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Saint-André-lez-Lille, France

Balder J.-W.,University of Groningen | Staels B.,Lille 2 University of Health and Law | Staels B.,French Institute of Health and Medical Research | Staels B.,Institute Pasteur Of Lille | And 2 more authors.
Current Opinion in Lipidology | Year: 2013

PURPOSE OF REVIEW: This review focuses on the recent developments in the field of drugs that affect HDL metabolism. Additionally, some general (retrospective) thoughts on fighting cardiovascular disease through modulating circulating lipids are discussed. RECENT FINDINGS: Recently, the large 'Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes', 'Treatment of HDL to Reduce the Incidence of Vascular Events' and dal-OUTCOMES studies have challenged the idea that raising HDL cholesterol (HDL-c) decreases cardiovascular disease risk. Concerning the failure of these trials, it may, however, be noted that patients with close to normal HDL-c levels were included. It is shown that anacetrapib and evacetrapib massively increase HDL-c, and both compounds are currently tested in phase-III clinical trials. More specific and stronger activators of liver X receptor and peroxisome proliferator-activated receptor (PPAR) are being developed and tested in a preclinical setting. RVX-208 treatment failed to decrease atheroma volume in coronary artery disease patients. Lecithin:cholesterol acyltransferase replacement therapy showed positive results in a patient with lecithin:cholesterol acyltransferase deficiency. SUMMARY: Inhibition of cholesteryl ester transfer protein, antagomirs against microRNA-33, ApoA-I mimetics and PPARα or PPARα/δ agonists hold on the basis of the current data most promise. However, it will in our opinion be the key that patients with low HDL-c and increased triglyceride should be treated and not those at generally increased risk only. In the poststatin era, personalized medicine, which is inevitably on the horizon, is likely to be helpful for patients who do not reach the goals for LDL cholesterol and HDL-c according to the guidelines. Furthermore, functions of HDL will hopefully be identified as future pharmacological targets. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Bolego C.,University of Padua | Cignarella A.,University of Padua | Staels B.,University of Lille Nord de France | Staels B.,French Institute of Health and Medical Research | And 6 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2013

Macrophages are plastic and versatile cells adapting their function/phenotype to the microenvironment. Distinct macrophage subpopulations with different functions, including classically (M1) and (M2) activated macrophages, have been described. Reciprocal skewing of macrophage polarization between the M1 and M2 state is a process modulated by transcription factors, such as the nuclear peroxisome proliferator-Activated receptors. However, whether the estrogen/estrogen receptor pathways control the balance between M1/M2 macrophages is only partially understood. Estrogen-dependent effects on the macrophage system may be regarded as potential targets of pharmacological approaches to protect postmenopausal women from the elevated risk of cardiovascular disease. © 2013 American Heart Association, Inc. Source

Bonnefond A.,French National Center for Scientific Research | Bonnefond A.,Lille University | Bonnefond A.,European Genomic Institute for Diabetes EGID | Froguel P.,French National Center for Scientific Research | And 2 more authors.
Cell Metabolism | Year: 2015

Type 2 diabetes (T2D) had long been referred to as the "geneticist's nightmare." Genome-wide association studies have fully confirmed the polygenic nature of T2D, demonstrating the role of many genes in T2D risk. The increasingly busier picture of T2D genetics is quite difficult to understand for the diabetes research community, which can create misunderstandings with geneticists, and can eventually limit both basic research and translational outcomes of these genetic discoveries. The present review wishes to lift the fog around genetics of T2D with the hope that it will foster integrated diabetes modeling approaches from genetic defects to personalized medicine. © 2015 Elsevier Inc. Source

Sverrisdottir O.O.,Uppsala University | Timpson A.,University College London | Toombs J.,University College London | Lecoeur C.,European Genomic Institute for Diabetes EGID | And 9 more authors.
Molecular Biology and Evolution | Year: 2014

Lactase persistence (LP) is a genetically determined trait whereby the enzyme lactase is expressed throughout adult life. Lactase is necessary for the digestion of lactose - the main carbohydrate in milk - and its production is downregulated after the weaning period in most humans and all other mammals studied. Several sources of evidence indicate that LP has evolved independently, in different parts of the world over the last 10,000 years, and has been subject to strong natural selection in dairying populations. In Europeans, LP is strongly associated with, and probably caused by, a single C to T mutation 13,910 bp upstream of the lactase (LCT) gene (-13,910*T). Despite a considerable body of research, the reasons why LP should provide such a strong selective advantage remain poorly understood. In this study, we examine one of the most widely cited hypotheses for selection on LP - that fresh milk consumption supplemented the poor vitamin D and calcium status of northern Europe's early farmers (the calcium assimilation hypothesis). We do this by testing for natural selection on -13,910*T using ancient DNA data from the skeletal remains of eight late Neolithic Iberian individuals, whom we would not expect to have poor vitamin D and calcium status because of relatively high incident UVB light levels. None of the eight samples successfully typed in the study had the derived T-allele. In addition, we reanalyze published data from French Neolithic remains to both test for population continuity and further examine the evolution of LP in the region. Using simulations that accommodate genetic drift, natural selection, uncertainty in calibrated radiocarbon dates, and sampling error, we find that natural selection is still required to explain the observed increase in allele frequency. We conclude that the calcium assimilation hypothesis is insufficient to explain the spread of LP in Europe. © 2014 The Author. Source

Bonnefond A.,French National Center for Scientific Research | Bonnefond A.,Lille University | Bonnefond A.,European Genomic Institute for Diabetes EGID | Skrobek B.,French National Center for Scientific Research | And 28 more authors.
Nature Genetics | Year: 2013

Large chromosomal clonal mosaic events (CMEs) have been suggested to be linked to aging and to predict cancer. Type 2 diabetes (T2D) has been conceptualized as an accelerated-aging disease and is associated with higher prevalence of cancers. Here we aimed to assess the association between T2D and CME occurrence in blood. We evaluated the presence of CMEs in 7,659 individuals (including 2,208 with T2D) using DNA arrays. A significant association between CME occurrence and T2D was found (odds ratio (OR) = 5.3; P = 5.1 × 10 -5) and was stronger when we only considered non-obese individuals with T2D (OR = 5.6; P = 4.9 × 10 -5). Notably, CME carriers with T2D had higher prevalence of vascular complications than non-carriers with T2D (71.4% versus 37.1%, respectively; P = 7.7 × 10 -4). In CME carriers, we found an increase in the percentage of abnormal cells over 6 years (P = 8.60 × 10 -3). In conclusion, given the increased risk of cancer in CME carriers, our results may have profound clinical implications in patients with severe T2D. © 2013 Nature America, Inc. All rights reserved. Source

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