Publications by authors named "Vasiliki Lagou"

55 Publications

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Microglia Require CD4 T Cells to Complete the Fetal-to-Adult Transition.

Cell 2020 08 22;182(3):625-640.e24. Epub 2020 Jul 22.

VIB Center for Brain and Disease Research, VIB, Leuven 3000, Belgium; Department of Microbiology and Immunology, KU Leuven-University of Leuven, Leuven 3000, Belgium; Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK. Electronic address:

The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function remains largely unknown. We used a combination of imaging, single cell, and surgical approaches to identify a CD69 CD4 T cell population in both the mouse and human brain, distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells and was shaped by self-antigen and the peripheral microbiome. Single-cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between the fetal and adult states. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities. These results illuminate a role for CD4 T cells in brain development and a potential interconnected dynamic between the evolution of the immunological and neurological systems. VIDEO ABSTRACT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2020.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427333PMC
August 2020

Heterogeneous Effects of Calorie Content and Nutritional Components Underlie Dietary Influence on Pancreatic Cancer Susceptibility.

Cell Rep 2020 07;32(2):107880

Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; VIB Center for Brain and Disease Research, VIB, Leuven 3000, Belgium; Department of Microbiology and Immunology, KU Leuven-University of Leuven, Leuven 3000, Belgium. Electronic address:

Pancreatic cancer is a rare but fatal form of cancer, the fourth highest in absolute mortality. Known risk factors include obesity, diet, and type 2 diabetes; however, the low incidence rate and interconnection of these factors confound the isolation of individual effects. Here, we use epidemiological analysis of prospective human cohorts and parallel tracking of pancreatic cancer in mice to dissect the effects of obesity, diet, and diabetes on pancreatic cancer. Through longitudinal monitoring and multi-omics analysis in mice, we found distinct effects of protein, sugar, and fat dietary components, with dietary sugars increasing Mad2l1 expression and tumor proliferation. Using epidemiological approaches in humans, we find that dietary sugars give a MAD2L1 genotype-dependent increased susceptibility to pancreatic cancer. The translation of these results to a clinical setting could aid in the identification of the at-risk population for screening and potentially harness dietary modification as a therapeutic measure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2020.107880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370178PMC
July 2020

Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.

J Allergy Clin Immunol 2020 11 20;146(5):1180-1193. Epub 2020 Apr 20.

Department of Microbiology and Immunology, Laboratory of Adaptive Immunity, KU Leuven, Leuven, Belgium; VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium; Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom. Electronic address:

Background: The molecular cause of severe congenital neutropenia (SCN) is unknown in 30% to 50% of patients. SEC61A1 encodes the α-subunit of the Sec61 complex, which governs endoplasmic reticulum protein transport and passive calcium leakage. Recently, mutations in SEC61A1 were reported to be pathogenic in common variable immunodeficiency and glomerulocystic kidney disease.

Objective: Our aim was to expand the spectrum of SEC61A1-mediated disease to include autosomal dominant SCN.

Methods: Whole exome sequencing findings were validated, and reported mutations were compared by Western blotting, Ca2 flux assays, differentiation of transduced HL-60 cells, in vitro differentiation of primary CD34 cells, quantitative PCR for unfolded protein response (UPR) genes, and single-cell RNA sequencing on whole bone marrow.

Results: We identified a novel de novo missense mutation in SEC61A1 (c.A275G;p.Q92R) in a patient with SCN who was born to nonconsanguineous Belgian parents. The mutation results in diminished protein expression, disturbed protein translocation, and an increase in calcium leakage from the endoplasmic reticulum. In vitro differentiation of CD34 cells recapitulated the patient's clinical arrest in granulopoiesis. The impact of Q92R-Sec61α1 on neutrophil maturation was validated by using HL-60 cells, in which transduction reduced differentiation into CD11bCD16 cells. A potential mechanism for this defect is the uncontrolled initiation of the unfolded protein stress response, with single-cell analysis of primary bone marrow revealing perturbed UPR in myeloid precursors and in vitro differentiation of primary CD34 cells revealing upregulation of CCAAT/enhancer-binding protein homologous protein and immunoglobulin heavy chain binding protein UPR-response genes.

Conclusion: Specific mutations in SEC61A1 cause SCN through dysregulation of the UPR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2020.03.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649975PMC
November 2020

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Nat Genet 2019 05 1;51(5):804-814. Epub 2019 May 1.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522365PMC
May 2019

Machine learning identifies an immunological pattern associated with multiple juvenile idiopathic arthritis subtypes.

Ann Rheum Dis 2019 05 12;78(5):617-628. Epub 2019 Mar 12.

VIB Center for Brain and Disease Research, Leuven, Belgium

Objectives: Juvenile idiopathic arthritis (JIA) is the most common class of childhood rheumatic diseases, with distinct disease subsets that may have diverging pathophysiological origins. Both adaptive and innate immune processes have been proposed as primary drivers, which may account for the observed clinical heterogeneity, but few high-depth studies have been performed.

Methods: Here we profiled the adaptive immune system of 85 patients with JIA and 43 age-matched controls with indepth flow cytometry and machine learning approaches.

Results: Immune profiling identified immunological changes in patients with JIA. This immune signature was shared across a broad spectrum of childhood inflammatory diseases. The immune signature was identified in clinically distinct subsets of JIA, but was accentuated in patients with systemic JIA and those patients with active disease. Despite the extensive overlap in the immunological spectrum exhibited by healthy children and patients with JIA, machine learning analysis of the data set proved capable of discriminating patients with JIA from healthy controls with ~90% accuracy.

Conclusions: These results pave the way for large-scale immune phenotyping longitudinal studies of JIA. The ability to discriminate between patients with JIA and healthy individuals provides proof of principle for the use of machine learning to identify immune signatures that are predictive to treatment response group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2018-214354DOI Listing
May 2019

NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology.

Ann Rheum Dis 2019 03 14;78(3):342-349. Epub 2018 Dec 14.

Department of Microbiology and Immunology, KUL - University of Leuven, Leuven, Belgium

Objectives: is a key immunological transcription factor, with knockout mice studies identifying functional roles in multiple immune cell types. Despite the importance of NFIL3, little is known about its function in humans.

Methods: Here, we characterised a kindred of two monozygotic twin girls with juvenile idiopathic arthritis at the genetic and immunological level, using whole exome sequencing, single cell sequencing and flow cytometry. Parallel studies were performed in a mouse model.

Results: The patients inherited a novel p.M170I in NFIL3 from each of the parents. The mutant form of NFIL3 demonstrated reduced stability in vitro. The potential contribution of this mutation to arthritis susceptibility was demonstrated through a preclinical model, where Nfil3-deficient mice upregulated IL-1β production, with more severe arthritis symptoms on disease induction. Single cell sequencing of patient blood quantified the transcriptional dysfunctions present across the peripheral immune system, converging on IL-1β as a pivotal cytokine.

Conclusions: NFIL3 mutation can sensitise for arthritis development, in mice and humans, and rewires the innate immune system for IL-1β over-production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2018-213764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390028PMC
March 2019

Genetic Architecture of Adaptive Immune System Identifies Key Immune Regulators.

Cell Rep 2018 10;25(3):798-810.e6

KU Leuven Department of Neurosciences, Laboratory for Neuroimmunology, 3000 Leuven, Belgium; Leuven Brain Institute (LBI), Leuven, Belgium. Electronic address:

The immune system is highly diverse, but characterization of its genetic architecture has lagged behind the vast progress made by genome-wide association studies (GWASs) of emergent diseases. Our GWAS for 54 functionally relevant phenotypes of the adaptive immune system in 489 healthy individuals identifies eight genome-wide significant associations explaining 6%-20% of variance. Coding and splicing variants in PTPRC and COMMD10 are involved in memory T cell differentiation. Genetic variation controlling disease-relevant T helper cell subsets includes RICTOR and STON2 associated with Th2 and Th17, respectively, and the interferon-lambda locus controlling regulatory T cell proliferation. Early and memory B cell differentiation stages are associated with variation in LARP1B and SP4. Finally, the latrophilin family member ADGRL2 correlates with baseline pro-inflammatory interleukin-6 levels. Suggestive associations reveal mechanisms of autoimmune disease associations, in particular related to pro-inflammatory cytokine production. Pinpointing these key human immune regulators offers attractive therapeutic perspectives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2018.09.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205839PMC
October 2018

NOD mice, susceptible to pancreatic autoimmunity, demonstrate delayed growth of pancreatic cancer.

Oncotarget 2017 Oct 24;8(46):80167-80174. Epub 2017 Sep 24.

Translational Immunology Laboratory, VIB, Leuven, Belgium.

Pancreatic cancer is a high mortality form of cancer, with a median survival only six months. There are multiple associated risk factors associated, most importantly type 2 diabetes, obesity, pancreatitis and smoking. The relative rarity of the disease, however, has made it difficult to dissect causative risk factors, especially with related risk factors. A major unanswered question with important therapeutic implications is the effect of immunological responses on pancreatic cancer formation, with data from other cancers suggesting the potential for local immunological responses to either increase cancer development or increase cancer elimination. Due to the rarity and late diagnosis of pancreatic cancer direct epidemiological evidence is lacking, thus necessitating a reliance on animal models. Here we investigated the relationship between pancreatic autoimmunity and cancer by backcrossing the well characterised Ela1-Tag transgenic model of pancreatic cancer onto the pancreatic autoimmune susceptible NOD mouse strain. Through longitudinal magnetic resonance imaging we found that the NOD genetic background delayed the onset of pancreatic tumours and substantially slowed the growth rate of tumours after development. These results suggest that elevated autoimmune surveillance of the pancreas limits tumour formation and growth, identifying pancreatic cancer as a promising target for immune checkpoint blockade therapies that unleash latent autoimmunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.21261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655187PMC
October 2017

Murine Pancreatic Acinar Cell Carcinoma Growth Kinetics Are Independent of Dietary Vitamin D Deficiency or Supplementation.

Front Oncol 2017 28;7:133. Epub 2017 Jun 28.

Translational Immunology Laboratory, VIB, Leuven, Belgium.

Vitamin D has been proposed as a therapeutic strategy in pancreatic cancer, yet evidence for an effect of dietary vitamin D on pancreatic cancer is ambiguous, with conflicting data from human epidemiological and intervention studies. Here, we tested the role of dietary vitamin D in the context of the well-characterized Ela1-TAg transgenic mouse model of pancreatic acinar cell carcinoma. Through longitudinal magnetic resonance imaging of mice under conditions of either dietary vitamin D deficiency (<5 IU/kg vitamin D) or excess (76,500 IU/kg vitamin D), compared to control diet (1,500 IU/kg vitamin D), we measured the effect of variation of dietary vitamin D on tumor kinetics. No measurable impact of dietary vitamin D was found on pancreatic acinar cell carcinoma development, growth or mortality, casting further doubt on the already equivocal data supporting potential therapeutic use in humans. The lack of any detectable effect of vitamin D, within the physiological range of dietary deficiency or supplementation, in this model further erodes confidence in vitamin D as an effective antitumor therapeutic in pancreatic acinar cell carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2017.00133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488083PMC
June 2017

No Functional Role for microRNA-342 in a Mouse Model of Pancreatic Acinar Carcinoma.

Front Oncol 2017 18;7:101. Epub 2017 May 18.

Translational Immunology Laboratory, VIB, Leuven, Belgium.

The intronic microRNA (miR)-342 has been proposed as a potent tumor-suppressor gene. miR-342 is found to be downregulated or epigenetically silenced in multiple different tumor sites, and this loss of expression permits the upregulation of several key oncogenic pathways. In several different cell lines, lower miR-342 expression results in enhanced proliferation and metastasis potential, both and in xenogenic transplant conditions. Here, we sought to determine the function of miR-342 in an spontaneous cancer model, using the Ela1-TAg transgenic model of pancreatic acinar carcinoma. Through longitudinal magnetic resonance imaging monitoring of Ela1-TAg transgenic mice, either wild-type or knockout for , we found no role for miR-342 in the development, growth rate, or pathogenicity of pancreatic acinar carcinoma. These results indicate the importance of assessing miR function in the complex physiology of model systems and indicate that further functional testing of miR-342 is required before concluding it is a bona fide tumor-suppressor-miR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2017.00101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435746PMC
May 2017

miR-29a-deficiency does not modify the course of murine pancreatic acinar carcinoma.

Oncotarget 2017 Apr;8(16):26911-26917

VIB Center for Brain and Disease Research, Leuven, Belgium.

The development of cancers involves the complex dysregulation of multiple cellular processes. With key functions in simultaneous regulation of multiple pathways, microRNA (miR) are thought to have important roles in the oncogenic formation process. miR-29a is among the most abundantly expressed miR in the pancreas. Together with altered expression in pancreatic cancer cell lines and biopsies, and known oncogenic functions in leukemia, this expression data has identified miR-29a as a key candidate for miR involvement in pancreatic cancer biology. Here we used miR-29a-deficient mice and the TAg model of pancreatic acinar carcinoma to functionally test the role of miR-29a in vivo. We found no impact of miR-29a loss on the development or growth of pancreatic tumours, nor on the survival of tumour-bearing mice. These results suggest that, despite differential expression, miR-29a is oncogenically neutral in the pancreatic acinar carcinoma context. If these results are extended to other models of pancreatic cancer, they would reduce the attractiveness of miR-29a as a potential therapeutic target in pancreatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.15850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432306PMC
April 2017

No Effect of Dietary Aspartame or Stevia on Pancreatic Acinar Carcinoma Development, Growth, or Induced Mortality in a Murine Model.

Front Oncol 2017 9;7:18. Epub 2017 Feb 9.

Translational Immunology Laboratory, VIB, Leuven, Belgium; Department of Microbiology and Immunology, KU Leuven - University of Leuven, Leuven, Belgium.

Pancreatic cancer has an extremely poor prognosis, largely due to a poor record for early detection. Known risk factors for pancreatic cancer include obesity, diet, and diabetes, implicating glucose consumption and regulation as a key player. The role of artificial sweeteners may therefore be pertinent to disease kinetics. The oncogenic impact of artificial sweeteners is a highly controversial area. Aspartame, one of the most studied food additives, is widely recognized as being generally safe, although there are still specific areas where research is incomplete due to study limitations. Stevia, by contrast, has been the subject of relatively few studies, and the potential health benefits are based on extrapolation rather than direct testing. Here, we used longitudinal tracking of pancreatic acinar carcinoma development, growth, and lethality in a sensitized mouse model. Despite exposure to aspartame and stevia from the stage onward, we found no disease modification activity, in either direction. These results contribute to the data on aspartame and stevia safety, while also reducing confidence in several of the purported health benefits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2017.00018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298959PMC
February 2017

Beta-Cell Fragility As a Common Underlying Risk Factor in Type 1 and Type 2 Diabetes.

Trends Mol Med 2017 02 21;23(2):181-194. Epub 2017 Jan 21.

VIB Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Microbiology and Immunology, Leuven, Belgium.

Type 1 and type 2 diabetes are distinct clinical entities primarily driven by autoimmunity and metabolic dysfunction, respectively. However, there is a growing appreciation that they may share an etiopathological factor, namely the role of variation in beta-cell sensitivity to stress factors. Increased sensitivity increases the risk of beta-cell death or insulin secretion dysfunction. The beta-cell fragility model proposes that this variation contributes to the risk of developing either type 1 or type 2 diabetes, in the presence of immunological and/or metabolic stress factors. Therapeutics that increase the resistance of beta cells to these factors and decreasing fragility may constitute a new class of anti-diabetogenics, with potential use across both diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmed.2016.12.005DOI Listing
February 2017

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

Nat Genet 2016 12 31;48(12):1462-1472. Epub 2016 Oct 31.

Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695684PMC
December 2016

Genome-wide associations for birth weight and correlations with adult disease.

Nature 2016 10 28;538(7624):248-252. Epub 2016 Sep 28.

Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (R = -0.22, P = 5.5 × 10), T2D (R = -0.27, P = 1.1 × 10) and coronary artery disease (R = -0.30, P = 6.5 × 10). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature19806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164934PMC
October 2016

Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation.

Sci Transl Med 2016 Mar;8(332):332ra45

INSERM, UMR S933, Paris F-75012, France. Université Pierre et Marie Curie-Paris, UMR S933, Paris F-75012, France. Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris F-75012, France.

Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1β (IL-1β). Mutations in the B30.2/SPRY domain cause pathogen-independent activation of pyrin and are responsible for the autoinflammatory disease familial Mediterranean fever (FMF). We studied a family with a dominantly inherited autoinflammatory disease, distinct from FMF, characterized by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. The disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The mutation results in the loss of a 14-3-3 binding motif at phosphorylated S242, which was not perturbed by FMF mutations in the B30.2/SPRY domain. However, loss of both S242 phosphorylation and 14-3-3 binding was observed for bacterial effectors that activate the pyrin inflammasome, such as Clostridium difficile toxin B (TcdB). The S242R mutation thus recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1β production. Successful therapy targeting IL-1β has been initiated in one patient, resolving pyrin-associated autoinflammation with neutrophilic dermatosis. This disease provides evidence that a guard-like mechanism of pyrin regulation, originally identified for Nod-like receptors in plant innate immunity, also exists in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aaf1471DOI Listing
March 2016

Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes.

Nat Genet 2016 05 21;48(5):519-27. Epub 2016 Mar 21.

Center for the Biology of Disease, VIB, Leuven, Belgium.

Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role of beta cell fragility in genetic predisposition to diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584070PMC
May 2016

Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies.

PLoS Genet 2016 Feb 24;12(2):e1005874. Epub 2016 Feb 24.

UMR INSERM U1122, IGE-PCV "Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire", Faculté de Pharmacie, Université de Lorraine, Nancy, France.

Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79 x 10(-13)), rs74506613 (JMJD1C, P = 1.17 x 10(-19)), rs4782371 (ZFPM1, P = 1.59 x 10(-9)) and rs2639990 (ZADH2, P = 1.72 x 10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18); rs7043199, VLDLR-AS1, P = 5.12 x 10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467); rs1740073, C6orf223, P = 2.34 x 10(-17); rs6993770, ZFPM2, P = 2.44 x 10(-60); rs2375981, KCNV2, P = 1.48 x 10(-100)). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1005874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766012PMC
February 2016

The cellular composition of the human immune system is shaped by age and cohabitation.

Nat Immunol 2016 Apr 15;17(4):461-468. Epub 2016 Feb 15.

Translational Immunology Laboratory, VIB, Leuven 3000, Belgium.

Detailed population-level description of the human immune system has recently become achievable. We used a 'systems-level' approach to establish a resource of cellular immune profiles of 670 healthy individuals. We report a high level of interindividual variation, with low longitudinal variation, at the level of cellular subset composition of the immune system. Despite the profound effects of antigen exposure on individual antigen-specific clones, the cellular subset structure proved highly elastic, with transient vaccination-induced changes followed by a return to the individual's unique baseline. Notably, the largest influence on immunological variation identified was cohabitation, with 50% less immunological variation between individuals who share an environment (as parents) than between people in the wider population. These results identify local environmental conditions as a key factor in shaping the human immune system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ni.3371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890679PMC
April 2016

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk.

Nat Commun 2016 Feb 1;7:10495. Epub 2016 Feb 1.

Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms10495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740398PMC
February 2016

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

PLoS Genet 2015 Oct 1;11(10):e1005378. Epub 2015 Oct 1.

HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1005378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591371PMC
October 2015

The impact of low-frequency and rare variants on lipid levels.

Nat Genet 2015 Jun 11;47(6):589-97. Epub 2015 May 11.

1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. [2] German Center for Diabetes Research (DZD), Neuherberg, Germany. [3] Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757735PMC
June 2015

A central role for GRB10 in regulation of islet function in man.

PLoS Genet 2014 Apr 3;10(4):e1004235. Epub 2014 Apr 3.

Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.

Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1004235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974640PMC
April 2014

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

Nat Genet 2014 Mar 9;46(3):234-44. Epub 2014 Feb 9.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.2897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3969612PMC
March 2014

Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.

Diabetes 2014 Jun 2;63(6):2158-71. Epub 2013 Dec 2.

Wellcome Trust Sanger Institute, Hinxton, U.K.

Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db13-0949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030103PMC
June 2014

Identification of seven loci affecting mean telomere length and their association with disease.

Nat Genet 2013 Apr;45(4):422-7, 427e1-2

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.2528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006270PMC
April 2013