167 research outputs found
Study of the role of PROX1 gene in type 2 diabetes
No full textPROX1 étant un facteur de susceptibilité au diabète de type 2 (DT2), nousavons réalisé des études génétiques et moléculaires afin de comprendre son rôledans l’étiologie du DT2.Nous avons analysé l’impact de 80 SNPs de PROX1 sur des phénotypescliniques associés au DT2 dans l’étude HELENA (n=1155 adolescents) et montréque trois SNPs (rs340838, rs340837 et rs340836) sont associés à l’insulinémie àjeun. Nous avons évalué la fonctionnalité de 9 SNPs (les 3 SNPs associés et 6 SNPsen déséquilibre de liaison) en utilisant un gène rapporteur Luciférase dans descellules HepG2 et MIN6. Les allèles associés à la diminution de l’insulinémie desSNPs rs340874, rs340873 et rs340835 sont associés à une diminution del’expression du gène rapporteur Luciférase, suggérant que l’expression de PROX1est diminuée chez les individus porteurs des allèles à risque.Nous avons aussi montré que l’inhibition de l’expression de Prox1 par siRNAsdans les cellules INS-1E engendrait une diminution de 1,7 fois de la sécrétiond’insuline en réponse au glucose et qu’une concentration élevée en glucose modulaitpositivement l’expression de la protéine Prox1.Des analyses transcriptomiques réalisées dans les cellules INS-1E ont permisde montrer que certains des gènes cibles de PROX1 dans les cellules bêta sont desgènes impliqués dans des voies de sécrétion d’insuline.Enfin, nous avons également observé que l’agoniste de PPARgamma, latroglitazone, diminuait l’expression de Prox1 dans les cellules INS-1E.Ces résultats suggèrent qu’une altération de l’expression de Prox1 par desvariants cis-régulateurs pourrait conduire à une sécrétion d’insuline en réponse auglucose altérée des cellules bêta, conférant ainsi une susceptibilité au DT2.As PROX1 is a susceptibility factor for type 2 diabetes (T2D), we conductedgenetic and molecular studies to better understand the role of PROX1 in the etiology of T2D. We assessed the impact of 80 PROX1 SNPs on T2D-related biochemical traits in the HELENA study (n=1155 adolescents) and showed that 3 SNPs (rs340838, rs340837 and rs340836) were significantly associated with fasting plasma insulin levels. We evaluated the functional impact of 9 SNPs (the 3 insulin-associated SNPs plus 6 SNPs in linkage disequilibrium) using a Luciferase reporter gene expression in HepG2 and MIN6 cells. The insulin-lowering alleles of the rs340874, rs340873 and rs340835 SNPs were associated with lower Luciferase gene expression, suggesting that PROX1 expression may be lower in individuals carrying the insulin-lowering alleles. We also showed that the knock-down of Prox1 expression by siRNA in INS-1E cells resulted in a 1.7 fold reduced glucose-stimulated insulin secretion and that high concentrations of glucose positively modulated Prox1 protein expression. Then, microarray analyses performed in INS-1E cells showed that some PROX1 target genes in the _cells are implicated in insulin secretion pathways. Finally, we observed that the PPARgamma agonist, the troglitazone, decreased Prox1 expression in INS-1E cells. Altogether, these results suggest that an altered expression of Prox1 bys cisregulators variants results in an altered -cell glucose-stimulated insulin secretion andthereby confers susceptibility to T2D
Study of the prognosis of strokes and acute coronary syndromes in population : study based on the Lille stroke registry and the three french registries of acute coronary syndromes
No full textLes maladies cardiovasculaires sont une cause importante de morbi-mortalité. La surveillance des indicateurs épidémiologiques des Accidents Vasculaires Cérébraux (AVC) et des Syndromes Coronaires Aigus (SCA) au travers de registres de population joue un rôle important dans l'évaluation des politiques publiques. De plus, la prise en charge à la phase aiguë progressant rapidement au cours du temps, il est essentiel de pouvoir surveiller son évolution pour estimer l'impact potentiel des nouveaux traitements dans la vie réelle. Notre objectif était de caractériser le pronostic des AVC et des SCA en population et il s'est ordonné selon 3 axes.Dans une première étude, nous avons étudié la létalité après un AVC dans le registre des AVC de Lille. La létalité à 28 jours, chez les sujets âgés de >=35 ans, était de 48% après un AVC hémorragique, de 3 % après un AVC ischémique des grandes artères ou lacunaires et variait de 15 à 20 % pour les autres sous-types d'AVC ischémiques. A la phase aiguë, les délais entre les premiers symptômes et le contact avec les services de soins étaient dépassés chez 40% des patients, ne permettant pas une revascularisation. L'âge, la gravité et l'étiologie des AVC étaient les principaux prédicteurs de la létalité à 28 jours. La létalité plus élevée, observée chez les femmes par rapport aux hommes, s'expliquait, principalement par leur âge avancé. La FA, une comorbidité sous diagnostiquée, sous-traitée et retrouvée chez 57% des AVC cardioemboliques, était également un facteur de risque de létalité accrue.Dans un second travail nous avons étudié l'évolution de la prise en charge et de la létalité des SCA dans les registres français des SCA entre 2006 et 2016. Chez les patients de 35-74 ans, résidants dans l'une des 3 zones géographiques surveillées par les registres MONICA et hospitalisés pour un SCA, la létalité était de 8% à 28jours. Ces taux variaient selon le type de SCA (9% après un STEMI, 6 % après un NSTEMI à 1 an), mais ne différaient pas entre les hommes et les femmes. Sur le plan thérapeutique, nos résultats montraient une évolution davantage qualitative que quantitative avec une amélioration de l'efficacité de la prise en charge à la phase aiguë et des prescriptions en lien avec les thérapeutiques de nouvelles générations. Cependant, tandis que les caractéristiques des évènements tendent à converger entre les hommes et les femmes, un léger déficit de prise en charge était encore observé chez les femmes par rapport aux hommes.Dans une troisième partie, nous nous sommes intéressés aux patients qui avaient survécu à leur évènement incident pour étudier le risque de récidive après un SCA dans les registres français des SCA. Le taux de récidive après un SCA incident restait élevé (~20 % sur 9 ans), principalement l'année suivant l'évènement incident (6,7%) et ne dépendait pas du type du premier événement (STEMI/NSTEMI/UA), ni du sexe. Une FEVG altérée et les complications de l'évènement incident étaient des facteurs de risque majeurs de récidive. Les taux de récidive diminuaient entre 2009 et 2017.En conclusion, les évènements vasculaires aigus restent des maladies au pronostic grave dont l'étiologie et le mécanisme physiopathologique sont une source importante et indépendante de variabilité pronostique. Il convient de poursuivre l'amélioration de la prise en charge des femmes pour lesquelles la progression n'est pas aussi optimale que pour les hommes et d'apporter une attention particulière aux facteurs de gravité des AVC et des SCA. Ainsi, en fournissant des indicateurs épidémiologiques précis, l'enregistrement en continu des événements vasculaires aigus sur un territoire géographiquement défini, a permis la surveillance de l'état de santé vasculaire en population et nous a permis d'étudier le pronostic des AVC et des SCA selon les caractéristiques précises de l'événement.Cardiovascular diseases are an important cause of morbidity and mortality. The monitoring of epidemiological indicators of stroke and Acute Coronary Syndromes (ACS) through population registers plays an important role in the evaluation of public policies. In addition, as acute-phase care progresses rapidly over time, it is essential to be able to monitor its evolution, to estimate the potential impact of new treatments in real life. Our objective was to characterize the prognosis of strokes and ACS in the population and it was organized according to 3 axes.In a first study, we studied lethality after stroke in the Lille stroke registry. Lethality at 28 days, in subjects aged >=35 years, was 48% after hemorrhagic stroke, 3% after large artery atherosclerosis or lacunar stroke and varied from 15 to 20% for the other subtypes of ischemic strokes. In the acute phase, the time between the onset of symptoms and first contact with the care services was exceeded in 40% of patients, not allowing revascularization. Age, severity and stroke etiology were the main predictors of 28-day case fatality. The higher lethality observed in women compared to men was mainly explained by their advanced age. AF, an underdiagnosed and undertreated comorbidity found in 57% of cardioembolic strokes, was also a risk factor associated with lethality.In a second work we studied the evolution of the management and the lethality of ACS in the French registers of ACS between 2006 and 2016. In patients aged 35-74, residing in one of the 3 geographical areas monitored by MONICA registries and hospitalized for an ACS, the lethality was 8% at 28 days. These rates varied by type of ACS (9% after STEMI, 6% after NSTEMI at 1 year), but did not differ between men and women. On the therapeutic level, our results showed a more qualitative than quantitative evolution with an improvement in the effectiveness of management in the acute phase and prescriptions related to new generation therapies. However, while the characteristics of the events tend to converge between men and women, a slight deficit in management was still observed in women compared to men.In a third part, we focused on patients who had survived their incident event to study the risk of recurrence after an ACS in the French ACS registers. The recurrence rate after an incident ACS remained high (~20% over 9 years), mainly the year following the incident event (6.7%) and did not depend on the type of the first event (STEMI/NSTEMI/UA), or sex. Impaired LVEF and complications from the incident event were major risk factors for recurrence. Recurrence rates decreased between 2009 and 2017.In conclusion, acute vascular events remain diseases with a serious prognosis whose etiology and physiopathological mechanism are an important and independent source of prognostic variability. It is important to continue improving the management of women for whom the progression is not as optimal as for men and to pay particular attention to the severity factors of stroke and ACS. Thus, by providing precise epidemiological indicators, the continuous recording of acute vascular events in a geographically defined territory, has enabled the monitoring of the state of vascular health in the population and has enabled us to study the prognosis of strokes and ACS according to the precise characteristics of the event
Recherche de déterminants génétiques des phénotypes associés au syndrome métabolique en population
No full textLe concept de syndrome métabolique correspond à une association non fortuite chez un individu d'une obésité abdominale, d'une hyperglycémie, d'une hypertriglycéridémie, d'une hypoalphalipoproteinémie (faible taux de HDL-cholestérol) et d'une hypertension artérielle. La détection de sujets présentant ce syndrome permet d'identifier des individus à haut risque cardiovasculaire. Le syndrome métabolique est un désordre complexe et multifactoriel dont l'origine est due à l'interaction entre facteurs génétiques et environnementaux. Dans le but d'identifier de nouveaux facteurs de susceptibilité génétique aux phénotypes du syndrome métabolique, nous nous sommes intéressés à la variabilité génétique commune des gènes codant les récepteurs nucléaires LXRs (liver X receptor) ainsi qu'à la famille de protéines plasmatiques ANGPTLs (angiopoietin-like proteins) dans des études de population d'adultes (MONICA) et d'adolescents (HELENA) (n=1200 chacune). Nous avons mis en évidence une association entre le polymorphisme rs11039155 du gène codant LXRalpha et une diminution de 30% du risque de syndrome métabolique dans les échantillons MONICA Lille et Toulouse. De plus, ce polymorphisme est associé à une augmentation de la concentration plasmatique en HDL-cholestérol (Legry et al 2008). Nous n'avons pas détecté d'impact significatif de ce polymorphisme sur l'expression du gène codant LXRa ou de son gène cible ATP-binding cassette transporter A1 (ABCA1) dans des cultures primaires de macrophages humains. Cependant, l'impact de ce polymorphisme sur la concentration plasmatique en HDL-cholestérol a été confirmé dans l'étude HELENA. Concernant le gène codant LXRbeta, le polymorphisme rs17373080 est associé à une augmentation de 26% du risque d'obésité dans les études MONICA Lille et Toulouse et de 59% du risque de surpoids dans HELENA. Des études fonctionnelles de transfection cellulaire suggèrent que ce polymorphisme pourrait moduler l'expression de LXRbeta in vitro. Nous avons également étudié la variabilité génétique commune de ANGPTL3, 4 et 6, protéines impliquées dans la régulation du métabolisme énergétique. Le polymorphisme rs11207997 de ANGPTL3 est associé à une diminution des taux de HDL-cholestérol et d'ApoA1 dans les études MONICA Lille et HELENA. Par ailleurs, le polymorphisme rs4076317 de ANGPTL4 est associé à une augmentation de l'adiposité dans les études MONICA Lille et HELENA (Legry et al, soumis). De plus, nous avons analysé la variabilité génétique de ANGPTL6. Après avoir évalué la fréquence de 17 polymorphismes génétiques dans une centaine d'individus pris au hasard, nous avons montré que 4 polymorphismes (rs6511435, rs8112063, rs11671983 et rs15723) couvrent plus de 95% de la variabilité génétique connue de ANGPTL6. Le polymorphisme rs8112063 est associé à une diminution de la glycémie dans les études MONICA Lille, Toulouse et Strasbourg combinées. De plus, le polymorphisme rs6511435 est associé à une légère augmentation (20%) du risque de syndrome métabolique dans ces populations (Legry et al 2009, sous presse). Enfin, nous avons confirmé l'impact du polymorphisme rs9939609 du gène FTO (fat-mass and obesity-associated) sur le risque d'obésité (+29%) et de diabète de type 2 (+45%) dans les études MONICA Lille, Toulouse et Strasbourg (Legry et al, sous presse). En conclusion, ces résultats suggèrent un impact non négligeable de la variabilité génétique des gènes codant les LXRs et les ANGPTLs dans la détermination du profil gluco-lipidique et de la masse grasse ainsi que le risque de syndrome métabolique chez l'HommeLILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF
No association between polymorphisms in the INSIG1 gene and the risk of type 2 diabetes and related traits.
No full textBackground: The insulin-induced gene 1 (INSIG1) encodes a protein that blocks proteolytic activation of sterol regulatory element binding proteins, which are transcription factors that activate genes that regulate cholesterol, fatty acid, and glucose metabolism.Objective: We tested for associations between 6 INSIG1 tag single nucleotide polymorphisms (SNPs) (and captured all common variations in INSIG1) and the risk of type 2 diabetes (T2D), obesity, and related traits in 10,567 adults and 1155 adolescents from 5 population-based studies, a T2D case-control study, and a T2D case-series.Design: We genotyped tag SNPs and tested them for associations with the risk of T2D or obesity and with body mass index, waist circumference, systolic and diastolic blood pressure, and concentrations of fasting glucose, 2-h oral-glucose-tolerance test glucose, cholesterol, and triglyceride, assuming an additive effect of the minor allele. Dominant effects were tested for the less-frequent SNPs (minor allele frequency <5%). Summary statistics of each study underwent meta-analysis.Results: Meta-analyses, which included 1655 T2D cases and 2911 control subjects, showed no association between any of the INSIG1 SNPs and T2D (P > 0.08). Furthermore, none of the SNPs showed an association with obesity in 1666 obese and 5737 nonobese individuals (P > 0.17). In agreement, none of the associations between the SNPs and any of the metabolic traits showed convincing associations in the 7562 adults from 4 population-based studies. Although a few nominally significant associations emerged, none of the associations survived multiple-testing correction. We observed no convincing associations with any of the studied traits in 1155 adolescents.Conclusion: Although our study was sufficiently powered to identify small effects, the results suggest that common variation in INSIG1 is unlikely to have a major effect on T2D and obesity risk and related traits in white Europeans
A study of the relationships between <it>KLF2 </it>polymorphisms and body weight control in a French population
No full textAbstract Background Factors governing adipose tissue differentiation play a major role in obesity development in humans. The Krüppel-like zinc finger transcription factor KLF2/Lung KLF (LKLF) is a negative regulator of adipocyte differentiation. In this study, we sequenced the human KLF2 gene and several common polymorphisms were found, among them the Pro104Leu and 3'UTR 1239C>A polymorphisms. Methods To evaluate the impact of these polymorphisms on anthropometric variables in humans, we genotyped a general population composed of 1155 French individuals (including 232 obese subjects) for these polymorphisms and looked for potential statistical associations with obesity-related variables. Results The frequency of the Leu104 and 1239A alleles were 0.22 and 0.18 respectively. Genotype and allele frequencies of the two polymorphisms were comparable in obese, overweight and normal weight subjects. No association between the rare alleles of the polymorphisms and anthropometric variables (BMI, weight, waist and hip circumferences, waist-to-hip ratio and plasma leptin levels) could be detected. Haplotype analyses did not reveal further significant associations. Conclusion These data indicate that the Pro104Leu and 3'UTR 1239C>A polymorphisms in KLF2 are not associated with obesity and obesity-related traits in humans.</p
Characterization of the human, mouse and rat PGC1β (peroxisomeproliferator-activated receptor-γ co-activator 1β) gene in vitro and in vivo
No full textPGC1α is a co-activator involved in adaptive thermogenesis, fatty-acid oxidation and gluconeogenesis. We describe the identification of several isoforms of a new human PGC1α homologue, cloned independently and named PGC1β. The human PGC1β gene is localized to chromosome 5, has 13 exons and spans more than 78 kb. Two different 5′ and 3′ ends due to differential splicing were identified by rapid amplification of cDNA ends PCR and screening of human cDNA libraries. We show that PGC1β variants in humans, mice and rats are expressed predominantly in heart, brown adipose tissue, brain and skeletal muscle. PGC1β expression, unlike PGC1α, is not up-regulated in brown adipose tissue in response to cold or obesity. Fasting experiments showed that PGC1α, but not PGC1β, is induced in liver and this suggests that only PGC1α is involved in the hepatic gluconeogenesis. No changes in PGC1β gene expression were observed associated with exercise. Human PGC1β-1a and -2a isoforms localized to the cell nucleus and, specifically, the isoform PGC1β-1a co-activated peroxisome-proliferator-activated receptor-γ, -α and the thyroid hormone receptor β1. Finally, we show that ectopic expression PGC1β leads to increased mitochondrial number and basal oxygen consumption. These results suggest that PGC1β may play a role in constitutive adrenergic-independent mitochondrial biogenesis.</p
Gene x lifestyle interactions in type 2 diabetes mellitus and related traits [Elektronisk resurs]
No full text Background: Type 2 diabetes is thought to result from interactions between genetic and lifestyle factors, but few robust examples exist. The overarching aim of this thesis was to discover such interactions by studying cohorts of white youth and adults from northern Europe in which physical activity, genotypes, and diabetes-related traits or diabetes incidence had been ascertained. Methods: The thesis includes four papers. In Paper I, we investigated associations and interactions between 35 common PPARGC1A polymorphisms and cardiovascular and metabolic disease traits in 2,101 Danish and Estonian children from the European Youth Heart Study (EYHS). Paper II used the same cohort to test associations and interactions on cardiometabolic traits for the diabetes-predisposing TCF7L2 polymorphism. In Paper III, we assessed associations for 17 type 2 diabetes gene polymorphisms on impaired glucose regulation (IGR) or incident type 2 diabetes, and tested whether these effects are modified by physical activity in a prospective cohort study of ~16,000 initially non-diabetic Swedish adults – the Malmö Preventive Project (MPP). Paper IV aimed to replicate main genetic effects and gene x physical activity interactions for an FTO polymorphism on obesity in 18,435 primarily non-diabetic Swedish (MPP) and Finnish (Prevalence, Prediction and Prevention of Diabetes in Botnia) adults. Results: In Paper I, nominally significant associations were observed for BMI (rs10018239, P=0.039), waist circumference (rs7656250, P=0.012; rs8192678 [Gly482Ser], P=0.015; rs3755863, P=0.02; rs10018239, P=0.043), systolic blood pressure (rs2970869, P=0.018) and fasting glucose concentrations (rs11724368, P=0.045). Stronger associations were observed for aerobic fitness (rs7656250, P=0.005; rs13117172, P=0.008) and fasting glucose concentrations (rs7657071, P=0.002). None remained significant after correcting for multiple statistical comparisons. We proceeded by testing for gene × physical activity interactions for the polymorphisms that showed statistical evidence of association (P<0.05) in the main effect models, but none was statistically significant. In Paper II, the minor T allele at the rs7903146 variant was associated with higher glucose levels in older (beta=–0.098 mmol/l per minor allele copy, P=0.029) but not in younger children (beta=–0.001 mmol/l per minor allele copy, P=0.972). A significant inverse association between the minor allele at rs7903146 and height was evident in boys (beta=–1.073 cm per minor allele copy, P=0.001), but not in girls. The test of interaction between the TCF7L2 rs7903146 variant and physical activity on HOMA-B was nominally statistically significant (beta=0.022, Pinteraction=0.015), whereby physical activity reduced the effect of the risk allele on estimated beta-cell function. In Paper III, tests of gene x physical activity interactions on IGR-risk for three polymorphisms were nominally statistically significant: CDKN2A/B rs10811661 (Pinteraction=0.015); HNF1B rs4430796 (Pinteraction=0.026); PPARG rs1801282 (Pinteraction=0.04). Consistent interactions were observed for the CDKN2A/B (Pinteraction=0.013) and HNF1B (Pinteraction=0.0009) variants on 2 hr glucose concentrations. Where type 2 diabetes was the outcome, only one statistically significant interaction effect was observed and this was for the HNF1B rs4430796 variant (Pinteraction=0.0004). The interaction effects for HNF1B on 2 hr glucose and incident diabetes remained significant after correction for multiple testing (Pinteraction=0.015 and 0.0068, respectively). In Paper IV, the minor A allele at rs9939609 was associated with higher BMI (P<0.0001). The tests of gene x physical activity interaction on BMI were not statistically significant in either cohort (Sweden: P=0.71, Finland: P=0.18). Conclusions: Variation at PPARGC1A is unlikely to have a major impact on cardiometabolic health in European children, but physical activity may modify the effect of the TFC7L2 variants on beta-cell function in this cohort. In Swedish adults, physical activity modifies the effects of common HNF1B and CDKN2A/B variants on risk of IGR and also modifies the effect of the HNF1B on type 2 diabetes risk. In Swedish and Finnish adults, we were unable to confirm previous reports of an interaction between FTO gene variation and physical activity on obesity predisposition.</p
Large disparities in 28‐day case fatality by stroke subtype: data from a French stroke registry between 2008 and 2017
No full textInternational audienceBackground and purposeThe objectives of the present analysis were to assess 28-day stroke case fatality according to the stroke aetiology and to identify associated factors.MethodsAll stroke events in adults aged ≥35 years between 2008 and 2017 were collected in a population-based stroke registry in northern France.ResultsOut of a total of 2933 strokes, there were 479 (16%) haemorrhagic strokes and 2454 (84%) ischaemic strokes; the 28-day case fatality rates were 48% and 15%, respectively. Three-quarters of the 28-day case fatalities occurred within 6 days of the event for haemorrhagic strokes and within 16.5 days for ischaemic strokes. After an ischaemic stroke, the case fatality rate was higher for women (18%) than for men (12%, p < 0.0001); however, this difference disappeared after adjustment for age. Cardioembolic strokes (34%) and strokes of undetermined cause (33%) were the most common ischaemic subtypes, with case fatality rates of 16% and 18%, respectively. Large artery atherosclerosis (11%) and lacunar strokes (10%) were less common, and both types had a case fatality rate of 3%. Age at the time of the event and stroke severity were both significantly associated with case fatality. For some types of stroke, a history of cardiovascular events and residence in a nursing home were associated with a poor prognosis. Medical care in a neurology ward was inversely associated with case fatality, for all stroke subtypes.ConclusionsIn northern France, post-stroke case fatality remains high, especially for haemorrhagic stroke. Being treated in a neurology ward improved survival by around 80%
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