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SUMMARYThe Bridging Integrator 1 (BIN1) gene is a major susceptibility gene for Alzheimer’s disease (AD). Deciphering its pathophysiological role is challenging due to its numerous isoforms. Here we observed in Drosophila that human BIN1 isoform1 (BIN1iso1) overexpression, contrary to BIN1iso8 and BIN1iso9, induced an accumulation of endosomal vesicles and neurodegeneration. Systematic search for endosome regulators able to prevent BIN1iso1-induced neurodegeneration indicated that a defect at the early endosome level is responsible for the neurodegeneration. In human induced neurons (hiNs) and cerebral organoids, BIN1 knock-out resulted in the narrowing of early endosomes. This phenotype was rescued by BIN1iso1 but not BIN1iso9 expression. Finally, BIN1iso1 overexpression also led to an increase in the size of early endosomes and neurodegeneration in hiNs. Altogether, our data demonstrate that the AD susceptibility gene BIN1, and especially BIN1iso1, contributes to early-endosome size deregulation, which is an early pathophysiological hallmark of AD pathology.

International audience; BACKGROUND: Blood polyunsaturated fatty acid (PUFA) levels are determined by diet and by endogenous synthesis via Delta 5- and Delta 6-desaturases (encoded by the FADS] and FADS2 genes, respectively). Genome-wide association studies have reported associations between FADS)-FADS2 polymorphisms and the plasma concentrations of PUFAs, HDL- and LDL-cholesterol, and triglycerides. However, much remains unknown regarding the molecular mechanisms explaining how variants affect the function of FADS1-FADS2 genes. OBJECTIVE: Here, we sought to identify the functional variant(s) within the FADS gene cluster. METHODS: To address this question, we (1) genotyped individuals (n = 540) for the rs174547 polymorphism to confirm associations with PUFA levels used as surrogate estimates of desaturase activities and (2) examined the functionality of variants in linkage disequilibrium with rs174547 using bioinformatics and luciferase reporter assays. RESULTS: The rs174547 minor allele was associated with higher erythrocyte levels of dihomo-gamma-linolenic acid and lower levels of arachidonic acid, suggesting a lower Delta 5-desaturase activity. In silico analyses suggested that rs174545 and rs174546, in perfect linkage disequilibrium with rs174547, might alter miRNA binding sites in the FADS1 3'UTR. In HuH7 and HepG2 cells transfected with FADS1 3'UTR luciferase vectors, the haplotype constructs bearing the rs174546T minor allele showed 30% less luciferase activity. This relative decrease reached 60% in the presence of miR-149-5p and was partly abolished by cotransfection with an miR-149-5p inhibitor. CONCLUSION: This study identifies FADS1 rs174546 as a functional variant that may explain the associations between FADS1-FADS2 polymorphisms and lipid-related phenotypes.

article i nfo Background: In European populations, the NPPB rs198389 single nucleotide polymorphism (SNP) is associated with a reduced risk of type 2 diabetes mellitus (T2DM). We investigated the putative associations between NPPB rs198389, the T2DM risk and quantitative metabolic traits in an Algerian population. Methods:The association analysis was performed as a T2DM case-control study (with 78 cases and 645 controls) nested into the ISOR population-based study. Results: TheNPPBrs198389SNP wasnotassociatedwith T2DM(odds ratio(OR)(95%confidence interval (CI))= 0.73 (0.51-1.04), p = 0.08). However, the C allele was associated with lower fasting plasma insulin levels (p = 0.05) and a lower homeostaticmodel assessmentinsulin resistance index (p= 0.05) innon-diabeticindividuals. Conclusion: The NPPB rs198389 SNP might modulate fasting insulin levels in an Algerian population.

Genome-wide association studies have identified many lipid-associated loci primarily in European and Asian populations. In view of the differences between ethnic groups in terms of the frequency and impact of these variants, our objective was to evaluate the relationships between eight lipid-associated variants (considered individually and in combination) and fasting serum triglyceride, total cholesterol, HDL- and LDL-cholesterol levels in an Algerian population sample (ISOR study, n = 751). Three SNPs (in SORT1, CETP and GCKR) were individually associated with lipid level variations. Moreover, the risk allele scores for total cholesterol, triglyceride and LDL-C levels (encompassing between three and six SNPs) were associated with their corresponding lipid traits. Our study is the first to show that some of the lipid-associated loci in European populations are associated with lipid traits in Algerians. Although our results will have to be confirmed in other North African populations, this study contributes to a better understanding of genetic susceptibility to lipid traits in Algeria.

Previous studies have clearly demonstrated the beneficial effect of beta-blockers in patients with stable congestive heart failure (CHF). beta-blockers improve left ventricular ejection fraction (LVEF) and reduce cardiac mortality. However, there is an interindividual variability in the response to these agents. Two studies have suggested a possible impact of some functional betaAR gene polymorphisms on the effects of beta-blockade. The objective of the study is to analyse the association between genetic variations in the beta1 or the beta2 adrenoreceptor (AR) gene and the effects of beta-blockade in patients with stable CHF. We studied 199 consecutive patients with stable CHF not treated with beta-blockers. Before introduction of beta-blockers and 3 months after the maximal tolerated dose was reached, patients underwent an echocardiography and a radionuclide angiography. The beta1ARGly389Arg, beta1ARSer49Gly, beta2ARGly16Arg, beta2ARGln27Glu and beta2ARThr164Ile polymorphisms were determined: beta-blockade resulted in a significant decrease in heart rate, a significant increase in LVEF (from 30+/-10% to 40+/-13%, P

Beta-adrenergic receptor blockade is an established treatment of chronic heart failure (HF). Previous studies have suggested a potential pharmacogenetic interaction between beta-blocker therapy and the angiotensin-converting enzyme (ACE) I/D polymorphism in patients with HF.We designed this study to analyze changes in myocardial function of HF patients in response to beta-blocker therapy as a function of the ACE I/D polymorphism.We studied 199 consecutive patients with chronic HF not treated with beta-blockers. Before initiation of beta-blockers and 3 months after the maximal tolerated dose was reached, patients underwent echocardiography, radionuclide angiography, and a cardiopulmonary exercise test. We extracted genomic DNA from white blood cells and determined the ACE I/D polymorphism. Thirty-five (18%) patients had the II genotype, 86 (43%) the ID genotype and 78 (39%) the DD genotype. A significant and similar improvement in left ventricular ejection fraction (LVEF) was observed in II (from 0.30+/-0.10 to 0.41+/-0.13; P0.0001), ID (from 0.29+/-0.11 to 0.39+/-0.13; P0.0001) and DD patients (from 0.31+/-0.11 to 0.40+/-0.13; P0.0001). Peak Vo(2) before and after beta-blockade was similar among the three groups. The proportion of responders to beta-blockers (patients without cardiac events during titration who had an increase in LVEF5% after beta-blockers) was similar among the three groups (II: 65.9%%, ID: 60.6%%, DD: 65.9%; P=NS). During a median follow-up of 933 days, there was no evidence for any effect of ACE I/D polymorphism on cardiac survival.We observed no evidence of pharmacogenetic interaction between the ACE I/D polymorphism and the effects of beta-blockade on LVEF and other prognostic parameters in patients with chronic HF. Our results support the initiation of beta-blockers in HF patients with the II or the ID genotype as well as in those with the DD genotype.

Although possession of the epsilon 4 allele of the apolipoprotein E gene appears to be an important biological marker for Alzheimer's disease (AD) susceptibility, strong evidence indicates that at least one additional risk gene exists on chromosome 12. Here, we describe an association of the 3'-UTR +1073 C/T polymorphism of the OLR1 (oxidised LDL receptor 1) on chromosome 12 with AD in French sporadic (589 cases and 663 controls) and American familial (230 affected sibs and 143 unaffected sibs) populations. The age and sex adjusted odds ratio between the CC+CT genotypes versus the TT genotypes was 1.56 (p=0.001) in the French sample and 1.92 (p=0.02) in the American sample. Furthermore, we have discovered a new T/A polymorphism two bases upstream of the +1073 C/T polymorphism. This +1071 T/A polymorphism was not associated with the disease, although it may weakly modulate the impact of the +1073 C/T polymorphism. Using 3'-UTR sequence probes, we have observed specific DNA protein binding with nuclear proteins from lymphocyte, astrocytoma, and neuroblastoma cell lines, but not from the microglia cell line. This binding was modified by both the +1071 T/A and +1073 C/T polymorphisms. In addition, a trend was observed between the presence or absence of the +1073 C allele and the level of astrocytic activation in the brain of AD cases. However, Abeta(40), Abeta(42), Abeta total, and Tau loads or the level of microglial cell activation were not modulated by the 3'-UTR OLR1 polymorphisms. Finally, we assessed the impact of these polymorphisms on the level of OLR1 expression in lymphocytes from AD cases compared with controls. The OLR1 expression was significantly lower in AD cases bearing the CC and CT genotypes compared with controls with the same genotypes. In conclusion, our data suggest that genetic variation in the OLR1 gene may modify the risk of AD.

Objectives Our hypothesis was that functional polymorphisms in matrix metalloproteinase (MMP) genes may act as susceptibility factors for the development of coronary aneurysms (CAs). Background Different forms of remodeling have been described at the level of coronary arteries; CA, reported in 1% to 5% of patients with angiographic evidence of coronary artery disease (CAD), are one of them. Matrix metalloproteinases have been implicated in the pathogenesis of aneurysm development through increased proteolysis of extracellular matrix proteins. Methods We screened 3,862 patients who underwent coronary angiography and identified 113 patients with CAD with at least one CA (CA group); these patients were matched with 226 patients with CAD without CA (control group). The −1,306 C/T MMP-2, 5A/6A MMP-3, CA-repeat MMP-9 and −82 A/G MMP-12 polymorphisms were determined. Results The MMP-2, MMP-9 and MMP-12 polymorphisms were not associated with CA. By contrast, the 5A/5A genotype of MMP-3 was significantly more frequent in the CA group than in the control group (31% vs. 18%, p = 0.015); similarly, the MMP-3 5A allele was more frequent in the CA group (p = 0.009). Three variables were independently associated with CA: the MMP-3 5A/5A genotype (odds ratio [OR] = 2.23, 95% confidence interval [CI] [1.27 to 3.93]), a previous myocardial infarction (OR = 1.91, 95% CI [1.14 to 3.20]) and a history of aortic aneurysm (OR = 21.06, 95% CI [2.35 to 188]). Conclusions The MMP-3 5A allele is associated with the occurrence of CA. Our results suggest that an increased proteolysis in the arterial wall may act as a susceptibility factor for the development of CA in patients with coronary atherosclerosis.

Background Genome-wide association studies have identified variants associated with BMI in populations of European descent. We sought to establish whether genetic variants that are robustly associated with BMI could modulate anthropometric traits and the obesity risk in an Algerian population sample, the ISOR study. The ISOR study of 787 adult subjects (aged between 30 and 64) provided a representative sample of the population living in the city of Oran (north-west of Algeria). We investigated the combined effect of 29 BMI established genetic variants using a genetic predisposition score (GPS) on anthropometric traits and obesity risk in 740 subjects. Results We found that each additional risk allele in the GPS was associated with an increment in the mean [95% CI] for BMI of 0.15 [0.06 - 0.24] kg/m2 (p = 0.001). Although the GPS was also associated with higher waist (p = 0.02) and hip (p = 0.02) circumferences, these associations were in fact driven by BMI. The GPS was also associated with an 11% higher risk of obesity (OR [95%CI] = 1.11 [1.05 - 1.18], p = 0.0004). Conclusions Our data showed that a GPS comprising 29 BMI established loci developed from Europeans seems to be a valid score in a North African population. Our findings contribute to a better understanding of the genetic susceptibility to obesity in Algeria. Electronic supplementary material The online version of this article (doi:10.1186/s12863-014-0128-1) contains supplementary material, which is available to authorized users.

Genome-wide association studies and subsequent replication studies have pinpointed 29 genetic variants associated with blood pressure (BP). None of these studies included North African populations. We therefore looked at whether or not these genetic variants modulated BP and hypertension (HTN) risk in an Algerian population sample. Twenty-nine single-nucleotide polymorphisms (SNPs) were genotyped in a representative sample of 787 subjects from the InSulino-résistance à ORan (ISOR) study (378 men and 409 women aged between 30 and 64 years and recruited from within the city of Oran, Algeria). Genetic variants were considered both individually and when combined as genetic predisposition scores (GPSs) for systolic BP (SBP), diastolic BP (DBP) and HTN risk. The SNPs in CYP1A1-ULK3, HFE and SH2B3 were significantly associated with BP and/or HTN. The SBP-GPS, DBP-GPS and HTN-GPS were associated with higher levels of DBP (+0.24 mm Hg P=0.05, +0.23 mm Hg P = 0.05 and +0.26 mm Hg P = 0.03, respectively). Moreover, the three GPSs tended to be associated with a 6% higher risk of HTN. Our study is the first to show that some of the BP loci validated in subjects of European descent were associated (either individually or when combined as GPSs) with BP traits and/or the HTN risk in an Algerian population, but to a lesser extent than in European populations. Although larger studies and meta-analyses of North African populations are needed to confirm the present results, our data contribute to a better understanding of genetic susceptibility to HTN.

Summary 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.

Objectif Le gene TCF7L2 (Transcription Factor 7-Like 2) est le facteur de predisposition au diabete de type 2 (DT2) le plus important. Cependant, son impact n'est pas connu dans la population Algerienne. Materiels et methodes Une enquete en population a ete realisee, en 2007-2009 sur la population adulte oranaise (30 a 64 ans). Au total, 751 sujets, tires au sort dans la liste des assures sociaux, ont participe a l'etude. Les apports alimentaires ont ete estimes par un questionnaire de frequence de consommation hebdomadaire. Le polymorphisme rs7903146 a ete genotype par la methode KASPar. Resultats L'allele T du polymorphisme rs7903146 est associe a une diminution du poids corporel ( p = 0,02), de l'indice de masse corporel (IMC) ( p = 0,009), ainsi que du tour de taille ( p = 0,01) et du ratio tour de taille-tour de hanches ( p = 0,02). L'allele T est associe a une augmentation du risque de DT2 (OR (intervalle de confiance 95 %) = 1,55 (1,09–2,20), p = 0,01), cette association etant independante de l'IMC. En considerant le risque de la survenue du DT2, des interactions significatives entre le polymorphisme rs7903146 et la consommation de dessert ( p = 0,05) ou de lait ( p = 0,01) ont ete observees. Le risque de DT2 est augmente chez les individus porteurs de l'allele T ayant une forte consommation de dessert et de lait (OR = 2,61 (1,51-4,52), p = 0,0006, et OR=2,46 (1,47-4,12), p = 0,0006, respectivement). De plus, chez les sujets ayant une consommation elevee en dessert, l'allele T est egalement associe a une glycemie a jeun plus elevee (4,78 ± 0,51 mmol/L chez les sujets ml, 4,72 ± 0,48 mmol/L chez les sujets CT et 4,89 ± 0,46 mmol/L chez les sujets TT, p = 0,03). Conclusion Nous avons montre que l'allele T du polymorphisme rs7903146 de TCF7L2 est associe a un risque plus eleve de DT2 dans une population alge-rienne. Cette association est exacerbee en cas de consommation elevee de dessert, ce qui suggere que certaines interactions gene-alimentation peuvent augmentent le risque de DT2. Declaration d’interet Les auteurs declarent ne pas avoir d'interet direct ou indirect (financier ou en nature) avec un organisme prive, industriel ou commercial en relation avec le sujet presente.

Background The importance of apolipoprotein E (APOE) in lipid and lipoprotein metabolism is well established. However, the impact of APOE polymorphisms has never been investigated in an Algerian population. This study assessed, for the fist time, the relationships between three APOE polymorphisms (epsilon, rs439401, rs4420638) and plasma lipid concentrations in a general population sample from Algeria. Methods The association analysis was performed in the ISOR study, a representative sample of the population living in Oran (787 subjects aged between 30 and 64). Polymorphisms were considered both individually and as haplotypes. Results In the ISOR sample, APOE ϵ4 allele carriers had higher plasma triglyceride (p=0.0002), total cholesterol (p=0.009) and LDL-cholesterol (p=0.003) levels than ϵ3 allele carriers. No significant associations were detected for the rs4420638 and rs439401 SNPs. Linkage disequilibrium and haplotype analyses confirmed the respectively deleterious and protective impacts of the ϵ4 and ϵ2 alleles on LDL-cholesterol levels and showed that the G allele of the rs4420638 polymorphism may exert a protective effect on LDL-cholesterol levels in subjects bearing the APOE epsilon 4 allele. Conclusion Our results showed that (i) the APOE epsilon polymorphism has the expected impact on the plasma lipid profile and (ii) the rs4420638 G allele may counterbalance the deleterious effect of the ϵ4 allele on LDL-cholesterol levels in an Algerian population.

To more rapidly identify candidate genes located within chromosomal regions of interest defined by genome scan studies in Alzheimer's disease (AD), we have developed a customized microarray containing all the ORFs (n=2741) located within nine of these regions. Levels of gene expression were assessed in total RNA from brain tissue of 12 controls and 12 AD patients. Of all genes showing differential expression, we focused on the ornithine transcarbamylase (OTC) gene on Xp21.1., a key enzyme of the urea cycle which we found to be expressed in AD brains but not in controls, as confirmed by RT-PCR. We also detected mRNA expression of all the other urea cycle enzymes in AD brains. Immunochemistry experiments revealed that the OTC expression was strictly restricted to vascular endothelial cells in brain. Furthermore, OTC activity was 880% increased in the CSF of probable AD cases compared with controls. We analysed the association of the OTC -389 G/A and -241 A/G promoter polymorphisms with the risk of developing AD. We observed that rare haplotypes may be associated with the risk of AD through a possible modulation of the methylation of the OTC promoter. In conclusion, our results suggest the involvement of a new pathway in AD brains involving the urea cycle.

Background Previous studies have demonstrated that the adenosine monophosphate deaminase 1 (AMPD1) C34T polymorphism may be associated with survival in cardiac populations with a protective effect of the T allele. However, these studies included limited number of patients with few cardiovascular events. Methods We prospectively analyzed the impact of the C34T polymorphism of the AMPD1 gene in 686 unrelated white patients with stable congestive heart failure related to left ventricular systolic dysfunction. Patients underwent echocardiography, radionuclide angiography, and a cardiopulmonary exercise test. Blood samples were drawn for standard and hormonal determinations and for genetic analysis. Results There were 517 (75%) CC homozygotes, 155 (23%) CT heterozygotes, and 14 (2%) TT mutated homozygotes. We did not demonstrate any impact of this polymorphism on clinical, biologic, echocardiographic, radionuclide, and exercise parameters in the whole population and in ischemic and nonischemic subgroups of patients. During a median follow-up period of 3 years, there were 145 cardiac-related deaths and 6 urgent transplantations. There was no impact of this polymorphism on survival. Conclusions In our population, we did not demonstrate any effect of the C34T polymorphism of the AMPD1 gene on major congestive heart failure parameters and on survival.

Cerebral accumulation of beta-amyloid peptide (Abeta) is a central event in the pathogenesis of Alzheimer's disease (AD). Several proteases were shown to hydrolyze Abeta in vitro or in cell-based assays, and are likely candidates for a role in Abeta clearance in brain. Previous reports suggest that matrix metalloproteinases (MMPs) could be involved in such a mechanism. A functional polymorphism at position -1171 (5A/6A) in MMP-3 was examined in two independent studies to investigate the impact of this polymorphism on the risk of developing dementia. We found that subjects APOE epsilon4 non-carriers and 6A/6A homozygous for the MMP-3 polymorphism were at increased risk of dementia. Our findings support the hypothesis that MMPs may influence the risk of dementia.

Objective: Discordant results have been published regarding a possible association between beta-adrenoreceptor (βAR) gene polymorphisms and survival in patients with congestive heart failure (CHF). The aim of the study was to analyze the impact of five functional βAR gene polymorphisms in patients with stable CHF. Methods: We prospectively studied 444 consecutive patients with CHF related to left ventricular systolic dysfunction. The β1ARSer49Gly, β1ARGly389Arg, β2AR Arg16Gly, β2AR Gln27Glu and β2AR Thr164Ile polymorphisms were determined. Patients underwent echocardiography, radionuclide angiography and a cardiopulmonary exercise test. Results: Mean age was 56.6±11.9 years old, left ventricular ejection fraction (LVEF) was 32±12%, and peak VO2 was 15.5±4.9 ml/min/kg or 63±18% of maximal predicted VO2. Most of the patients (95%) were receiving angiotensin converting enzyme inhibitors and 91% β-blockers. There was no statistically significant differences between baseline characteristics among β1AR and β2AR genotypes. During a median follow-up period of 1232 days, there were 110 cardiac-related deaths and five urgent transplantations. Independent predictors of survival were percent (%) of maximal predicted VO2 (p

Neurofibrillary tangles and senile plaques, constituted of extracellular amyloid deposits (Abeta), are the two defining pathological hallmarks of Alzheimer's disease (AD). Inhibiting the synthesis or aggregation of Abeta or increasing its clearance may reduce the detrimental effects of this peptide and consequently improve cognitive functions in patients. Previous studies indicated that metalloproteinases are involved in Abeta degradation and the presence of matrix metalloproteinases (MMP) in AD plaques has been described. In this study, we examined the distribution of a functional polymorphism in the gene for MMP-9, -1562 C-->T, in an independent population of 229 demented and 253 control individuals. We observed a weak protective effect of the high activity allele (T) in apolipoprotein E epsilon4 allele non-bearers (odds ratio=0.5 (95% confidence interval, 0.3-0.9), P=0.04).

Aims To assess the possible effect of functional polymorphisms in matrix metalloproteinase (MMP) gene promoters on the clinical outcome of patients with heart failure. Methods and results We studied 444 consecutive patients who were referred to our centre for evaluation of left ventricular dysfunction. We extracted genomic DNA from white blood cells and determined the −1306 C\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(>\) \end{document}T MMP-2, −1171 5A\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(>\) \end{document}6A MMP-3, and −1562 C\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(>\) \end{document}T MMP-9 polymorphisms. Clinical follow-up (median 717 days) was obtained for 443 patients. The MMP-3 polymorphism had a different impact on cardiac survival in HF patients with ischaemic and non-ischaemic cardiomyopathy (interaction \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(p{

BACKGROUND: Conflicting results have been reported regarding the association of gene polymorphisms in the renin-angiotensin system (RAS) with different aspects of coronary artery disease (CAD), such as myocardial infarction, neointimal hyperplasia or coronary artery vasomotion. Since previous studies have linked angiotensin II to aneurysmal disease, our study hypothesis was that RAS gene polymorphisms may be associated with aneurysm remodeling in response to CAD. METHODS: The study population was selected from a series of 3862 consecutive patients who underwent coronary angiography in our institution. One hundred and thirteen consecutive patients with at least one coronary aneurysm (CA) were compared to 226 randomized control patients without CA. DNA was extracted from white blood cells. The angiotensin-converting enzyme (ACE) I/D and angiotensin type 1 receptor (AT1-R) A/C polymorphisms were detected using previously published techniques. RESULTS: The distributions of the three ACE genotypes were similar in both groups: CA: 13%, 46%, and 41% for II, ID, and DD respectively; controls: 18%, 41%, and 41% for II, ID, and DD respectively, p = 0.45. The distributions of the three AT1-R genotypes were also similar in both groups: CA: 54%, 41%, and 5% for AA, AC, and CC respectively; controls: 55%, 33%, and 12%, for AA, AC, and CC respectively, p = 0.08. CONCLUSION: Our results provide further information on the role of RAS polymorphisms on specific mechanisms implicated in CAD. Although an activated RAS may theoretically promote aneurysm formation, the 2 RAS polymorphisms analyzed in this study are not associated with this process in coronary arteries.

International audience; BackgroundThe transcription factor 7-like 2 (TCF7L2) gene is the most significant genetic risk factor for type 2 diabetes (T2D). Association analyses were performed on participants (n¿=¿751, aged between 30 and 64) in the ISOR population-based study in the city of Oran. Dietary intakes were estimated using a weekly food frequency questionnaire.ResultsThe T allele of the rs7903146 single nucleotide polymorphism (SNP) was associated with lower body weight (p¿=¿0.02), lower BMI (p¿=¿0.009), lower waist circumference (p¿=¿0.01) and a lower waist-to-hip ratio (p¿=¿0.02). The T allele was associated with a significantly higher risk of T2D (odds ratio (OR) (95% confidence interval)¿=¿1.55 (1.09¿2.20), p¿=¿0.01) and this association was independent of BMI. When considering the T2D risk, there were nominal interactions between the rs7903146 SNP and dessert (p¿=¿0.05) and milk intakes (p¿=¿0.01). The T2D risk was greater in T allele carriers with high dessert and milk intakes (OR¿=¿2.61 (1.51-4.52), p¿=¿0.0006, and 2.46 (1.47-4.12), p¿=¿0.0006, respectively). In subjects with a high dessert intake, the T allele was also associated with higher fasting plasma glucose concentrations (4.89¿±¿0.46 mmol/L in TT subjects, 4.72¿±¿0.48 mmol/L in CT subjects and 4.78¿±¿0.51 mmol/L in CC subjects; p¿=¿0.03).ConclusionsThe T allele of the rs7903146 SNP is associated with a significantly higher risk of T2D in an Algerian population. This association was further strengthened by a high dessert intake, suggesting that gene-diet interactions increase the T2D risk.

International audience; BACKGROUND: The Saitohin gene has recently been identified in intron 9 of the Tau gene. Because an association between Parkinson's disease and Tau has been described, Saitohin represents a candidate gene for Parkinson's disease. OBJECTIVE: To test these two genes for their association with Parkinson's disease in a large community based case-control study. RESULTS: Cases (n = 208) were more often homozygotes for the Tau H1 haplotype than controls (n = 483; odds ratio (OR) = 1.71 (95% confidence interval, 1.20 to 2.43); p = 0.003), and the saitohin Q allele was in complete linkage disequilibrium with the H1 haplotype. This association was stronger among cases with Parkinson's disease onset below 65 years (< or =65 years: OR = 2.52 (1.49 to 4.25); p65 years: OR = 1.20 (0.73 to 1.98); p

Objective— The peroxisome proliferator-activated receptor-γ (PPARγ) plays a role in adipocyte differentiation and insulin sensitization. It has been shown that genetic variation in the PPARγ gene alters body weight control, lipid and insulin homeostasis, and the susceptibility to type 2 diabetes. Four PPARγ isoforms are generated by alternative splicing and promoter usage. PPARγ3 is only expressed in adipose tissue, colon, and macrophages and therefore seems to be a good candidate gene for metabolic and cardiovascular-associated diseases. In the present study, we looked for genetic variation in the PPARγ3 promoter. Methods and Results— The proximal PPARγ3 promoter was sequenced in 20 individuals. We detected a C/G polymorphism at position −681 from exon A2. Interestingly, it was located in a signal transducer and activator of transcription 5B (STAT5B) binding consensus site. In a French population (n=836), the −681G allele was associated with increased height and plasma low-density lipoprotein cholesterol concentrations. In vitro, we showed that the −681G allele completely abolished the binding of STAT5B to the cognate promoter element as well as the transactivation of the PPARγ3 promoter by the growth hormone/STAT5B pathway. Conclusions— Our results suggest that PPARγ3 may regulate the control of height and lipid homeostasis via the STAT5B pathway.

International audience; Excess of nitric oxide (NO) has been shown to exert neurotoxic impacts in the brain. Moreover, inhibition of two NO-synthesizing enzymes, neuronal NOS (nNOS) and inducible NOS (iNOS), displays neuroprotective effects in the MPTP model of Parkinson's disease (PD). These data suggest a possible involvement of NOS as factors controlling the resistance of the nigral dopaminergic neurons to environmental insults. Therefore, we investigated whether polymorphisms present in these genes could contribute to the risk of developing PD. We carried out a community-based case-control study among subjects enrolled in the Mutualit?ociale Agricole, the French health insurance organization for workers connected to agriculture. Two-hundred and nine PD patients and 488 controls of European (mostly French) ancestry and matched for age, sex and region of residency were included in this study. Associations were observed with polymorphisms present in exon 22 of iNOS (OR for AA carriers=0.50, 95% CI=0.29-0.86, P=0.01) and in exon 29 of nNOS (OR for carriers of the T allele=1.53, 95% CI=1.08-2.16, P=0.02); no association was observed with a polymorphism in exon 18 of nNOS (OR for carriers of the T allele=1.20, 95% CI=0.85-1.69, P=0.30). Moreover, a significant interaction of the nNOS polymorphisms with current and ever cigarette smoking was found (nNOS 18, P=0.05; nNOS 29, P=0.04). All together, these data favour an involvement of these two genes as new modifier genes in PD.