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The purpose of this study was to examine the impact of two polymorphisms (rs4291A>T and rs4343G>A) in the ACE gene on the risk of Alzheimer's disease (AD), using a population-based cohort of 9294 subjects selected from the electoral rolls of three French cities (the Three-City Study). Two follow-up examinations took place 2 and 4 years after inclusion. Diagnosis of dementia was assessed at baseline and at each follow-up examination by neurologists independent of the 3C Study group. For the present analysis, subjects whose mother tongue was not French, those from abroad and those lost at follow-up were excluded, leaving a sample of 6791 subjects. 108 subjects were demented at baseline and 216 subjects, among which 141 had AD, developed a dementia during follow-up. The genotype distributions of the ACE SNPs rs4291 and rs4343 did not differ according to cognitive status. After adjustment for confounding variables, the risk of developing AD was similar whatever the genotype (rs4291 AT vs TT: OR=0.90, p=0.65; AA vs TT: OR=1.05, p= 0.84; rs4343 GA vs GG: OR=1.15, p= 0.48; AA vs GG: OR=1.25, p= 0.37). No global haplotype effect could be observed on the risk of AD. [ABSTRACT FROM AUTHOR]

BACKGROUND/AIMS: Accumulating biological and epidemiological evidence suggests a close link between cholesterol metabolism and the pathophysiology of Alzheimer's disease (AD). The observation that the use of statins reduces the risk of AD sustains this hypothesis. Apolipoprotein A-I (APOA1) is the major component of the high-density lipoproteins, particles involved in reverse cholesterol transport. Therefore, genetic polymorphisms in the gene encoding APOA1 might influence cholesterol metabolism and be a risk factor for AD. A previous study suggested an impact of a G-->A polymorphism at position -75 bp in the APOA1 gene on the risk for early-onset AD and on the age at onset of the disease. We studied this polymorphism in 3 independent European population samples. METHODS: Genotyping was conducted asdescribed in the previous study. RESULTS: We were unable to show any impact of this polymorphism on the risk of AD. Conversely, subjects bearing the A allele of this polymorphism were at risk of cognitive decline. CONCLUSION: Our resultssuggest an impact of the G-->A polymorphism at position -75 bp in the APOA1 gene on cognitive impairment, but not on the risk of AD. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The gene encoding HNF-4α, 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 HNP-4α 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 HNP4α region had been shown. Results: The association seen in the Finnish and Ashkenazi studies for SNPs rs2 144908 and rs 1884614 located within a haplotype block encompassing the beta cell promoter P2 of HNP-4α 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 rs2 144908; 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 HNP-4α and type 2 diabetes in several ethnic groups. [ABSTRACT FROM AUTHOR]

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 β3 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 β3 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 β3 subunit may be a genetic determinant of coronary artery vasomotion in humans. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the impact of two common polymorphisms in the human β[sub 2]-adrenoceptor gene (Gly16Arg and GIn27Glu 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 35-64y 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, 419men/417 women, age = 49.5 ± 8.1y, body mass index (BMI)=25.7±4.4kg/m²). Subjects with a body mass index ≥30kg/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 GIn27Glu polymorphisms were in complete linkage disequilibrium. GIn27GIn 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 GIn27GIn genotype had higher body weight, BMI, waist and hip circumferences and waist-to-hip ratio than others. Moreover, if GIn27GIn 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 β2-adrenoceptor gene is implicated in body weight regulation and in the onset of obesity in French men. [ABSTRACT FROM AUTHOR]