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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. Highlights • The rs174547 polymorphism is associated with n-6 polyunsaturated fatty acid levels in erythrocytes. • Among the 25 polymorphisms of the rs174547 haplotype block, rs174546 is functional. • The rs174546 minor allele triggers FADS1 gene downregulation. • The rs174546 minor allele creates an miR-149-5p binding site in the FADS1 3′UTR. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]

Abstract: 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<0.0001), age (p<0.0001), LVEF (p=0.004), creatinine (p=0.02) and atrial fibrillation (p=0.04). No βAR polymorphisms were associated with survival. However, patients with the combined β2ARGly16Gly/β2ARGln27Gln 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 βAR polymorphisms and survival in patients with stable CHF. However, we demonstrated, only in univariate analysis, a possible association between the combined β2ARGly16Gly/β2ARGln27Gln genotype and survival. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstract: Cerebral accumulation of β-amyloid peptide (Aβ) is a central event in the pathogenesis of Alzheimer''s disease (AD). Several proteases were shown to hydrolyze Aβ in vitro or in cell-based assays, and are likely candidates for a role in Aβ 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 ɛ4 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. [Copyright &y& Elsevier]

: ObjectivesOur hypothesis was that functional polymorphisms in matrix metalloproteinase (MMP) genes may act as susceptibility factors for the development of coronary aneurysms (CAs).: BackgroundDifferent 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.: MethodsWe 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.: ResultsThe 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]).: ConclusionsThe 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]