Alcohol Consumption, Beverage Preference, and Diet in Middle-Aged Men from the STANISLAS Study

The question about differences in dietary patterns associated with beer, wine, and spirits is still unresolved. We used diet data from 423 middle-aged males of the STANISLAS Study. Using adjusted values for covariates, we observed a negative significant association between increasing alcohol intakes and the consumption of milk, yogurt, and fresh/uncured cheese, sugar and confectionery, vegetables and fruits, and a significant positive relationship with cheese, meat and organs, pork-butcher's meat, and potatoes. In addition, the first dietary pattern identified by factor analysis (characterized a more prudent diet) was inversely related to alcohol intakes. Conversely, when analyzing daily consumption of specific food groups and diet patterns according to beverage preference (wine, beer, and spirits), no significant difference was observed. In conclusion, in this sample of middle-aged French males, there was a linear trend between increasing alcohol intakes and worsening of quality of diet, while no difference was observed according to beverage preference

Interpretation of two-dimensional electrophoresis gels

The study of human protein polymorphism presents a major advantage in clinical chemistry to discover forms associated with risks or involved in well specified pathological states. If this polymorphism corresponds to structural differences reflected by physical property modifications it can be visualized on a map obtained by 2-dimensional electrophoretic technique. This study deals with apolipoproteins A-I, A-II, A-IV, C2, C3, and E that can be found on 2-dimensional gels. Each of these proteins appears on images under the form of a constellation of several spots. An expertise was extracted on these apolipoproteins in order to itemize all their known variants and their geometrical representations. This knowledge was implemented in a system to recognize what are the constellations we are actually dealing with, on a gel. A management system handles specific techniques taken from image processing to extract parameters from 2-dimensional gel images and artificial intelligence. Knowledge-based expert systems which perform the matching, allowing a partial interpretation of the gel. The accuracy of quantity measurement and quality control are greatly improved by adding calibration proteins. This same system will allow us to further implement conceptual clustering techniques to identify relevant relations in apolipoprotein metabolism. Apolipoprotein polymorphism is used in this work as a model which could be extended to other protein constellations in the future

VEGF-related polymorphisms identified by GWAS and risk for major depression

La depresión es una enfermedad mental común, grave e incapacitante que afecta a millones de personas de todas las edades en todo el mundo. Varios estudios han demostrado que los factores neurotróficos / de crecimiento tienen un papel clave en la depresión y, más específicamente, el factor de crecimiento endotelial vascular (VEGF) está implicado en la patogénesis de la depresión. El propósito de este estudio fue investigar los posibles vínculos entre cuatro polimorfismos de un solo nucleótido (SNP) relacionados con VEGF, previamente identificados a través de un estudio de asociación de genoma completo (GWAS) y la depresión. Los efectos directos y las interacciones epistáticas de los cuatro SNP relacionados con VEGF (rs10738760, rs6921438, rs6993770 y rs4416670) sobre la depresión se investigaron a través de un estudio de casos y controles que incluyó a 437 personas diagnosticadas con depresión y 477 voluntarios sanos como controles. El sexo, la edad y la influencia del índice de masa corporal se analizaron adicionalmente. El SNP rs4416670 se asoció con un mayor riesgo de depresión (OR: 1.60, P: 0.010). Este resultado demuestra la existencia de relaciones entre los determinantes genéticos del VEGF y la depresión. Esta novedosa asociación revela nuevos mecanismos moleculares que sugieren el papel potencial del VEGF en el desarrollo de la depresión que podría ayudar a promover una predicción personalizada para esta enfermedad común grave.Depression is a common, severe, disabling mental disease that affects millions of people of all ages worldwide. Various studies have shown that neurotrophic/growth factors have a key role in depression and, more specifically, vascular endothelial growth factor (VEGF) is implicated in the pathogenesis of depression. The purpose of this study was to investigate the potential links between four VEGF-related single-nucleotide polymorphisms (SNPs), previously identified through a genome-wide association study (GWAS) and depression. The direct effects and epistatic interactions of the four VEGF-related SNPs (rs10738760, rs6921438, rs6993770 and rs4416670) on depression were investigated through a case–control study including 437 individuals diagnosed with depression and 477 healthy volunteers as controls. Gender, age and body mass index influence was additionally analyzed. The SNP rs4416670 was associated with increased risk for depression (OR: 1.60, P: 0.010). This result demonstrates the existence of relationships between VEGF genetic determinants and depression. This novel association reveals new molecular mechanisms suggesting the potential role of VEGF in depression development that could help to promote a personalized prediction for this severe common disease.• Région Lorraine y Fondo Social Europeo. Ayuda • Junta de Extremadura. Ayuda TE14002, para Áura Delgado Regalado • Instituto de Salud Carlos III. Programa Sara Borrell. Proyecto CD13/00348, para Fernando de Andrés SegurapeerReviewe

A Genome-Wide Association Study Identifies rs2000999 as a Strong Genetic Determinant of Circulating Haptoglobin Levels

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

La pharmacogénomique, meilleur exemple de médecine personnalisée

International audiencePharmacogenetics and pharmacogenomics allow for appreciating the individual response to drugs. After reminding that this personalized medicine was already practiced in ancient times, it is only about sixty years ago, that this discipline really appeared after highlighting the toxicity due to gene mutations such as that of acetyltransferases for isoniazide, cytochromes P450 2D6 for many drugs such as pexid, betablockers, antidepressors and cytochrome P450 2C19 for clopidogrel.It is thus necessary to consider the 3 phases of transformation of a drug in the organism (essentially the liver): oxidation, conjugation and transport.Therefore the drugs or their metabolites reach the therapeutic targets such as proteins ((Apolipoprotein E – ApoE) or receptors at the cell surface (cancerous therapy).The final aim is to adapt the right dose of medicines to each patient in order to avoid or diminish the adverse or toxic reactions and to prescribe a substitute drug for therapy-resistant patients.We describe some examples with anticoagulants (coumarin) or antithrombotic (clopidogrel)The improvement of clinical use requires a multilevel strategy (training, information, quality of genotyping methods, clinical trials) in order to transfer this knowledge to clinicians and patients.La pharmacogénétique et la pharmacogénomique permettent de connaître la réponse individuelle au médicament. Après un rappel montrant que cette médecine personnalisée était déjà entrevue dans l’Antiquité, ce n’est qu’il y a une soixantaine d’années que cette discipline a vu le jour avec la mise en évidence des toxicités dues à des mutations de gènes comme ceux des acétyltransférases pour l’isoniazide, des cytochromes P450 2D6 pour de ombreux médicaments comme le pexid, des béta-bloquants, des anti-dépresseurs, du cytochrome P450 2C19 pour le clopidogrel. Il est donc nécessaire de connaître les 3 phases de la transformation d’un médicament dans l’organisme (essentiellement le foie) : oxydation, conjugaison et transport. Ce sont donc les médicaments ou leurs métabolites qui atteignent les cibles thérapeutiques comme des protéines (Apolipoprotéine E – ApoE) ou des récepteurs à la surface des cellules (thérapie cancéreuse). L’objectif final est d’adapter la bonne dose de médicament à chaque patient, d’éviter ou diminuer les effets indésirables ou toxiques et de prescrire un médicament de substitution pour les sujets résistants. Des exemples pour les anticoagulants (coumarines) ou les anti-thrombotiques (clopidogrel) sont décrits. L’amélioration de l’utilisation clinique nécessite une stratégie à plusieurs niveaux (formation, information, qualité des méthodes de génotypage, essais cliniques) pour transférer ces connaissances aux cliniciens et aux patients

Analyse génétique et transcriptomique du transporteur ABCB1 en physiopathologie cardiovasculaire

ABCB1 est une protéine impliquée dans le transport des médicaments mais aussi probablement du cholestérol. Des phénomènes de résistance médicamenteuse sont associés à ses polymorphismes et à des modulations de son expression via le facteur PXR. Notre objectif était de réaliser une analyse génomique et transcriptomique d ABCB1 basée sur ces hypothèses : 1) les variants d ABCB1 expliquent-ils une part de la variabilité des taux de lipides et de lipoprotéines plasmatiques ? 2) le profil d expression d ABCB1 dans les cellules mononuclées du sang périphérique (PBMCs) constitue-t-il un biomarqueur cardiovasculaire nouveau ? Nous avons déterminé la prévalence de polymorphismes d ABCB1 chez 371 sujets de la cohorte STANISLAS. Nous montrons que ces variants modulent les concentrations en lipides des sujets sains. Des associations significatives avec les lipides sont aussi notées chez des sujets à haut risque cardiovasculaire. Nous observons qu une majorité d enzymes du métabolisme des xénobiotes et de facteurs de transcription sont exprimés dans les PBMCs de sujets sains. Nous montrons par RTPCR qu ABCB1 et PXR sont exprimés dans les PBMCs de 83 sujets de la cohorte. Enfin, il n y a pas d association entre l expression d ABCB1 dans les PBMCs et le taux de lipides plasmatiques chez le sujet sain. En conclusion, les polymorphismes d ABCB1 peuvent moduler le taux de lipides et d apolipoprotéines. Nous ne pouvons toutefois pas proposer l expression d ABCB1 dans les PBMCs comme biomarqueur du risque cardiovasculaire. Il serait intéressant de reproduire cette étude chez des sujets à risque cardiovasculaire élevé ou d utiliser un modèle in vitro permettant d induire l expression d ABCB1.ABCB1 is an ubiquitously expressed membrane transporter. Resistance to drugs is associated with genetic variations of its gene and with modulation of its expression through the PXR transcription factor. Given that ABCB1 could also transport cholesterol, our goal was to conduct a genomic and transcriptomic analysis of ABCB1 based on the following hypotheses: 1) ABCB1 variants would partly explain plasma lipid and apolipoprotein concentrations, and 2) ABCB1 expression profile in PBMCs would be a new, and easily available, cardiovascular biomarker. We have determined frequency of ABCB1 variants in 371 subjects from the STANISLAS cohort. We have shown in these healthy people that ABCB1 variants modulate lipid concentrations, sometimes in a sex-dependant manner. Significant associations were also observed in subjects with a high cardiovascular risk. In addition, DNA microarray analysis showed that most of the xenobiotic metabolizing enzymes and transcription factors are constitutively expressed in PBMCs of healthy subjects. ABCB1 and PXR were measured by quantitative RT-PCR in 83 subjects from the STANISLAS cohort. They are both expressed in PBMCs but their expressions do not correlate. Finally, there is no association between ABCB1, or PXR, expression in PBMCs and lipid plasma concentrations in healthy subjects. To conclude, ABCB1 variants would modulate lipid and apolipoprotein concentrations. However, from our results, we cannot propose ABCB1 expression in PBMCs as a biomarker of cardiovascular risk. It would be of interest to reproduce this study in PBMCs of people at high cardiovascular risk or in an in vitro model of PBMCs with induction studies of ABCB1 expression.NANCY1-Bib. numérique (543959902) / SudocSudocFranceF