The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects.

The 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 human BIN1 isoform8 (BIN1iso8) and human BIN1 isoform9 (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.

Identification of a functional FADS1 3'UTR variant associated with erythrocyte n-6 polyunsaturated fatty acids levels.

BACKGROUND: Blood polyunsaturated fatty acid (PUFA) levels are determined by diet and by endogenous synthesis via Δ5- and Δ6-desaturases (encoded by the FADS1 and FADS2 genes, respectively). Genome-wide association studies have reported associations between FADS1-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-γ-linolenic acid and lower levels of arachidonic acid, suggesting a lower Δ5-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.

Associations of common SNPs in the SORT1, GCKR, LPL, APOA1, CETP, LDLR, APOE genes with lipid trait levels in an Algerian population sample.

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.

Examination of the brain natriuretic peptide rs198389 single-nucleotide polymorphism on type 2 diabetes mellitus and related phenotypes in an Algerian population.

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: The NPPB rs198389 SNP was not associated with 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 homeostatic model assessment insulin resistance index (p=0.05) in non-diabetic individuals. CONCLUSION: The NPPB rs198389 SNP might modulate fasting insulin levels in an Algerian population.

The TCF7L2 rs7903146 polymorphism, dietary intakes and type 2 diabetes risk in an Algerian population.

BACKGROUND: The 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. RESULTS: The 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). CONCLUSIONS: The 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.

Combined effect of established BMI loci on obesity-related traits in an Algerian population sample.

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. 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.

Impact of APOE gene polymorphisms on the lipid profile in an Algerian population.

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.

Genetic and molecular insights into the role of PROX1 in glucose metabolism.

Genome-wide association studies have shown that the rs340874 single nucleotide polymorphism (SNP) in PROX1 is a genetic susceptibility factor for type 2 diabetes. We conducted genetic and molecular studies to better understand the role of PROX1 in type 2 diabetes. We assessed the impact of the whole common genetic variability of PROX1 (80 SNPs) on type 2 diabetes-related biochemical traits in the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) study (n = 1,155). Three SNPs (rs340838, rs340837, and rs340836) were significantly associated with fasting plasma insulin levels (P ≤ 0.00295). We evaluated the impact of nine PROX1 SNPs (the three insulin-associated SNPs plus six SNPs in strong linkage disequilibrium) on luciferase reporter gene expression. The insulin-lowering alleles of rs340874, rs340873, and rs340835 were associated with lower luciferase activity in MIN6 and HepG2 cells (except for rs340874, which was in HepG2 cells only). Electrophoretic mobility shift assays indicated that specific nuclear protein bindings occur at the three SNPs in HepG2 cells, with allele-binding differences for rs340874. We also showed that the knockdown of Prox1 expression by small interfering RNAs in INS-1E cells resulted in a 1.7-fold reduction in glucose-stimulated insulin secretion. All together, we propose that reduced expression of PROX1 by cis-regulatory variants results in altered ß-cell insulin secretion and thereby confers susceptibility to type 2 diabetes.

Impact of the matrix metalloproteinase MMP-3 on dementia.

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.

The impact of the AMPD1 gene polymorphism on exercise capacity, other prognostic parameters, and survival in patients with stable congestive heart failure: a study in 686 consecutive patients.

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.

The impact of beta-adrenoreceptor gene polymorphisms on survival in patients with congestive heart failure.

OBJECTIVE: Discordant results have been published regarding a possible association between beta-adrenoreceptor (betaAR) gene polymorphisms and survival in patients with congestive heart failure (CHF). The aim of the study was to analyze the impact of five functional betaAR gene polymorphisms in patients with stable CHF. METHODS: We prospectively studied 444 consecutive patients with CHF related to left ventricular systolic dysfunction. The beta1ARSer49Gly, beta1ARGly389Arg, beta2AR Arg16Gly, beta2AR Gln27Glu and beta2AR 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% beta-blockers. There was no statistically significant differences between baseline characteristics among beta1AR and beta2AR 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<0.0001), age (p<0.0001), LVEF (p=0.004), creatinine (p=0.02) and atrial fibrillation (p=0.04). No betaAR polymorphisms were associated with survival. However, patients with the combined beta2ARGly16Gly/beta2ARGln27Gln genotype, who express receptors highly sensitive to down-regulation, had a significantly lower survival rate than patients with other genotypes but only in univariate analysis. CONCLUSIONS: In this prospective study, we found no association between five functional betaAR polymorphisms and survival in patients with stable CHF. However, we demonstrated, only in univariate analysis, a possible association between the combined beta2ARGly16Gly/beta2ARGln27Gln genotype and survival.

Association between beta-1 and beta-2 adrenergic receptor gene polymorphisms and the response to beta-blockade in patients with stable congestive heart failure.

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<0.0001). There was no association between the five polymorphisms and heart rate or LVEF, either before or after beta-blockade. Heart rate and LVEF responses to beta-blockade were not associated with the beta1AR or the beta2AR polymorphisms. betaAR polymorphisms did not explain the interindividual variability in the response to beta-blockers.

Prognostic impact of matrix metalloproteinase gene polymorphisms in patients with heart failure according to the aetiology of left ventricular systolic dysfunction.

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 >T MMP-2, -1171 5A > 6A MMP-3, and -1562 C >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 p <0.03). The MMP-3 5A/5A genotype was an independent predictor of cardiac mortality (HR 2.92 [1.23-6.69]; p = 0.01) in patients with non-ischaemic HF. In contrast, there was no evidence for any effect of the MMP-3 genotype on cardiac events in patients with ischaemic cardiomyopathy. The MMP-9 polymorphism was associated with cardiac survival (p < 0.03) independently of HF aetiology. In multivariate analysis, the MMP-9 T allele was an independent predictor of cardiac mortality (HR 1.81 [1.09-3.02]; p = 0.02). Finally, there was no evidence for any association between MMP-2 polymorphism and cardiac survival. CONCLUSION: MMP-3 and MMP-9 polymorphisms contribute to variability in cardiac survival in HF patients. These data suggest that MMP genotyping could provide important additional information for refining risk stratification in patients with heart failure. MMP genotyping may help to select patients who could benefit from MMP inhibition.

Beta-adrenergic receptor blockade and the angiotensin-converting enzyme deletion polymorphism in patients with chronic heart failure.

BACKGROUND: 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. AIMS: 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. METHODS AND RESULTS: 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; P<0.0001), ID (from 0.29+/-0.11 to 0.39+/-0.13; P<0.0001) and DD patients (from 0.31+/-0.11 to 0.40+/-0.13; P<0.0001). 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 LVEF >5% 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. CONCLUSIONS: 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.

The role of matrix metalloproteinase-9 in dementia.

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).

Angiotensin Converting Enzyme and Angiotensin II Type 1 Receptor Polymorphisms in Patients with Coronary Aneurysms.

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.

Polymorphisms in the promoter regions of MMP-2, MMP-3, MMP-9 and MMP-12 genes as determinants of aneurysmal coronary artery disease.

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.