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Venous thromboembolism (VTE), comprising both deep vein thrombosis (DVT) and pulmonary embolism (PE) is a common, multi-causal disease with potentially serious short- and long-term complications. In clinical practice, there is a need for improved plasma biomarker-based tools for VTE diagnosis and risk prediction. We used multiplex proteomics profiling to screen plasma from patients with suspected acute VTE, and a case-control study of patients followed up after ending anticoagulant treatment for a first VTE. With replication in 5 independent studies, together totalling 1137 patients and 1272 controls, we identify Complement Factor H Related Protein (CFHR5), a regulator of the alternative pathway of complement activation, as a novel VTE associated plasma biomarker. Using GWAS analysis of 2967 individuals we identified a genome-wide significant pQTL signal on chr1q31.3 associated with CFHR5 levels. We showed that higher CFHR5 levels are associated with increased thrombin generation in patient plasma and that recombinant CFHR5 enhances platelet activationin vitro. Thrombotic complications are a frequent feature of COVID-19; in hospitalised patients we found CFHR5 levels at baseline were associated with short-time prognosis of disease severity, defined as maximum level of respiratory support needed during hospital stay. Our results indicate a clinically important role for regulation of the alternative pathway of complement activation in the pathogenesis of VTE and pulmonary complications in acute COVID-19. Thus, CFHR5 is a potential diagnostic and/or risk predictive plasma biomarker reflecting underlying pathology in VTE and acute COVID-19.

In studies of time-to-events, it is common to collect information about events that occurred before the inclusion in a prospective cohort. In an ambispective design, when the risk factors studied are independent of time, including both pre- and post-inclusion events in the analyses increases the statistical power but may lead to a selection bias. To avoid such a bias, we propose a survival analysis weighted by the inverse of the survival probability at the time of data collection about the events.This method is applied to the study of the association of ABO blood groups with the risk of venous thromboembolism (VT) recurrence in the MARTHA and MEGA cohorts. The former relying on an ambispective design and the latter on a standard prospective one. In the combined sample totalling 2,752 patients including 993 recurrences, compared with the O1 group, A1 has an increased risk (Hazard Ratio (HR) of 1.18, p=4.2×10−3), homogeneously in MARTHA and in MEGA. The same trend (HR=1.19, p=0.06) was observed for the less frequent A2 group.In conclusion, this work clarified the association ofABOblood groups with the risk of VT recurrence. Besides, the methodology proposed here to analyse time-independent risk factors of events in an ambispective design has an immediate field of application in the context of genome wide association studies.

Venous thromboembolism (VTE) is the third most common cardiovascular disease, affecting ∼ 1,000,000 individuals each year in Europe. VTE is characterized by an annual recurrent rate of ∼ 6%, and ∼ 30% of patients with unprovoked VTE will face a recurrent event after a six-month course of anticoagulant treatment. Even if guidelines recommend life-long treatment for these patients, about ∼ 70% of them will never experience a recurrence and will receive unnecessary lifelong anti-coagulation that is associated with increased risk of bleeding and is highly costly for the society. There is then urgent need to identify biomarkers that could distinguish VTE patients with high risk of recurrence from low-risk patients. Capitalizing on a sample of 913 patients followed up for the risk of VTE recurrence during a median of ∼ 10 years and profiled for 376 plasma proteomic antibodies, we here develop an artificial neural network (ANN) based strategy to identify a proteomic signature that helps discriminating patients at low and high risk of recurrence. In a first stage, we implemented a Repeated Editing Nearest Neighbors algorithm to select a homogeneous sub-sample of VTE patients. This sub-sample was then split in a training and a testing sets. The former was used for training our ANN, the latter for testing its discriminatory properties. In the testing dataset, our ANN led to an accuracy of 0.86 that compared to an accuracy of 0.79 as provided by a random forest classifier. We then applied a Deep Learning Important FeaTures (DeepLIFT) – based approach to identify the variables that contribute the most to the ANN predictions. In addition to sex, the proposed DeepLIFT strategy identified 6 important proteins (DDX1, HTRA3, LRG1, MAST2, NFATC4 and STXBP5) whose exact roles in the etiology of VTE recurrence now deserve further experimental validations. © 2021, Springer Nature Switzerland AG.

Venous thromboembolism is the third common cardiovascular disease and is composed of two entities, deep vein thrombosis (DVT) and its fatal form, pulmonary embolism (PE). While PE is observed in ∼40% of patients with documented DVT, there is limited biomarkers that can help identifying patients at high PE risk.To fill this need, we implemented a two hidden-layers artificial neural networks (ANN) on 376 antibodies and 19 biological traits measured in the plasma of 1388 DVT patients, with or without PE, of the MARTHA study. We used the LIME algorithm to obtain a linear approximate of the resulting ANN prediction model. As MARTHA patients were typed for genotyping DNA arrays, a genome wide association study (GWAS) was conducted on the LIME estimate. Detected single nucleotide polymorphisms (SNPs) were tested for association with PE risk in MARTHA. Main findings were replicated in the EOVT study composed of 143 PE patients and 196 DVT only patients.The derived ANN model for PE achieved an accuracy of 0.89 and 0.79 in our training and testing sets, respectively. A GWAS on the LIME approximate identified a strong statistical association peak (p = 5.3×10−7) at the PLXNA4 locus, with lead SNP rs1424597 at which the minor A allele was further shown to associate with an increased risk of PE (OR = 1.49 [1.12 – 1.98], p = 6.1×10−3). Further association analysis in EOVT revealed that, in the combined MARTHA and EOVT samples, the rs1424597-A allele was associated with increased PE risk (OR = 1.74 [1.27 – 2.38, p = 5.42×10−4) in patients over 37 years of age but not in younger patients (OR = 0.96 [0.65 – 1.41], p = 0.848).Using an original integrated proteomics and genetics strategy, we identified PLXNA4 as a new susceptibility gene for PE whose exact role now needs to be further elucidated.Author SummaryPulmonary embolism is a severe and potentially fatal condition characterized by the presence of a blood clot (or thrombus) in the pulmonary artery. Pulmonary embolism is often the consequence of the migration of a thrombus from a deep vein to the lung. Together with deep vein thrombosis, pulmonary embolism forms the so-called venous thromboembolism, the third most common cardiovascular disease, and its prevalence strongly increases with age. While pulmonary embolism is observed in ∼40% of patients with deep vein thrombosis, there is currenly limited biomarkers that can help predicting which patients with deep vein thrombosis are at risk of pulmonary embolism. We here deployed an Artificial Intelligence based methodology integrating both plasma proteomics and genetics data to identify novel biomarkers for PE. We thus identified the PLXNA4 gene as a novel molecular player involved in the pathophysiology of pulmonary embolism. In particular, using two independent cohorts totalling 1,881 patients with venous thromboembolism among which 467 experienced pulmonary embolism, we identified a genetic polymorphism in the PLXNA4 gene that associates with ∼2 fold increased risk of pulmonary embolism in patients aged more than ∼40 years.

Objective: Deep vein thrombosis and pulmonary embolism referred as venous thromboembolism (VTE) are a common cause of morbidity and mortality. Plasma from healthy controls or individuals who have experienced a VTE were analyzed using metabolomics to characterize biomarkers and metabolic systems of patients with VTE. Approach and Results: Polar metabolite and lipidomic profiles from plasma collected 3 months after an incident VTE were obtained using liquid chromatography mass spectrometry. Fasting-state plasma samples from 42 patients with VTE and 42 healthy controls were measured. Plasma metabolomic profiling identified 512 metabolites forming 62 biological clusters. Multivariate analysis revealed a panel of 21 metabolites altogether capable of predicting VTE status with an area under the curve of 0.92 ( P =0.00174, selectivity=0.857, sensitivity=0.971). Multiblock systems analysis revealed 25 of the 62 functional biological groups as significantly affected in the VTE group ( P Conclusions: These findings show promise for the elucidation of underlying mechanisms and the design of a diagnostic test to assess the likely efficacy of clinical care in patients with VTE.

IntroductionABO blood group influence the risk of venous thrombosis (VT) by modifying A and B glycosyltransferases (AGT and BGT) activities that further modulates Factor VIII (FVIII) and von Willebrand Factor (VWF) plasma levels. The aim of this work was to evaluate the association of plasma GTs activities with VWF/FVIII plasma levels and VT risk in a case-control study.Materials and Methods420 cases were matched with 420 controls for age and ABO blood group. GT activities in plasma were measured using the quantitative transfer of tritiated N-acetylgalactosamine or galactose to the 2’-fucosyl-lactose and expressed in disintegration per minute/30µL of plasma and 2 hours of reaction (dpm/30µL/2H). FVIII and VWF plasma levels were respectively measured using human FVIII-deficient plasma in a 1-stage factor assay and STA LIATEST VWF (Diagnostica Stago).ResultsA and B GT activities were significantly lower in cases than in controls (8119±4027 vs 9682±4177 dpm/30µL/2H, p=2.03 × 10−5, and 4931±2305 vs 5524±2096 dpm/30µL/2H, p=0.043 respectively). This association was observed whatever the ABO blood groups. The ABO A1 blood group was found to explain∼80% of AGT activity. After adjusting for ABO blood groups, AGT activity was not correlated to VWF/FVIII plasma levels. Conversely, there was a moderate correlation (ρ∼0.30) between BGT activity and VWF/ FVIII plasma levels in B blood group carriers.ConclusionThis work showed, for the first time, that GT activities were decreased in VT patients in comparison to controls with the same ABO blood group. The biological mechanisms responsible for this association remained to be determined.

HELENA Study group, [Background/Objective]: Although the REV-ERBα is considered an important regulator of both clock function and metabolism, its relationship with sleep duration and obesity is less clear. The objective of this study was to examine the association between the REV-ERBα clock gene and two outcomes – sleep duration and body mass index (BMI) – in European adolescents. [Methods]: A sample of 831 adolescents (392 boys) aged 11.5–18.8 years from 10 European centers was used. The independent variables were REV-ERBα rs2071427 and rs2071570 SNPs, and their respective haplotypes. The outcomes were sleep duration and BMI. [Results]: In girls, no significant association were found between rs2071427 or rs2071570 and the studied outcomes (p ≥ 0.43). In boys, however, significant associations were found between rs2071570 and sleep duration (β: −0.32 h/day for T minor allele carriers; p = 0.0017), and rs2071427 and BMI (β: +0.72 kg/m for A minor allele carriers; p = 0.016). In the haplotype analysis, the TA haplotype (carrying the two minor alleles) was associated with both lower sleep duration (Δ = −0.38 h/day; p = 0.05) and higher BMI (Δ = +1.41 kg/m; p = 0.018) in boys, when compared with the common CC haplotype. [Conclusions]: The REV-ERBα rs2071427 and rs2071570 were associated with both sleep duration and BMI in boys. These findings confirmed the relevance of the REV-ERBα gene in human obesity, primarily in males, and also suggested that it has a potential role in affecting sleep duration., The HELENA study received funding from the European Union's Sixth RTD Framework Program (Contract FOOD-CT-2005-007034). The GENUD Research Group was co-financed by the European Regional Development Fund (MICINN-FEDER). Marcus V. Nascimento-Ferreira received a PhD Student Internships Abroad scholarship from the National Counsel of Technological and Scientific Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq; process: 200340/2015-8) and a Brazilian PhD Student scholarship from the São Paulo Research Foundation - FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo; process: 2016/18436-8 and 2017/11732-3). Heraclito Barbosa Carvalho received research funding from São Paulo Research Foundation (FAPSP, proc. 2014/11468-6). Augusto C. de Moraes was supported by the São Paulo Research Foundation (FAPESP; process: 2015/14319-4 and 2014/25233-0, respectively). Luis Moreno was supported by FAPESP (process: 2015/11406-3).

MicroRNAs (miRNAs) are small regulatory RNAs participating to several biological processes and known to be involved in various pathologies. Measurable in body fluids, miRNAs have been proposed to serve as efficient biomarkers for diseases and/or associated traits. Here, we performed a next-generation-sequencing based profiling of plasma miRNAs in 344 patients with venous thrombosis (VT) and assessed the association of plasma miRNA levels with several haemostatic traits and the risk of VT recurrence. Among the most significant findings, we detected an association between hsa-miR-199b-3p and haematocrit levels (P = 0.0016), these two markers having both been independently reported to associate with VT risk. We also observed suggestive evidence for association of hsa-miR-370-3p (P = 0.019), hsa-miR-27b-3p (P = 0.016) and hsa-miR-222-3p (P = 0.049) with VT recurrence, the observations at the latter two miRNAs confirming the recent findings of Wang et al. Besides, by conducting Genome-Wide Association Studies on miRNA levels and meta-analyzing our results with some publicly available, we identified 21 new associations of single nucleotide polymorphisms with plasma miRNA levels at the statistical significance threshold of P, Los micro-ARN (miARN) son pequeñas moléculas de ARN reguladoras que participan en varios procesos biológicos y están implicados en diversas patologías. Mensurables en los líquidos corporales, se ha planteado que los miARN pueden ser biomarcadores eficaces para el diagnóstico de enfermedades y/o características asociadas. Aquí hemos llevado a cabo un análisis de miARN plasmático con tecnología de secuenciación de última generación en 344 pacientes con trombosis venosa (TV) y hemos evaluado la asociación de los niveles de miARN con distintas características hemostáticas y el riesgo de recidiva de TV. Entre los hallazgos más significativos, hemos detectado una asociación entre hsa-miR-199b-3p y los niveles de hematocritos (p = 0,0016); dos marcadores que se habían asociado de forma independiente con el riesgo de sufrir TV. Asimismo, hemos observado una evidencia indicativa de asociación entre hsa-miR-370-3p (p = 0,019), hsa-miR-27b-3p (p = 0,016) y hsa-miR-222-3p (p = 0,049) y la recidiva de TV; los resultados los dos últimos miARN confirman los hallazgos recientes de Wang et al. (Clin Epigenetics, 2019). Además, al efectuar estudios de asociación del genoma completo sobre los niveles de miARN y al metaanalizar nuestros resultados con otros disponibles públicamente, hemos identificado 21 asociaciones nuevas de polimorfismos de un solo nucleótido (PSN) con niveles de miARN plasmático con un umbral de significación estadística de p

International audience; Background Factor V (FV) is a circulating protein primarily synthesized in the liver, and mainly present in plasma. It is a major component of the coagulation process. Objective To detect novel genetic loci participating to the regulation of FV plasma levels. Methods We conducted the first Genome Wide Association Study on FV plasma levels in a sample of 510 individuals and replicated the main findings in an independent sample of 1156 individuals. Results In addition to genetic variations at the F5 locus, we identified novel associations at the PLXDC2 locus, with the lead PLXDC2 rs927826 polymorphism explaining ~3.7% (P = 7.5 × 10−15 in the combined discovery and replication samples) of the variability of FV plasma levels. In silico transcriptomic analyses in various cell types confirmed that PLXDC2 expression is positively correlated to F5 expression. SiRNA experiments in human hepatocellular carcinoma cell line confirmed the role of PLXDC2 in modulating factor F5 gene expression, and revealed further influences on F2 and F10 expressions. Conclusion Our study identified PLXDC2 as a new molecular player of the coagulation process.

Factor V serves an important role in the regulation of blood coagulation. The rs6025 (R534Q) and rs4524 (K858R) polymorphisms in the F5 gene, are known to influence the risk of venous thrombosis. While the rare Q534 (factor V Leiden) allele is associated with an increased risk of venous thrombosis, the minor R858 allele is associated with a lower risk of disease. However, no study has deeply examined the cumulative impact of these two variations on venous thrombosis risk. We study the association of these polymorphisms with the risk of venous thrombosis in 4 French case-control populations comprising 3719 patients and 4086 controls. We demonstrate that the Q534 allele has a dominant effect over R858. Besides, we show that in individuals not carrying the Q534 allele, the protective effect of the R858 allele acts in a dominant mode. Thrombin generation-based normalized activated protein C sensitivity ratio was lower in the 858R/R homozygotes than in the 858K/K homozygotes (1.92 ± 1.61 vs 2.81 ± 1.57, p = 0.025). We demonstrate that the R858 allele of the F5 rs4524 variant protects from venous thrombosis only in non-carriers of the Q534 allele of the F5 rs6025. Its protective effect is mediated by reduced factor VIII levels and reduced activated protein C resistance.

Socio-economic status (SES) is a strong determinant of eating behavior and the obesity risk. To determine which eating and lifestyle behaviors mediate the association between SES and obesity. We performed a case–control study of 318 obese people and 371 non-obese people in northern France. Ten eating behavior traits were assessed using the Three-Factor Eating Questionnaire Revised 21-Item and an eating attitude questionnaire (on plate size, the number of servings, reasons for stopping eating and the frequency of eating standing up, eating in front of the television set (TV) and eating at night). The SES score (in three categories) was based on occupation, education and income categories. Mediation analysis was performed using the test of joint significance and the difference of coefficients test. The age- and gender-adjusted obesity risk was higher for individuals in the low-SES groups (odds ratio (OR) (95% confidence interval (CI)=1.82 (1.48–2.24), P

Background & aims: Blood levels of polyunsaturated fatty acids (PUFAs) are under control of endogenous synthesis via Delta 5- and Delta 6-desaturases, encoded by the FADS1 and FADS2 genes, respectively and of diet. Genome-wide associations studies (GWAS) reported associations between polymorphisms in FADS1-FADS2 and variations in plasma concentrations of PUFAs, HDL- and LDL-cholesterol and triglycerides. However, it is not established whether dietary PUFAs intake modulates these associations. We assessed whether dietary linoleic acid (LA) or alpha-linolenic acid (ALA) modulate the association between the FADS1 rs174547 polymorphism (a GWAS hit) and lipid and anthropometric phenotypes. Methods: Dietary intakes of LA and ALA, FADS1 rs174547 genotypes, lipid and anthropometric variables were determined in three French population-based samples (n = 3069). These samples were stratified according to the median dietary LA (= 9.5 g/d) and ALA (= 0.80 g/d) intakes. The meta-analysis was performed using a random-effect. Results: Our meta-analysis confirmed the association between rs174547 and plasma lipid levels and revealed an association with waist circumference and body mass index. These associations were not modified by dietary ALA intake (all p-interaction > 0.05). In contrast, the associations with HDL-cholesterol levels, waist circumference and BMI were modulated by the dietary intake of LA (p interaction < 0.05). In high LA consumers only, the rs174547 minor allele was significantly associated with lower HDL-cholesterol levels (beta = -0.05 mmol/L, p = 0.0002). Furthermore, each copy of the rs174547 minor allele was associated with a 1.58 cm lower waist circumference (p = 0.0005) and a 0.46 kg M-2 lower BMI (p = 0.01) in the low LA intake group, but not in the high LA intake group. Conclusions: The present study suggests that dietary LA intake may modulate the association between the FADS gene variants and HDL-cholesterol concentration, waist circumference and BMI. These gene -nutrient interactions, if confirmed, suggest that subjects carrying the rs174547 minor allele might benefit from low dietary LA intakes. (C) 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

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.

Background: Aging and lifestyle changes had led to an epidemiological transition, with a significant impact on the incidence of cardiovascular diseases in North Africa. Objective: The aim of this study was to determine the prevalence of metabolic syndrome and its associated factors, which were unknown, among an urban population in Algeria.Methods: During 2007-2009, 787 individuals aged 30-64 years, randomly selected from the list of insured persons residing in the city of Oran, participated in a clinical, anthropometric and biological survey. Participants were classified according to the National Cholesterol Education Program - Adult Treatment Panel (NCEP-ATP) III definition of metabolic syndrome.Results: The prevalence of metabolic syndrome was 20%, higher in women than men (25.9 vs 13.7%; Pcomponents of the syndrome, the most common risk factors observed in women were a low high-density lipoprotein (HDL) cholesterol concentration (60.4% vs 44.2% in men) and abdominal obesity (46.8% vs 30.1% in men) whereas men displayed more high blood pressure (42.5% vs 34.8% in women). In men, metabolic syndrome was more frequent in married and highly educated participants. In contrast, women with a high level of education and who had an intermediate level of physical activity seemed to be protected.Conclusions: Metabolic syndrome, prevalent in the urban population of North Algeria, is associated with a high proportion of low HDL-cholesterol and abdominal obesity, especially among women. There is a need for prevention strategies involving promotion of physical activity for the whole population and screening for hypertension among men. Ethn Dis. 2016;26(1):99-106; doi:10.18865/ed.26.1.99

International audience; Objective: Dyslipidemia is a key feature of the metabolic syndrome (MetS), which is determined by both genetic and dietary factors. Methods: We determined the relationships between ApoA1 and ApoB polymorphisms and MetS risk, and whether dietary fat modulates this in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1754). Results: ApoB rs512535 and ApoA1 rs670 major G allele homozygotes had increased MetS risk (OR 1.65 [CI 1.24, 2.20], P = 0.0006; OR 1.42 [CI 1.08, 1.87], P = 0.013), which may be, partly, explained by their increased abdominal obesity and impaired insulin sensitivity (P < 0.05) but not dyslipidemia. Interestingly these associations derived primarily from the male GG homozygotes (ApoB rs512535 OR 1.92 [CI 1.31, 2.81], P = 0.0008; ApoA1 rs670 OR 1.50 [CI 1.05, 2.12], P = 0.024). MetS risk was exacerbated among the habitual high-fat consumers (>35% energy) (ApoB rs512535 OR 2.00 [CI 1.14, 3.51], P = 0.015; OR 1.58 [CI 1.11, 2.25], P = 0.012 for ApoA1 rs670). In addition a high monounsaturated fat (MUFA) intake (>14% energy) increased MetS risk (OR 1.89 [CI 1.08, 3.30], P = 0.026 and OR 1.57 [CI 1.10, 2.40], P = 0.014 for ApoB rs512535 and ApoA1 rs670, respectively). MetS risk was abolished among the habitual low-fat consumers (

International audience; Acetyl-CoA carboxylase beta (ACC2) plays a key role in fatty acid synthesis and oxidation pathways. Disturbance of these pathways is associated with impaired insulin responsiveness and metabolic syndrome (MetS). Gene-nutrient interactions may affect MetS risk. This study determined the relationship between ACC2 polymorphisms (rs2075263, rs2268387, rs2284685, rs2284689, rs2300453, rs3742023, rs3742026, rs4766587, and rs6606697) and MetS risk, and whether dietary fatty acids modulate this in the LIPGENE-SU. VI.MAX study of MetS cases and matched controls (n = 1754). Minor A allele carriers of rs4766587 had increased MetS risk (OR 1.29 [CI 1.08, 1.58], P = 0.0064) compared with the GG homozygotes, which may in part be explained by their increased body mass index (BMI), abdominal obesity, and impaired insulin sensitivity (P < 0.05). MetS risk was modulated by dietary fat intake (P = 0.04 for gene-nutrient interaction), where risk conferred by the A allele was exacerbated among individuals with a high-fat intake (>35% energy) (OR 1.62 [CI 1.05, 2.50], P = 0.027), particularly a high intake (>5.5% energy) of n-6 polyunsaturated fat (PUFA) (OR 1.82 [CI 1.14, 2.94], P = 0.01; P = 0.05 for gene-nutrient interaction). Saturated and monounsaturated fat intake did not modulate MetS risk. Importantly, we replicated some of these findings in an independent cohort.jlr In conclusion, the ACC2 rs4766587 polymorphism influences MetS risk, which was modulated by dietary fat, suggesting novel gene-nutrient interactions.-Phillips, C. M., L. Goumidi, S. Bertrais, M. R. Field, L. Adrienne Cupples, J. M. Ordovas, J. McMonagle, C. Defoort, J. A. Lovegrove, C. A. Drevon, E. E. Blaak, B. Kiec-Wilk, U. Riserus, J. Lopez-Miranda, R. McManus, S. Hercberg, D. Lairon, R. Planells, and H. M. Roche. ACC2 gene polymorphisms, metabolic syndrome, and gene-nutrient interactions with dietary fat. J. Lipid Res. 2010. 51: 3500-3507.

Long chain acyl CoA synthetase 1 (ACSL1) plays an important role in fatty acid metabolism and triacylglycerol (TAG) synthesis. Disturbance of these pathways may result in dyslipidemia and insulin resistance, hallmarks of the metabolic syndrome (MetS). Dietary fat is a key environmental factor which may interact with genetic determinants of lipid metabolism to affect MetS risk. We investigated the relationship between ACSL1 polymorphisms (rs4862417, rs6552828, rs13120078, rs9997745 and rs12503643) and MetS risk, and determined potential interactions with dietary fat in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1754). GG homozygotes for rs9997745 had increased MetS risk (OR 1.90 [CI 1.15, 3.13] P = 0.01), displayed elevated fasting glucose (P = 0.001) and insulin concentrations (P = 0.002) and increased insulin resistance (P = 0.03) relative to the A allele carriers. MetS risk was modulated by dietary fat, whereby the risk conferred by GG homozygosity was abolished among individuals consuming either a low-fat (< 35% energy) or a high polyunsaturated fat (PUFA) diet (> 5.5% energy). In conclusion ACSL1 rs9997745 influences MetS risk, most likely via disturbances in fatty acid metabolism, which was modulated by dietary fat consumption, particularly PUFA intake, suggesting novel gene-nutrient interactions.

The leptin receptor (LEPR) is associated with insulin resistance, a key feature of metabolic syndrome (MetS). Gene-fatty acid interactions may affect MetS risk. The objective was to investigate the relationship among LEPR polymorphisms, insulin resistance, and MetS risk and whether plasma fatty acids, a biomarker of dietary fatty acids, modulate this. LEPR polymorphisms (rs10493380, rs1137100, rs1137101, rs12067936, rs1805096, rs2025805, rs3790419, rs3790433, rs6673324, and rs8179183), biochemical measurements, and plasma fatty acid profiles were determined in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1754). LEPR rs3790433 GG homozygotes had increased MetS risk compared with the minor A allele carriers [odds ratio (OR) = 1.65; 95% CI: 1.05-2.57; P = 0.028], which may be accounted for by their increased risk of elevated insulin concentrations (OR 2.40; 95% CI: 1.28-4.50; P = 0.006) and insulin resistance (OR = 2.15; 95% CI: 1.18-3.90; P = 0.012). Low (less than median) plasma (n-3) and high (n-6) PUFA status exacerbated the genetic risk conferred by GG homozygosity to hyperinsulinemia (OR 2.92-2.94) and insulin resistance (OR 3.40-3.47). Interestingly, these associations were abolished against a high (n-3) or low (n-6) PUFA background. Importantly, we replicated some of these findings in an independent cohort. Homozygosity for the LEPR rs3790433 G allele was associated with insulin resistance, which may predispose to increased MetS risk. Novel gene-nutrient interactions between LEPR rs3790433 and PUFA suggest that these genetic influences were more evident in individuals with low plasma (n-3) or high plasma (n-6) PUFA.

Signal transducer and activator of transcription 3 (STAT3) plays a key role in body weight regulation and glucose homeostasis, 2 important determinants of metabolic syndrome (MetS). Dietary fat is a key environmental factor that may interact with genotype to affect MetS risk. In this study, we investigated the relationship between STAT3 polymorphisms and MetS phenotypes and determined potential interactions with dietary fatty acids. STAT3 polymorphisms (rs8069645, rs744166, rs2306580, rs2293152, and rs10530050), biochemical measurements, and dietary fat composition were determined in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1754). STAT3 polymorphisms were not associated with MetS risk. However, minor G allele carriers for rs8069645, rs744166, and rs1053005 and major GG homozygotes for rs2293152 had increased risk of abdominal obesity compared with noncarriers [odds ratio (OR) = 2.22, P = 0.0005; OR = 2.08, P = 0.0017; OR = 2.00, P = 0.0033; and OR = 1.95, P = 0.028, respectively]. The number of risk alleles additively increased obesity risk (P = 0.0003). Dietary SFA intake exacerbated these effects; among all participants with the highest SFA intake (> or =15.5% of energy), individuals carrying >2 risk alleles had further increased risk of obesity (OR = 3.30; 95% CI = 1.50-7.28; P = 0.0079) compared with those carrying < or =1 risk allele. Interaction analysis confirmed this gene-nutrient interaction whereby increasing SFA intake was predictive of increased waist circumference (P = 0.038). In conclusion, STAT3 gene polymorphisms influenced the risk of abdominal obesity, which is modulated by dietary SFA intake, suggesting novel gene-nutrient interactions.

AIM: Although the ANGPTL6 (angiopoietin-like 6) gene product is now known to be involved in the regulation of fat mass and insulin sensitivity in mice, its physiological functions in humans have yet to be determined. METHODS: Subjects from the population-based French MONICA Study (n=3402) were genotyped for single nucleotide polymorphisms (SNPs) in ANGPTL6, and associations with anthropometric or biochemical phenotypes were looked for. RESULTS: On evaluating the frequency of 17 ANGPTL6 SNPs in 100 randomly selected subjects on the basis of linkage disequilibrium mapping, four SNPs (rs6511435, rs8112063, rs11671983 and rs15723) were found to cover more than 95% of the known ANGPTL6 genetic variability. Subjects from the entire MONICA Study were then genotyped for these four SNPs. No significant association was detected for rs11671983 and rs15723. In contrast, the G allele of rs8112063 was associated with lower plasma glucose levels (P=0.009). Also, obese subjects carrying the G allele of rs6511435 had higher plasma insulin levels than AA subjects (P=0.0055). Moreover, the G allele of rs6511435 tended to be associated with a 20% higher risk of the metabolic syndrome (P=0.034). However, when false discovery rate testing (40 tests) was applied, these associations were no longer statistically significant. CONCLUSION: These findings constitute the first study in humans of ANGPTL6 genetic variability. Although there was no evidence that polymorphisms in ANGPTL6 might be significantly associated with the metabolic syndrome-related phenotypes, a weak association of these polymorphisms with these parameters cannot be excluded. Further association studies are needed to arrive at any definite conclusions.

OBJECTIVES: ZAC1 (zinc finger protein regulating apoptosis and cell cycle arrest) is a member of the new subfamily of zinc-finger transcription factors, designated as PLAG (pleomorphic adenoma gene) family. The ZAC1 gene is maternally imprinted and is linked to developmental disorders such as growth retardation and transient neonatal diabetes mellitus. We wanted to assess whether the genetic variability of the ZAC1 gene was associated with anthropometric (weight, BMI, waist-to-hip ratio) or biochemical (plasma lipid, insulin, glucose levels, blood pressure level) phenotypes. METHODS: We selected 37 independent SNPs (single nucleotide polymorphisms) or tagSNPs in the ZAC1 locus from the literature and several databases and, based on the linkage disequilibrium map, identified 27 independent SNPs. Those 27 SNPs were genotyped in a French population-based sample (n = 1155). Associations with a P value lower than 0.0019 (Bonferroni correction) were considered significant. RESULTS: We found that women carrying the T allele of rs9403542 had lower waist-to-hip ratio (P = 0.0006) than women with the CC genotype. Also, men bearing the T allele of rs13218225 had lower systolic (P = 3.6 x 10(-5)) and diastolic (P = 4.1 x 10(-4)) blood pressure than GG men. As a consequence, the adjusted (for age, smoking habit, alcohol consumption, physical activity level and BMI) odds ratio (95% confidence interval) of hypertension for T allele carrier men was 0.55 [0.35-0.86], P = 0.009. We genotyped two other independent samples (MONICA Toulouse, n = 1130 and MONICA Strasbourg, n = 1048) for rs9403542 and rs13218225 but we could not confirm these associations. CONCLUSION: We found no evidence that polymorphisms in ZAC1 might influence anthropometric, biochemical or clinical parameters in French individuals.

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.

Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10−107) and stratified analyses (all P < 3.3 × 10−30). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the

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.

The FE65 protein was previously described interacting with amyloid protein precursor (APP) and mediating its internalization. Hu et al. (Hum. Genet., 103 (1998) 295) recently reported that a deletion polymorphism in intron 13 of the FE65 gene may be protective for sporadic Alzheimer's disease (AD) forms and suggested that this deletion may modify splicing between exon 13 and 14 (the two exons encoding the interaction domain of FE65 with APP). We tested the impact of this polymorphism in 646 controls and 639 sporadic AD cases. We were only able to detect a protective effect of the deletion in the population over 75 years (odds ratio = 0.53, 95% confidence interval (0.35-0.82), P= 0.002). Furthermore, no association of this polymorphism with Abeta40, Abeta42(43) and total Abeta loads were detected in 74 AD brains, although, we could expect that this deletion was associated with modifications of the APP metabolism. In conclusion, the FE65 gene may be a minor genetic determinant only for sporadic late-onset AD forms, although, we cannot conclude that this impact is mediated by a modulation of the APP process and/or Abeta peptide deposition.

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.

International audience; Scavenger receptor class B type I (SR-BI) and cluster determinant 36 (CD36) have been involved in cellular uptake of some provitamin A carotenoids. However, data are incomplete (e.g., there are no data on a-carotene), and it is not known whether genetic variants in their encoding genes can affect provitamin A carotenoid status. The objectives were 1) to assess the involvement of these scavenger receptors in cellular uptake of the main provitamin A carotenoids (i.e., beta-carotene, alpha-carotene, and beta-cryptoxanthin) as well as that of preformed vitamin A (i.e., retinol) and 2) to investigate the contribution of genetic variations in genes encoding these proteins to interindividual variations in plasma concentrations of provitamin A carotenoids. The involvement of SR-BI and CD36 in carotenoids and retinol cellular uptake was investigated in Caco-2 and human embryonic kidney (HEK) cell lines. The involvement of scavenger receptor class B type I (SCARB1) and CD36 genetic variants on plasma concentrations of provitamin A carotenoids was assessed by association studies in 3 independent populations. Cell experiments suggested the involvement of both proteins in cellular uptake of provitamin A carotenoids but not in that of retinol. Association studies showed that several plasma provitamin A carotenoid concentrations were significantly different (P < 0.0083) between participants who bore different genotypes at single nucleotide polymorphisms and haplotypes in CD36 and SCARB1. In conclusion, SR-BI and CD36 are involved in cellular uptake of provitamin A carotenoids, and genetic variations in their encoding genes may modulate plasma concentrations of provitamin A carotenoids at a population level. J. Nutr. 143: 448-456, 2013.

Objectif Au vu de l'augmentation des facteurs de risque des maladies cardiovasculaires en Algerie, il s'agit de degager les elements pertinents pour un programme de prevention. Materiels et Methodes Une enquete transversale a ete realisee en 2008, sur un echantillon de 787 sujets âges de 30 a 64 ans (Ratio xM/F=0,94). Les sujets tires au sort dans la liste des assures sociaux residant dans la ville d'Oran, ont participe volontairement a un bilan clinique, anthropometrique et biochimique. Resultats L'obesite est plus frequente chez les femmes que chez les hommes (32,5 % vs 9,0 %). La prevalence du syndrome metabolique, selon les criteres NCEP-ATPIII est plus elevee chez les femmes (25,9 vs 13,7 % chez les hommes ; p vs 44,2 % chez les hommes) et l'obesite abdominale (46,8 vs 30,1 % chez les hommes). Les hommes affichent une prevalence plus importante de pression arterielle elevee (42,5 vs 34,8 % chez les femmes) et seuls 9,0 % se connaissent hypertendus. Chez les hommes, le syndrome metabolique est plus frequent parmi les sujets maries et tres instruits. Les femmes presentant un niveau eleve d'education et une activite physique intermediaire semblent etre protegees. Conclusions Le syndrome metabolique est associe en zone urbaine, a une forte proportion de HDL-cholesterol bas et d'obesite abdominale, principalement chez les femmes. Bien que le niveau de cholesterol total n'atteigne pas des valeurs pathologiques, on observe, notamment chez elles, des niveaux deleteres de HDL-cholesterol lies l'inactivite physique. Chez les hommes, le recours aux soins reste d'un faible niveau compte tenu du nombre eleve d'hypertendus meconnus. Il y a un besoin de prevention portant sur la promotion de l'activite physique pour l'ensemble de la population, du depistage de l'hypertension chez les hommes et de l'obesite chez les femmes, comme il est necessaire de redefinir a travers des etudes longitudinales, les valeurs seuils specifiques du tour de taille dans la population Algerienne.

Introduction La prevalence du diabete de type 2 qui etait de 7,1 % en 1998 chez les adultes residant dans la ville d'Oran (Nord-Ouest), est passee a 12,3 % en 2005 dans la population du Nord Algerien. L'objectif de cette etude est de mesurer 10 ans apres, la prevalence du diabete a Oran et de mettre en evidence ses facteurs de risque associes. Materiels et Methodes Une enquete en population a ete realisee, en 2007-2009 chez les adultes (30 a 64 ans) residant dans la ville d'Oran. Les sujets tires au sort dans la liste des assures sociaux ont participe volontairement a un bilan clinique, anthropometrique et biochimique. Au total, 787 sujets (Ratio M/F = 0,94) ont participe a l'enquete. Resultats La prevalence du diabete de type 2 est de 10,5 % (IC = 9,4-11,6), et celle de l'IFG 11,6 %, de facon similaire dans les deux sexes. Les sujets diabetiques sont plus âges (52,0 ± 9,5 ans vs 42,8 ± 9,6 ans, p = 9,4 × 10 15) et presentent les valeurs suivantes de glycoregulation : glycemie a jeun (9,58 ± 3,02 mmol/l), insulinemie a jeun (11,34 ± 10,70 μIU/mL), HOMA-IR (4,7 ± 5,2) et HOMA (51,8 ± 55,9). Comparativement aux sujets non diabetiques, ils presentent des valeurs cliniques elevees concernant le BMI (27,9 ± 5,2 vs 25,8 ± 5,1 kg/m2, p = 0,001), le tour de taille (95,6 ± 10,9 vs 86,4 ± 12,2 cm, p = 5,8 × 10 10), la pression arterielle systolique (133,6 ± 22,2 vs 122,1 ± 17,2 mm Hg, p = 6,3 × 10 8) et la pression arterielle diastolique (81,1 ± 9,2 vs 76,2 ± 9,9, p = 4,5 × 10 5). Les niveaux du cholesterol et de ses fractions (HDL et LDL cholesterol) sont similaires dans les deux groupes pendant que les triglycerides sont eleves dans le groupe des diabetiques (1,58 ± 0,70 vs 1,11 ± 0,47, p = 4,4 × 10 11). Conclusions L'accroissement significatif de la maladie chez les adultes oranais, associe a la frequence elevee de l'IFG, demontre que la population a rapidement atteint un niveau de risque eleve de diabete de type 2. Il est urgent de mettre en place un programme de prevention base sur l'alimentation et l'activite physique, et associant la surveillance des parametres cliniques et biochimiques.

Thyroid hormone receptor-beta resistance has been associated with metabolic traits. THRA gene sequencing of an obese woman (index case) who presented as empirical thyroid hormone receptor-α (THRA) resistance, disclosed a polymorphism (rs12939700) in a critical region involved in TRα alternative processing.THRA gene variants were evaluated in three independent europid populations (i) in two population cohorts at baseline (n=3417 and n=2265), 6 years later (n=2139) and (ii) in 4734 high cardiovascular risk subjects (HCVR, PREDIMED trial).The minor allele of the index case polymorphism (rs12939700), despite having a very low frequency (4%), was significantly associated with higher body mass index (BMI) (P=0.042) in HCVR subjects. A more frequent THRA polymorphism (rs1568400) was associated with higher BMI in subjects from the population (P=0.00008 and P=0.05) after adjusting for several confounders. Rs1568400 was also strongly associated with fasting triglycerides (P dominant=3.99 × 10(-5)). In the same sample, 6 years later, age and sex-adjusted risk of developing obesity was significantly increased in GG homozygotes (odds ratio 2.93 (95% confidence interval, 1.05-6.95)). In contrast, no association between rs1568400 and BMI was observed in HCVR subjects, in whom obesity was highly prevalent. This might be explained by the presence of an interaction (P0.001) among the rs1568400 variant, BMI and saturated fat intake. Only when saturated fat intake was high (24.5 g d(-1)), GG carriers showed a significantly higher BMI than A carriers after controlling for energy intake and physical activity.THRA gene polymorphisms are associated with obesity development. This is a novel observation linking the THRA locus to metabolic phenotypes.

International audience; Background:REV-ERBα has been shown to regulate adipogenesis and lipid metabolism as well as to link the circadian timing system to whole body metabolic homeostasis. We thus tested whether polymorphisms in REV-ERBα could be associated with metabolic phenotypes in human population samples.Methods:We analyzed the associations between 5 REV-ERBα polymorphisms and anthropometric (body weight, body mass index (BMI), waist and hip circumferences), biochemical (plasma lipid, glucose and insulin levels) and clinical (systolic and diastolic blood pressure) variables in three population-based studies (MONICA Lille n=1155 adults, MONA LISA Lille n=1170 adults and HELENA n=1155 adolescents). We assessed in vitro, the potential influence of one REV-ERBα polymorphism in transient transfection assays using two different cell lines.Results:We observed significant and consistent associations between the T minor allele of the REV-ERBα rs2071427 polymorphism (located in intron 1) and higher BMI (mean allele effect=+0.33 kg m(-2)) in the MONICA Lille (P=0.02), MONA LISA (P=0.02) and HELENA (P=0.03) studies. The odds ratios for obesity associated with this allele were 1.67 (1.00-2.79) (P=0.05) in MONICA Lille, 1.29 (1.01-1.65) (P=0.04) in MONA LISA Lille and the odds ratio for overweight was 1.48 (1.08-2.03) (P=0.01) in HELENA. In transfection experiments in human hepatocyte-derived cell lines, the REV-ERBα intron 1 directed the transcription of a luciferase reporter gene independently of the rs2071427 polymorphism.Conclusion:Our results suggest that the REV-ERBα rs2071427 polymorphism modulates body fat mass in both adult and young people.International Journal of Obesity advance online publication, 17 July 2012; doi:10.1038/ijo.2012.117.

International audience; Transcription factor 7-like 2 (TCF7L2) is the strongest genetic determinant of type 2 diabetes (TDM) and insulin-related phenotypes to date. Dietary fat is a key environmental factor which may interact with genotype to affect risk of metabolic syndrome (MetS) and T2DM. This study investigated the relationship between the TCF7L2 rs7903146 polymorphism, insulin sensitivity/resistance and MetS in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n=1754) and determined potential interactions with dietary fat intake. Female minor T allele carriers of rs7903146 had increased MetS risk (odds ratio [OR] 1.66, confidence interval [CI] 1.02-2.70, P=.04) and displayed elevated insulin concentrations (P=.005), impaired insulin sensitivity (P=.011), increased abdominal obesity (P=.008) and body mass index (P=.001) and higher blood pressure (P= 15.5% energy) exacerbated MetS risk (OR 2.35, 95% CI 1.29-4.27, P=.005) and was associated with further impaired insulin sensitivity in the T allele carriers relative to the CC homozygotes (P=.025) and particularly to the T allele carriers with the lowest SFA intake (P=.008). No significant genotype effect on MetS risk or insulin sensitivity was evident among low-SFA consumers. In conclusion, the TCF7L2 rs7903146 polymorphism influences MetS risk, which is augmented by both gender and dietary SFA intake, suggesting novel gene-diet-gender interactions. (C) 2012 Elsevier Inc. All rights reserved.

Estrogen treatment can modulate the risk for developing dementia in women. Therefore, single nucleotide polymorphisms (SNPs) in the estrogen receptor genes may constitute genetic susceptibility factors to Alzheimer's disease (AD). Thus, we investigated the impact of the genetic variability of the estrogen receptor α 1 (ESR1) and estrogen receptor α 2 (ESR2) genes on late onset AD risk. We analyzed 39 SNPs in ESR1 and 5 SNPs in ESR2 in a French case-control study of sporadic AD (1007 cases/647 controls). Individuals carrying the minor allele of rs7450824 had a lower risk of AD than homozygous subjects for the major allele (age, gender, and APOE e4 allele adjusted odds ratio = 0.71 [0.57-0.89], p = 0.003). However, this association did not resist Bonferroni correction for multiple testing (p-threshold < 0.001). Consistently, no significant association could be detected when considering age of onset. We also tested for possible interactions between the ESR SNPs and APOE status (e4 allele) or gender but no significant interaction could be observed. Even after stratifying the sample on APOE status or gender, no significant association with AD risk could be detected. Finally, we searched for potential gene-gene interactions between ESR1 and ESR2 SNPs but no significant interaction could be detected. Our results reinforce the notion that SNPs in the ESR1 or ESR2 genes do not seem to play a major role in the genetic susceptibility of AD.

Background: Blood vitamin E concentrations are modulated by dietary, metabolic, and genetic factors. CD36 (cluster of differenti- ation 36), a class B scavenger receptor, might be involved in tissue vitamin E uptake and thus would influence blood vitamin E con- centrations. Objective: The goal of the study was to assess the association be- tween CD36 single nucleotide polymorphisms (SNPs) and plasma a-tocopherol concentrations in humans. Design: A subsample from the adult SU.VI.MAX (SUpplementa- tion en VItamines et Mineraux AntioXydants) cohort (n = 621) and the adolescent cross-sectional HELENA (Healthy Lifestyle in Eu- rope by Nutrition in Adolescence) Study (n = 993) were genotyped for CD36 SNPs (4 and 10 SNPs, respectively). Fasting plasma a-tocopherol concentrations were assayed by using HPLC. Associ- ations were determined by haplotype analyses and by general linear regression models. Results: In the SU.VI.MAX subsample, haplotype analyses showed that some haplotypes of SNPs rs1984112, rs1527479, rs7755, and rs1527483 tended to be associated with plasma a-tocopherol concentrations (P = 0.08 and P = 0.09 for haplotypes 1222 and 1122, respectively). We then investigated the whole known common genetic variability (10 SNPs) of CD36 in the HELENA Study. Three SNPs were associated with lower plasma a-tocopherol concentra- tions (rs1984112: 23.2%, P = 0.053; rs1761667: 22.9%, P = 0.046; rs1527479: 23.7%, P = 0.0061). After correction for multi- ple testing, the association between rs1527479 and a-tocopherol concentrations remained significant. This association was modu- lated by concentrations of fasting serum triglycerides (P for inter- action = 0.006) and long-chain polyunsaturated fatty acids (P for interaction = 0.005). Conclusion: Our results suggest that CD36 can modulate blood a-tocopherol concentrations and may therefore be involved in the intestinal absorption or tissue uptake of vitamin E. Am J Clin Nutr doi: 10.3945/ajcn.110.004176.

Because the action of thyroid hormone (T3) is involved in adult cognitive functions, we wanted to assess the association between THRA gene polymorphisms, which encodes the T3 nuclear receptor TRα1, and Alzheimer's disease (AD) risk. We analysed 5 single nucleotide polymorphisms (SNPs) of THRA, covering the known common genetic variability of the gene, in the Lille AD case-control study (710 cases/597 controls). We observed that subjects bearing the rs939348 TT genotype had a tendency to have a higher risk of developing AD (adjusted OR [95%CI]=1.71 [0.99-2.95] p=0.06). We extended our finding to three other independent AD case-control studies and observed similar trends. When combining the 4 studies (1749 cases/1339 controls), we observed an overall significant higher risk of AD in TT subjects (adjusted OR [95%CI]=1.42 [1.03-1.96], p=0.03) compared with C allele bearers. However, when combining our data with the available data coming from 2 American genome wide association studies on AD, we observed a weak and not significant association (OR=1.19 [0.97-1.45], p=0.10). The relationship between the genetic variability of the THRA gene and AD risk remains uncertain but cannot be entirely excluded.

BACKGROUND Thyroid hormones (THs) exert multiple biological roles including effects on the cardiovascular system (lipid profile, blood pressure (BP) and cardiac output). The lipid-lowering actions of TH are mediated by the TH receptor-beta whereas the mechanisms explaining the BP variations concomitant with the thyroid disorders are less understood. As the TH receptor-alpha (TR-alpha) has been associated with many of TH actions on the cardiovascular system in mice models, we hypothesized that it could be involved in the latter. We thus tested whether polymorphisms in TR-alpha (THRA gene) could be associated with BP level variation. Secondarily, we tested for association with coronary heart disease (CHD) risk. METHODS We analyzed the associations between five THRA polymorphisms and (i) BP level in two population-based studies (MONICA Lille n = 1,155; MONICA Toulouse n = 1,170) and (ii) the risk of CHD in two case-control studies (Lille CHD n = 558 cases/568 controls; PRIME n = 527 cases/584 controls). RESULTS Individuals carrying the rs939348T allele had higher systolic BP (similar to+1.3 mm Hg) than CC individuals in both the MONICA Lille (P = 0.02) and Toulouse (P = 0.03) studies. The odds ratio (OR) for hypertension was 1.25 (P = 0.02) in the combined sample. Concerning the CHD risk, no significant association could be detected. CONCLUSIONS For the first time, our study showed associations between the THRA rs939348 polymorphism and systolic BP and the risk of hypertension but not with CHD, although we admit that the statistical power available to study any relationship with CHD was very limited. Further larger association studies are needed to confirm our findings.

Introduction Le vieillissement combine aux changements du mode de vie a conduit a une transition epidemiologique en Afrique du Nord. Ces changements ont un impact significatif sur l’incidence des maladies cardiovasculaires. Dans ce contexte, les prevalences du syndrome metabolique et des facteurs associes sont mal connues. Cette etude se propose de mesurer ces prevalences dans la population urbaine d’Oran. Methodes Une enquete en population a ete realisee, en 2007–2009 dans la population oranaise (30 a 64 ans). Les sujets, tires au sort dans la liste des assures sociaux de la ville d’Oran, ont ete adresses au laboratoire CNASS. Au total, 787 sujets (ratio M/F = 0,94) ont participe a l’enquete. Le syndrome metabolique est defini selon les criteres de la « National Cholesterol Education Program, Adult Treatment Panel III ». Resultats La prevalence du syndrome metabolique, defini selon les criteres NCEP-ATPIII, est de 20,0 % et plus elevee chez les femmes versus les hommes (25,9 contre 13,7 %; p Discussion Le syndrome metabolique est frequent dans la population urbaine au Nord de l’Algerie, principalement chez les femmes qui montrent des frequences elevees de cholesterol-HDL bas et d’obesite abdominale.

International audience; Context: Cytokine polymorphisms and dietary fat composition may influence the risk of the metabolic syndrome (MetS). Objective: The objective of the study was to determine the relationship between lymphotoxin-α (LTA), TNF-α, and IL-6 gene polymorphisms with MetS risk and investigate whether plasma fatty acid composition, a biomarker of dietary fat intake, modulated these associations. Design: Polymorphisms (LTA rs915654, TNF-α rs1800629, IL-6 rs1800797), biochemical measurements, and plasma fatty acids were determined in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1754). Results: LTA rs915654 minor A allele carriers and TNF-α rs1800629 major G allele homozygotes had increased MetS risk [odds ratio (OR) 1.37 (confidence interval [CI] 1.12–1.66), P = 0.002 and OR 1.35 (CI 1.08–1.70), P = 0.009] compared with their TT homozygotes and A allele carriers. Possession of the IL-6 rs1800797 GG genotype by the LTA and TNF-α risk genotype carriers further increased risk of the MetS [OR 2.10 (CI 1.19–3.71) P = 0.009], fasting hyperglycemia [OR 2.65 (CI 1.12–6.28), P = 0.027], high systolic blood pressure [OR 1.99 (CI 1.07–3.72), P = 0.03], and abdominal obesity [OR 1.52 (CI 1.01–2.28), P = 0.04]. Plasma polyunsaturated to saturated fat ratio exacerbated these effects; subjects in the lowest 50th percentile had even greater risk of the MetS [OR 4.40 (CI 1.55–12.45), P = 0.005], fasting hyperglycemia, high systolic blood pressure, and abdominal obesity (P < 0.05). Conclusions: LTA, TNF-α, and IL-6 genotype interactions increased MetS risk, which was further exacerbated by a low plasma polyunsaturated to saturated fat exposure, indicating important modulation of genetic risk by dietary fat exposure

Background: Complement component 3 (C3) is a novel determi- nant of the metabolic syndrome (MetS). Gene-nutrient interactions with dietary fat may affect MetS risk. Objectives: The objectives were to determine the relation between C3 polymorphisms and MetS and whether interaction with plasma polyunsaturated fatty acids (PUFAs), a biomarker of dietary PUFA, modulate this relation. Design: C3 polymorphisms (rs11569562, rs2250656, rs1047286, rs2230199, rs8107911, rs344548, rs344550, rs2241393, rs7257062, rs163913, and rs2230204), biochemical measurements, and plasma fatty acids were measured in the LIPGENE-SUpple- mentation en VItamines et Mineraux AntioXydants (SU.VI.MAX) study in MetS cases and matched controls (n = 1754). Results: Two single nucleotide polymorphisms were associated with MetS. rs11569562 GG homozygotes had decreased MetS risk compared with the minor A allele carriers (odds ratio (OR): 0.53; 95% CI: 0.35, 0.82; P = 0.009), which was augmented by high plasma PUFA status (OR: 0.32; 95% CI: 0.11, 0.93; P = 0.04). GG homozygotes had lower C3 concentrations than those in AA homozygotes (P = 0.03) and decreased risk of hypertriglyceridemia compared with A allele carriers (OR: 0.54; 95% CI: 0.34, 0.92; P = 0.02), which was further ameliorated by an increase in long-chain n-3 (omega-3) PUFAs (OR: 0.46; 95% CI: 0.22, 0.97; P = 0.04) or a decrease in n-6 PUFAs (OR: 0.32; CI: 0.16, 0.62; P = 0.002). rs2250656 AA homozygotes had increased MetS risk relative to the minor G allele carriers (OR: 1.78; CI: 1.19, 2.70; P = 0.02), which was exacerbated by low n-6 PUFA status (OR: 2.20; CI: 1.09, 4.55; P = 0.03). Conclusion: Plasma PUFAs may modulate the susceptibility to MetS that is conferred by C3 polymorphisms, which suggests novel gene- nutrient interactions. This trial was registered at clinicaltrials.gov as NCT00272428. Am J Clin Nutr doi: 10.3945/ajcn.2009.28101.

Metabolic syndrome (MS) is a cluster of metabolic abnormalities associated with an increased risk of developing cardio-vascular diseases, stroke or type II diabetes. Overall, the aetiology of MS is complex and is determined by the interplay between genetic and environmental factors although it is still difficult to untangle their respective roles. The aim of this study was to determine which factors and/or combination of factors could be predictive of MS status. Using a large case–control study nested in a well-characterized cohort, we investigated genetic and dietary factors collected at entry in subjects having developed MS 7 years later. We used a classification technique called Random Forest to predict the MS status from the analysis of these data. We obtained an overall out-of-bag estimation of the correct classification rate of 71.7% (72.1% for the control subjects and 70.7% for the cases). The plasma concentration of 16.1 was the most discriminative variable, followed by plasma concentration of C18.3(n-6) and C18.2. Three SNPs were selected by Random Forest (APOB rs512535, LTA rs915654 and ACACB rs4766587). These SNPs were also significantly associated to the MS by a univariate Fisher test.