target the various therapies available for treatment of NIDDM.

ATP-Binding Cassette Transporters↗
PubMed2001

VLDL receptor polymorphism, cognitive impairment, and dementia.

OBJECTIVE: Clinical, epidemiologic, and pathologic observations suggest that vascular risk factors are associated with impaired cognition. Previous studies supported an association between cognitive decline and APOE. Although the underlying mechanism is not clear, it might involve apoE receptors, such as the very low density lipoprotein receptor. METHODS: The impact of a polymorphic triplet repeat in the very low density lipoprotein receptor gene (VLDLR) on cognitive function was examined in two independent studies: a population study involving 221 demented subjects compared with 249 control subjects and a clinical study involving 124 demented subjects compared with 179 control subjects. RESULTS: In the population study, the presence of the VLDLR-5-repeat allele was associated with a relative risk of dementia (OR, 1.9; 95% CI, 1.2 to 3.0). This result was confirmed in the clinical study (OR, 8.1; 95% CI, 4.4 to 15.1) and was more pronounced in subjects with mixed or vascular dementia than in patients with AD. CONCLUSION: The VLDLR-5-repeat allele may constitute a genetic susceptibility factor for dementia, particularly in the presence of vascular risk factors. This observation suggests the influence of vascular risk factors in the occurrence of dementia.

Aged↗
PubMed2001

Polymorphisms in the insulin response element of APOC-III gene promoter influence the correlation between insulin and triglycerides or triglyceride-rich lipoproteins in humans.

OBJECTIVE: To assess whether the -455 and -482 mutations in APOC-III gene insulin response element affect the relationships between plasma insulin and triglyceride-rich lipoprotein levels. DESIGN: Population-based studies. SUBJECTS: The population sample was composed of 983 subjects (485 men and 498 women), aged between 35 and 65 y, randomly sampled from the electoral rolls in Northern France and stratified on gender and 10 y age groups. MEASUREMENTS: Plasma triglyceride, apolipoprotein C-III, apoB, LpC-III:B and LpE:B lipoprotein particles and insulin levels were measured. Two polymorphisms in APOC-III gene insulin response element (T-->C at -455 and/or C-->T at -482) were determined. RESULTS: Plasma insulin was positively correlated to triglyceride levels (P<0.0001), apo C-III (P<0.003), LpC-III:B (P<0.0001), apoB (P<0.0001) and LpE:B (P<0.0001). This association differed significantly according to APOC-III insulin response element polymorphisms. The relationship between insulin and LpC-III:B (P<0.02) or apoB (P<0.02) was greater in women bearing the C allele of -455 than the T allele. Similarly, the relationship between insulin and LpC-III:B (P<0.02) or LpE:B (P<0.05) was greater in women bearing the T allele of -482 than the C allele. There was no evidence for any effect in men. CONCLUSION: These results suggest that the relationship between plasma insulin and triglyceride-rich lipoprotein levels is partly influenced by polymorphisms in APOC-III insulin response element.

Adult↗
PubMed2001

The human G-protein beta3 subunit C825T polymorphism is associated with coronary artery vasoconstriction.

AIMS: Abnormal coronary vasomotion plays a role in the clinical expression of coronary artery disease. We hypothesized that the functional C825T polymorphism located in the ubiquitous G-protein beta3 subunit, implicated in the cellular signal transduction of many receptors, could modify artery coronary vasomotion. We assessed the potential association of the pertussis toxin-sensitive G protein beta3 subunit (GNB3) gene C825T polymorphism on coronary vasomotion in humans. METHODS AND RESULTS: We examined the response of angiographically normal human coronary arteries (n=131) after intravenous injection of methylergonovine maleate, a vasoconstrictor, followed by injection of isosorbide dinitrate, a vasodilator, according to GNB3 genotypes. Coronary vasomotion was assessed with quantitative coronary angiography. Subjects bearing at least one T allele had greater susceptibility to vasoconstriction in response to methylergonovine maleate than CC subjects, whereas vasodilation in response to isosorbide dinitrate did not differ among the different genotypes. CONCLUSION: The C825T polymorphism of the G-protein beta3 subunit may be a genetic determinant of coronary artery vasomotion in humans.

Coronary Angiography↗
PubMed2000

Very low density lipoprotein receptor in Alzheimer disease.

The apolipoprotein (APO) E4 isoform is associated with an accelerated rate of Alzheimer disease (AD) expression in sporadic as well as late-onset familial forms of the disease but the precise mechanism is unknown. In an attempt to approach the possible mechanisms involved, APOE receptors have been studied. They all belong to the low density lipoprotein (LDL) receptor family and share the same structural motifs. Some of them are preferentially expressed in the brain such as the LDL receptor related protein, the apolipoprotein E receptor 2, and the very low density lipoprotein (VLDL) receptor. These receptors have been suspected to be involved in Alzheimer disease at various levels. Among them, the VLDL receptor was extensively explored. Although genetic studies conducted on a polymorphism in the promoter of the VLDL receptor in Japanese and Caucasian populations gave divergent results, this does not exclude a possible involvement of the VLDL receptor in AD.

Alzheimer Disease↗
PubMed2000

Interactions between apolipoprotein E and apolipoprotein(a) in patients with late-onset Alzheimer disease.

BACKGROUND: Apolipoprotein(a) [apo(a)], the distinctive, highly polymorphic glycoprotein of lipoprotein(a), shares a series of common features with apolipoprotein E (apoE), which is implicated in the development of Alzheimer disease. OBJECTIVE: To determine whether apo(a) is associated with Alzheimer disease. DESIGN: Case-control study. SETTING: University hospitals in Europe. PARTICIPANTS: 285 patients with Alzheimer disease and 296 controls. MEASUREMENTS: Plasma lipoprotein(a) levels, size of the apo(a) isoforms, and apoE and apo(a) genotyping. RESULTS: Among carriers of the apoE epsilon4 allele, lipoprotein(a) was associated with a progressive, age-dependent increased risk for late-onset Alzheimer disease (odds ratio for patients >80 years of age, 6.0 [95% CI, 1.2 to 30.8]; P<0.01). Among noncarriers older than 80 years of age, lipoprotein(a) was associated with a reduced risk for Alzheimer disease (odds ratio, 0.4 [CI, 0.2 to 0.91; P<0.05). CONCLUSIONS: In this convenience sample, lipoprotein(a) was an additional risk factor for late-onset Alzheimer disease in carriers of the apoE epsilon4 allele. However, lipoprotein(a) may protect against late-onset Alzheimer disease in noncarriers.

Age of Onset↗
PubMed2000

An uncoupling protein 3 gene polymorphism associated with a lower risk of developing Type II diabetes and with atherogenic lipid profile in a French cohort.

AIMS/HYPOTHESIS: The UCP2-UCP3 gene region has been previously associated with obesity and diabetes. In a large representative cohort of Northern France (MONICA project), we studied the effect of a recently reported C/T polymorphism located in the 5' sequences of the UCP3 gene on anthropometric measurements and lipid profile. We also examined the association of this polymorphism with obesity and Type II (non-insulin-dependent) diabetes mellitus. METHODS: The -55 C/T polymorphism of the UCP3 gene has been genotyped in 1155 subjects from the MONICA project. Association studies were done with diabetes, obesity and related phenotypes. Results were ascertained in a second cohort of well-characterized Type II diabetic and control subjects. RESULTS: The variant T allele was associated with a decreased risk of developing Type II diabetes. Frequencies of the T allele were 13.3% compared with 22%, p = 0.04, in the diabetic and control groups, respectively. This observation was confirmed in the second cohort of French Type II diabetic (n = 171) and control (n = 124) subjects: 17.8% compared with 25%, p = 0.03. Moreover, subjects bearing the TT genotype had higher plasma total cholesterol and LDL-cholesterol concentrations (p = 0.0006 and p = 0.001, respectively) than subjects bearing wild or heterozygous genotypes. CONCLUSION/INTERPRETATION: The UCP3 -55 C/T polymorphism was associated with a higher atherogenic profile and modified the risk for the development of Type II diabetes.

Adult↗
PubMed2000

Gender related association between genetic variations of APOC-III gene and lipid and lipoprotein variables in northern France.

The goal of the present study was to assess the impact of variability at the APOC-III insulin response element (APOC-III IRE) genetic locus on lipid, lipoprotein and complex lipoprotein particle levels as well as on the risk of dyslipidemia, in the population of northern France. To this end, 590 men and 579 women were randomly selected in the urban community of Lille in the framework of the MONICA project. Three polymorphisms, -482, -455 in the APOC-III insulin response element (IRE) and SstI in the 3'-noncoding region of the APOC-III gene locus were assessed. Compared to the most common alleles, the rare alleles of -482 and -455 were associated with increased levels of apoB-containing particles (LDL-cholesterol, apoB) and of triglyceride-related markers (apoC-III and LpC-III:B) in women, but not in men, suggesting a gender-related impact of APOC-III polymorphisms on these variables. Similarly, triglycerides, LpC-III:B and apoB were higher in women bearing the rare allele of SstI than in those with the most common allele. There was no evidence for any significant association between any of the -482, -455, and SstI alleles and lipid disorders (mixed hyperlipidemia, hypertriglyceridemia and hypercholesterolemia) in this sample of randomly selected men and women from northern France. In contrast, the prevalence of the haplotype that combined the rare alleles of the -482 and -455 sites was increased only in women with hypertriglyceridemia. Therefore, although the individual risk of hypertriglyceridemia is increased in women with the haplotype T, C at -482, -455, it appears that the -482, -455 and SstI APOC-III gene polymorphisms are not major contributors to the risk of dyslipidemia in the population of northern France.

Adult↗
PubMed2000

Impact of the Peroxisome Proliferator Activated Receptor gamma2 Pro12Ala polymorphism on adiposity, lipids and non-insulin-dependent diabetes mellitus.

OBJECTIVE: The Pro12Ala polymorphism of the Peroxisome Proliferator Activated Receptor gamma2 (PPARgamma2) gene has been inconsistently associated with body mass index variations and non-insulin-dependent diabetes mellitus (NIDDM). We investigated the impact of this polymorphism on obesity markers, lipid and glucose variables in a sample of French subjects and evaluated its possible role in the onset of NIDDM. DESIGN AND SUBJECTS: Within the framework of the WHO-MONICA project, a population study composed of 1195 subjects aged 35-64 y was randomly sampled from the electoral rolls of the urban community of Lille, in northern France. Subjects receiving medical treatment for hypercholesterolemia, hypertension or diabetes mellitus were excluded for the analyses, to avoid any interferences between medical treatment and biological variables. This resulted in a sample size of 839 subjects (421 men/418 women, age=49.4+/-8.1 y, body mass index (BMI)=25.7+/-4.4 kg/m2). To evaluate the role of the Pro12Ala polymorphism in the onset of NIDDM, we evaluated its distribution in 170 Caucasian NIDDM subjects from a clinical series (117 men/53 women, age=62.3+/-9.0 y, BMI=30.1+/-3.6 kg/m2). MEASUREMENTS: The PPARgamma2 Pro12Ala polymorphism genotyping was carried out with allele specific oligonucleotides hybridisation. Data were statistically analysed for association with various obesity markers (body weight (BW), BMI, waist-to-hip ratio (WHR), plasma leptin concentrations, lipid and glucose variables. RESULTS: In the WHO-MONICA population, the Ala allele frequency was 0.11. The presence of the Ala allele was significantly associated with higher body weight (P=0.002), BMI (P=0.02), height (P=0.02) and waist circumference (P=0.04). Increased plasma concentrations of total cholesterol (P=0.01), LDL-cholesterol (P=0.004) and apolipoprotein B (P=0.01) were also detected in Ala allele bearers. The distribution of the Pro12Ala polymorphism was similar in NIDDM subjects (Ala allele frequency: 0.10) and in the WHO-MONICA population subjects. CONCLUSION: Our results suggest that genetic variability of PPARgamma2 affects body weight control and lipid homeostasis in humans and do not support a significant role for the PPARgamma2 Pro12Ala polymorphism in the aetiology of NIDDM. International Journal of Obesity (2000) 24, 195-199

Adult↗
PubMed2000

Impact of polymorphisms of the human beta2-adrenoceptor gene on obesity in a French population.

OBJECTIVE: To investigate the impact of two common polymorphisms in the human beta2-adrenoceptor gene (Gly16Arg and Gln27Glu substitutions) on obesity and anthropometric measurements as well as blood variables in a large sample of a French population. DESIGN AND SUBJECTS: Within the framework of the WHO-MONICA project, a population study composed of 1195 subjects aged 35-64 y was randomly sampled from the electoral rolls of the Urban Community of Lille, in northern France. Subjects without any medical treatment (for hypercholesterolaemia, hypertension or diabetes mellitus) susceptible to interfere with body weight and biological variables were selected (n = 836, 419 men/417 women, age = 49.5+/-8.1 y, body mass index (BMI) = 25.7+/-4.4 kg/m2). Subjects with a body mass index > or = 30 kg/m2 were considered as obese (n = 119, age = 49.5+/-8.2 y, BMI = 33.9+/-3.3 kg/m2 range 30-44). MEASUREMENTS: Genotyping was carried out with allele-specific oligonucleotides hybridization. Association between genotypes and various obesity markers (body weight, body mass index, waist and waist-to-hip ratio), lipid, glucose and insulin variables were studied. RESULTS: The Gly16Arg and Gln27Glu polymorphisms were in complete linkage disequilibrium. Gln27Gln subjects had an increased risk of obesity (odds ratio (OR) = 1.77, 95% CI 1.19-2.62, P = 0.005). This effect was mainly detected in men (OR = 2.40, 95% CI 1.34-4.27, P = 0.003). Men bearing the Gln27Gln genotype had higher body weight, BMI, waist and hip circumferences and waist-to-hip ratio than others. Moreover, if Gln27Gln men carried in addition the Arg16 allele, the increase in body weight, BMI and waist-to-hip ratio was more important. CONCLUSION: Our results suggest that genetic variability of the beta2-adrenoceptor gene is implicated in body weight regulation and in the onset of obesity in French men.

Adult↗
PubMed2000

The renin angiotensin system and Alzheimer's disease.

Recent reports sustain the hypothesis of tight links between vascular and neurodegenerative diseases: associations between atherosclerosis lesions and Alzheimer's disease (AD), increased risk of AD for hypertensive subjects, decreased risk of dementia for elderly treated with hypotensive drugs, and a major impact of apolipoprotein E polymorphism, a protein of the lipid metabolism, on the occurrence of AD. All these results suggest that vascular determinants, both environmental and genetic, may predispose to or speed up dementia. As a major player of vascular homeostasis, the renin angiotensin system (RAS) proteins constitute an interesting source of candidate genes. Among these, the angiotensin I-converting enzyme gene (ACE), a central enzyme of the RAS, presents in its sequence a deletion (D)/insertion (I) polymorphism associated with variations of plasma ACE levels and with the risk of myocardial infarction. We explored the impact of this genetic polymorphism on the risk of cognitive impairment and of dementia in several epidemiological studies. Physiopathological hypotheses suggest a possible involvement of the RAS proteins in the occurrence and evolution of AD. Moreover, although inconsistent, several results of case-control studies tend to suggest that the ACE I/D genetic polymorphism may constitute a genetic susceptibility factor for dementia, reinforcing the hypothesis of a major implication of vascular risk factors in the occurrence of dementia.

Aged↗