DOCSLIB.ORG

Type 2 Diabetes: Genetic Data Sharing to Advance Complex Disease Research

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Type 2 Diabetes: Genetic Data Sharing to Advance Complex Disease Research REVIEWS Type 2 diabetes: genetic data sharing to advance complex disease research Jason Flannick1,2 and Jose C. Florez1–4 Abstract | As with other complex diseases, unbiased association studies followed by physiological and experimental characterization have for years formed a paradigm for identifying genes or processes of relevance to type 2 diabetes mellitus (T2D). Recent large-scale common and rare variant genome-wide association studies (GWAS) suggest that substantially larger association studies are needed to identify most T2D loci in the population. To hasten clinical translation of genetic discoveries, new paradigms are also required to aid specialized investigation of nascent hypotheses. We argue for an integrated T2D knowledgebase, designed for a worldwide community to access aggregated large-scale genetic data sets, as one paradigm to catalyse convergence of these efforts. Heritability Genetic studies of human disease seek insight into disease In the era that has followed these early GWAS, studies The proportion of phenotypic processes or novel therapies from naturally occurring have become much larger and more diverse, technologies variance in a population owing heritable variation in a population. Characterizing the assay rarer variants across the entire exome or genome, to genetic differences, as degree to which disease-informative variants exist, and biological experiments have begun to translate opposed to environmental identifying them and their effects, and understanding reported associations to insights into causal variants differences. how they might guide preventive or therapeutic inter- and disease processes. Here, we review the history and ventions are thus related but distinct goals of genetic recent progress towards mapping genes for T2D and con- association studies. sequent implications for disease genetic architecture. We Type 2 diabetes mellitus (T2D) is a complex, herit- then review studies to understand pathogenic mechan- able disease with a sibling relative risk of approximately isms that may point to new therapeutic modalities. We 2 1Programs in Metabolism 2 (REF. 1) and a heritability estimated at 30–70% . For dec- argue that future research into each area will be most and Medical and Population ades, analyses of natural genetic variation have been used powerful and synergistic with a new model for open and Genetics, Broad Institute of to understand T2D mechanisms or to improve prognoses inter active sharing of data and results between previously MIT and Harvard, 415 Main for the approximately 415 million people who suffer from loosely coupled communities. Street, Cambridge, Massachusetts 02142, USA. its effects; these include prolonged hyperglycaemia from 3 2Center for Human Genetic insulin resistance and relative insulin deficiency , numer- Mapping disease loci Research, Department of ous micro- and macrovascular complications4 and an Common variant association studies. Motivated by Medicine, Massachusetts increased risk of early death5. the increased power of association studies over prior General Hospital, genome-wide association 14 common disease common 185 Cambridge Street, Before common variant family studies , as well as the 15 Boston, Massachusetts studies (GWAS), it was not known to what extent variant hypothesis (CDCV hypothesis) , GWAS exploited 02062, USA. such ‘experiments of nature’ could lend insight into inexpensive single-nucleotide polymorphism (SNP) 3Diabetes Research Center, T2D. Early genetic mapping studies for T2D involved microarrays and reference catalogues of population-level Diabetes Unit, Department comparatively small-scale candidate gene and linkage variation16 to analyse through linkage disequilibrium nearly of Medicine, Massachusetts General Hospital, studies. Although these approaches localized several all common variants in the genome. The first T2D GWAS, 6 17–21 185 Cambridge Street, disease genes (for example, PPARG , KCNJ11 (REF. 7) and which studied a few thousand samples each , collec- Boston, Massachusetts TCF7L2 (REF. 8)), they were on the whole unsuccessful9. tively identified 10 genomic loci, and many loci were 02062, USA. By contrast, GWAS yielded — for the first time — a sub- reported by multiple studies. These findings validated 4Department of Medicine, Harvard Medical School, stantial number of genomic loci reproducibly linked to the GWAS design but suggested that common variants 25 Shattuck Street, Boston, T2D risk, suggesting previously unsuspected biological of large effects were mostly absent from the population: Massachusetts 02115, USA. pathways10,11. And yet, the modest fraction of heritability all associated variants affected risk by less than 40%, and Correspondence to J.C.F. attributable to GWAS associations, together with insuf- most affected risk by closer to 15%. [email protected] ficient resolution to identify specific causal variants or In order to identify common variants of weaker doi:10.1038/nrg.2016.56 effector transcripts, led to suggestions that the endeavour effects, collaboration and data sharing were necessary to Published online 11 Jul 2016 produced minimal insights12,13. increase power (FIG. 1). The Diabetes Genetics Replication NATURE REVIEWS | GENETICS ADVANCE ONLINE PUBLICATION | 1 ©2016 Mac millan Publishers Li mited. All ri ghts reserved. REVIEWS 225 MTMR3 POC5 African American PNPLA3 East Asian ZZEF1 FAM63A UBE3C 200 European PLEKHA1 Hispanic or Native American NRXN3 NHEG1 South Asian MAP3K11 HSF1 175 Initial sample size UBE2E2 HSD17B12 TMEM154 HORMAD2 Replication sample size TLE4 HLA-DQ1 C2CD4B–C2CD4A TCF19–POU5F1 GLP2R Linkage or candidate gene ZFAND6 RREB1–SSR1 CMIP 150 ZBED3 MPHOSPH9 CENPW GWAS or Metabochip TP53INP1 LPP ATP5G1 PRC1 SGCG FAF1 APOE Exome array KLF14 CILP2–TM6SF2 TMEM163 ARL15 ACSL1 Genome or exome sequencing IRS1 RBM43–RND3 MACF1 DNER IGF2 125 HNF1A ZFAND3 RASGRP1 SLC16A11 PDX1 HLA-B HMGA2 PSMD6 GRK5 MIR129–LEP TBC1D4 ABO DUSP9 PEPD FAM58A GPSM1 PAM CHCHD9 PAX4–GCC1 ZMIZ1 ITGB6–RBMS1 VPS26A TLE1 100 SRR CENTD2 ST6GAL1 MGC21675 MC4R PROX1 HNF4A BCL2 KLHDC5 MTNR1B HMG20A MAEA GIPR GCKR GRB14 KCNK16 LAMA1 DGKB GCK AP3S2 GLIS3 ANK1 CCND2 75 DGKB–TMEM195 BCAR1 THADA DUSP8 BCL11A ANKRD55 NOTCH2–ADAM30 PTPRD C6orf57 Sample size (1,000s) LGR5–TSPAN8 ADCY5 SPRY2 HNF1B JAZF1 50 CDKAL1 CDC123–CAMK1D FTO KCNQ1 IGF2BP2 ADAMTS9 CDKN2A–CDKN2B WFS1 SLC30A8 25 HHEX KCNJ11 TCF7L2 PPARG 0 et al. et al. 10973253 12540637 16415884 17463249 17293876 17463246 17460697 17463248 17603485 17554300 17668382 17603484 18372903 18711367 18711366 19056611 19401414 20016592 20174558 20081858 20418489 20581827 20818381 20862305 21490949 21573907 21874001 21799836 22101970 22238593 22158537 22325160 22293688 22456796 22693455 22961080 23160641 23209189 22885922 23300278 23532257 23945395 24101674 24509480 24390345 24464100 25043022 25102180 Scott ASHG 25483131 Mahajan ASHG Fuchsberger Fuchsberger 2001 2005 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Year Figure 1 | The history of T2D GWAS. Over the years, type 2 diabetes mellitus (T2D) genome-wideNature association Reviews studies| Genetics (GWAS), which typically consist of a two-stage discovery and replication study design, have increased in size and diversity. Plotted are circles representing T2D GWAS, as specified by the US National Human Genome Research Institute–European Bioinformatics Institute (NHGRI–EBI) GWAS catalogue163, as well as additional candidate gene or sequencing studies of note. The x-axis shows the year of publication, whereas the y-axis shows discovery sample size. The inner (darker) circles are also scaled in proportion to discovery sample size, whereas the outer (lighter) circles are scaled in proportion to total (discovery + replication) sample size. Circles are coloured according to ethnic composition of the sample set: African American (dark blue), East Asian (light blue), European (purple), Hispanic or Native American (yellow) or South Asian (green). PubMed identifiers (or first author name) for each study are shown at the base of the figure and connected to the corresponding circle with a dotted line. Identifiers are coloured according to the technology used in the study: linkage or candidate gene studies (red), GWAS or Metabochip (beige), exome array (orange) or sequencing (dark grey). Additionally, T2D loci are listed directly above the first reporting study. With some exceptions based on retrospective knowledge, a P value of 5 × 10−8 is used as a threshold for significance, and loci are named as originally reported. Genome-wide association studies and Meta-analysis (DIAGRAM) Consortium increased in either overlapping samples or more diverse ethnic 32–34 (GWAS). An approach for sample size above 10,000 (with approximately 4,500 T2D groups . The similar goals, organization and method- genetic mapping that cases), identifying a further six loci22. Enabled by a willing- ology of these consortia, as well as of those investigating compares frequencies of ness of researchers to collaborate rather than to compete, other metabolic traits, led to the joint design of a custom variants across the genome 35 between disease cases and an availability of resources and tools to harmonize data genotyping array that facilitated analysis of still larger 23 matched controls. This is a sets and a means to share statistics while protecting study sample sizes. A T2D association study used this array to paradigm for identifying genes participants24, GWAS meta-analysis consortia quickly analyse almost 150,000 individuals (approximately 34,800 or biological
Load more

Recommended publications
  • Expression Signatures of the Lipid-Based Akt Inhibitors Phosphatidylinositol Ether Lipid Analogues in NSCLC Cells
    Published OnlineFirst May 6, 2011; DOI: 10.1158/1535-7163.MCT-10-1028 Molecular Cancer Therapeutic Discovery Therapeutics Expression Signatures of the Lipid-Based Akt Inhibitors Phosphatidylinositol Ether Lipid Analogues in NSCLC Cells Chunyu Zhang1, Abdel G. Elkahloun2, Hongling Liao3, Shannon Delaney1, Barbara Saber1, Betsy Morrow1, George C. Prendergast4, M. Christine Hollander1, Joell J. Gills1, and Phillip A. Dennis1 Abstract Activation of the serine/threonine kinase Akt contributes to the formation, maintenance, and therapeutic resistance of cancer, which is driving development of compounds that inhibit Akt. Phosphatidylinositol ether lipid analogues (PIA) are analogues of the products of phosphoinositide-3-kinase (PI3K) that inhibit Akt activation, translocation, and the proliferation of a broad spectrum of cancer cell types. To gain insight into the mechanism of PIAs, time-dependent transcriptional profiling of five active PIAs and the PI3K inhibitor LY294002 (LY) was conducted in non–small cell lung carcinoma cells using high-density oligonucleotide arrays. Gene ontology analysis revealed that genes involved in apoptosis, wounding response, and angiogen- esis were upregulated by PIAs, whereas genes involved in DNA replication, repair, and mitosis were suppressed. Genes that exhibited early differential expression were partitioned into three groups; those induced by PIAs only (DUSP1, KLF6, CENTD2, BHLHB2, and PREX1), those commonly induced by PIAs and LY (TRIB1, KLF2, RHOB, and CDKN1A), and those commonly suppressed by PIAs and LY (IGFBP3, PCNA, PRIM1, MCM3, and HSPA1B). Increased expression of the tumor suppressors RHOB (RhoB), KLF6 (COPEB), and CDKN1A (p21Cip1/Waf1) was validated as an Akt-independent effect that contributed to PIA-induced cytotoxicity. Despite some overlap with LY, active PIAs have a distinct expression signature that contributes to their enhanced cytotoxicity.
    [Show full text]
  • Study of Human Regulatory Mutations Associated with Pancreatic Diseases
    Study of human regulatory mutations associated with pancreatic diseases by humanizing the zebrafish genome. Inês Maria Batista da Costa Mestrado em Biologia Celular e Molecular Departamento de Biologia da Faculdade de Ciências da Universidade do Porto (FCUP) Orientador José Bessa, PhD, Instituto de Investigação e Inovação em Saúde (i3S) Coorientador Chiara Perrod, PhD, Instituto de Investigação e Inovação em Saúde (i3S) 2018/19 This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant Todas as correções agreement No 680156 – ZPR). determinadas pelo júri, e só essas, foram efetuadas. O Presidente do Júri, Porto, ______/______/_________ Study of human regulatory mutations associated with pancreatic diseases by humanizing the zebrafish genome. Inês Maria Batista da Costa Mestrado em Biologia Celular e Molecular Departamento de Biologia da Faculdade de Ciências da Universidade do Porto (FCUP) Orientador José Bessa, PhD, Instituto de Investigação e Inovação em Saúde (i3S) Coorientador Chiara Perrod, PhD, Instituto de Investigação e Inovação em Saúde (i3S) 2018/19 FCUP i Study of human regulatory mutations associated with pancreatic diseases by humanizing the zebrafish genome. Inês Maria Batista da Costa, BSc Mestrado em Biologia Celular e Molecular Departamento de Biologia Faculdade de Ciências da Universidade do Porto (FCUP) Rua do Campo Alegre s/n 4169-007 Porto, Portugal [email protected] / [email protected] Tel.: +351 917457361 Supervisor
    [Show full text]
  • Laser Capture Microdissection of Human Pancreatic Islets Reveals Novel Eqtls Associated with Type 2 Diabetes
    Original Article Laser capture microdissection of human pancreatic islets reveals novel eQTLs associated with type 2 diabetes Amna Khamis 1,2,11, Mickaël Canouil 2,11, Afshan Siddiq 1, Hutokshi Crouch 1, Mario Falchi 1, Manon von Bulow 3, Florian Ehehalt 4,5,6, Lorella Marselli 7, Marius Distler 4,5,6, Daniela Richter 5,6, Jürgen Weitz 4,5,6, Krister Bokvist 8, Ioannis Xenarios 9, Bernard Thorens 10, Anke M. Schulte 3, Mark Ibberson 9, Amelie Bonnefond 2, Piero Marchetti 7, Michele Solimena 5,6, Philippe Froguel 1,2,* ABSTRACT Objective: Genome wide association studies (GWAS) for type 2 diabetes (T2D) have identified genetic loci that often localise in non-coding regions of the genome, suggesting gene regulation effects. We combined genetic and transcriptomic analysis from human islets obtained from brain-dead organ donors or surgical patients to detect expression quantitative trait loci (eQTLs) and shed light into the regulatory mechanisms of these genes. Methods: Pancreatic islets were isolated either by laser capture microdissection (LCM) from surgical specimens of 103 metabolically phe- notyped pancreatectomized patients (PPP) or by collagenase digestion of pancreas from 100 brain-dead organ donors (OD). Genotyping (> 8.7 million single nucleotide polymorphisms) and expression (> 47,000 transcripts and splice variants) analyses were combined to generate cis- eQTLs. Results: After applying genome-wide false discovery rate significance thresholds, we identified 1,173 and 1,021 eQTLs in samples of OD and PPP, e respectively. Among the strongest eQTLs shared between OD and PPP were CHURC1 (OD p-value¼1.71 Â 10-24;PPPp-value ¼ 3.64 Â 10 24)and À À PSPH (OD p-value ¼ 3.92 Â 10 26;PPPp-value ¼ 3.64 Â 10 24).
    [Show full text]
  • Diana Maria De Figueiredo Pinto Marcadores Moleculares Para A
    Universidade de Aveiro Departamento de Química 2015 Diana Maria de Marcadores moleculares para a Nefropatia Figueiredo Pinto Diabética Molecular markers for Diabetic Nephropathy Universidade de Aveiro Departamento de Química 2015 Diana Maria de Marcadores moleculares para a Nefropatia Diabética Figueiredo Pinto Molecular markers for Diabetic Nephropathy Dissertação apresentada à Universidade de Aveiro para cumprimento dos requisitos necessários à obtenção do grau de Mestre em Bioquímica, ramo de Bioquímica Clínica, realizada sob a orientação científica da Doutora Maria Conceição Venâncio Egas, investigadora do Centro de Neurociências e Biologia Celular da Universidade de Coimbra, e da Doutora Rita Maria Pinho Ferreira, professora auxiliar do Departamento de Química da Universidade de Aveiro. Este trabalho foi efetuado no âmbito do programa COMPETE, através do projeto DoIT – Desenvolvimento e Operacionalização da Investigação de Translação, ref: FCOMP-01-0202-FEDER- 013853. o júri presidente Prof. Francisco Manuel Lemos Amado professor associado do Departamento de Química da Universidade de Aveiro Doutora Maria do Rosário Pires Maia Neves Almeida investigadora do Centro de Neurociências e Biologia Celular da Universidade de Coimbra Doutora Maria Conceição Venâncio Egas investigadora do Centro de Neurociências e Biologia Celular da Universidade de Coimbra Agradecimentos Em primeiro lugar quero expressar o meu agradecimento à Doutora Conceição Egas, orientadora desta dissertação, pelo seu apoio, palavras de incentivo e disponibilidade demonstrada em todas as fases que levaram à concretização do presente trabalho. Obrigada pelo saber transmitido, que tanto contribuiu para elevar os meus conhecimentos científicos, assim como pela oportunidade de integrar o seu grupo de investigação. O seu apoio e sugestões foram determinantes para a realização deste estudo.
    [Show full text]
  • Refined Genetic Mapping of Autosomal Recessive Chronic Distal Spinal Muscular Atrophy to Chromosome 11Q13.3 and Evidence of Link
    European Journal of Human Genetics (2004) 12, 483–488 & 2004 Nature Publishing Group All rights reserved 1018-4813/04 $30.00 www.nature.com/ejhg ARTICLE Refined genetic mapping of autosomal recessive chronic distal spinal muscular atrophy to chromosome 11q13.3 and evidence of linkage disequilibrium in European families Louis Viollet*,1, Mohammed Zarhrate1, Isabelle Maystadt1, Brigitte Estournet-Mathiaut2, Annie Barois2, Isabelle Desguerre3, Miche`le Mayer4, Brigitte Chabrol5, Bruno LeHeup6, Veronica Cusin7, Thierry Billette de Villemeur8, Dominique Bonneau9, Pascale Saugier-Veber10, Anne Touzery-de Villepin11, Anne Delaubier12, Jocelyne Kaplan1, Marc Jeanpierre13, Joshue´ Feingold1 and Arnold Munnich1 1Unite´ de Recherches sur les Handicaps Ge´ne´tiques de l’Enfant, INSERM U393. Hoˆpital Necker Enfants Malades, 149 rue de Se`vres, 75743 Paris Cedex 15, France; 2Service de Neurope´diatrie, Re´animation et Re´e´ducation Neuro-respiratoire, Hoˆpital Raymond Poincare´, 92380 Garches, France; 3Service de Neurope´diatrie, Hoˆpital Necker Enfants Malades, 149 rue de Se`vres, 75743 Paris Cedex 15, France; 4Service de Neurope´diatrie, Hoˆpital Saint Vincent de Paul, 82 boulevard Denfert Rochereau, 75674 Paris Cedex 14, France; 5Service de Neurope´diatrie, Hoˆpital Timone Enfants, 264 rue Saint Pierre 13385 Marseille Cedex, France; 6Secteur de De´veloppement et Ge´ne´tique, CHR de Nancy, Hoˆpitaux de Brabois, Rue du Morvan, 54511 Vandoeuvre Cedex, France; 7Service de Ge´ne´tique de Dijon, Hoˆpital d’Enfants, 2 blvd du Mare´chal de Lattre de Tassigny,
    [Show full text]
  • Variants in the IGF2BP2, JAZF1 and CENTD2 Genes Associated with Type 2 Diabetes Susceptibility in a Romanian Cohort
    Mini Review Curr Res Diabetes Obes J Volume 13 Issue 1 - April 2020 Copyright © All rights are reserved by : VE Radoi DOI: 10.19080/CRDOJ.2020.13.555855 Variants in the IGF2BP2, JAZF1 and CENTD2 Genes Associated with Type 2 Diabetes Susceptibility in a Romanian Cohort R Ursu1, P Iordache2, GF Ursu3, N Cucu4, V Calota5, A Voinoiu5, C Staicu5, D Mates5, E Poenaru1, A Manolescu6, V Jinga7, LC Bohiltea1 and VE Radoi1* 1Carol Davila University of Medicine and Pharmacy Carol Davila, Romania 2Department of Epidemiology, Carol Davila University of Medicine and Pharmacy, Romania 3Emergency Military Hospital, Romania 4University of Bucharest, Romania 5National Institute for Public Health, Romania 6University of Reykjavik, Iceland 7Department of Urology, Carol Davila University of Medicine and Pharmacy, Romania Submission: April 04, 2020; Published: April 22, 2020 *Corresponding author: VE Radoi, Medical Genetics, Faculty of General Medicine, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania Abstract Diabetes mellitus (DM) is one of the leading causes of mortality and morbidity worldwide. Globally, 422 million adults were diagnosed in 2014 [1]. According to the PREDATOR study the prevalence of DM in Romania was 11.6% [2]. DM is also an important socio-economic problem with high annual losses. In 2012, the estimations of the American Diabetes Association (ADA) regarding the total cost for DM patients` management was $245 billion, of which $ 176 billion in direct medical costs (hospitals, medical staff, treatment) and $69 billion in indirect costs (inability to work, decreased productive capacity, absenteeism) [3]. The genetic factor is known to play an important role in the development of DM type 2 [4, 5].
    [Show full text]
  • Dissecting Bcr-Abl Variant Signaling Pathways Using
    DISSECTING BCR-ABL VARIANT SIGNALING PATHWAYS USING NOVEL INTERACTOME IDENTIFICATION STRATEGIES By Jevon A. Cutler A dissertation submitted to The Johns Hopkins University in conformity with the requirement of the degree of Doctor of Philosophy Baltimore, MD May 2018 © 2018 Jevon A. Cutler All Rights Reserved ABSTRACT Cell signaling is an essential function of cells and tissues. Understanding cell signaling necessitates technologies that can identify protein-protein interactions as well as post translational modifications to proteins within protein complexes. The goals of this study are (1) to understand how BCR-ABL variants differentially signal to produce different clinical/experimental phenotypes and (2) to develop novel interactome detection strategies to understand signaling. This dissertation describes an integrated approach of the use of proximity dependent labeling protein-protein interaction analysis assays coupled with global phosphorylation analysis to investigate the differences in signaling between two variants the oncogenic fusion protein, BCR-ABL. Two major types of leukemogenic BCR-ABL fusion proteins are p190BCR-ABL and p210BCR-ABL. Although the two fusion proteins are closely related, they can lead to different clinical outcomes. A thorough understanding of the signaling programs employed by these two fusion proteins is necessary to explain these clinical differences. Our findings suggest that p190BCR-ABL and p210BCR-ABL differentially activate important signaling pathways, such as JAK-STAT, and engage with molecules that indicate interaction with different subcellular compartments. In the case of p210BCR-ABL, we observed an increased engagement of molecules active proximal to the membrane and in the case of p190BCR-ABL, an engagement of molecules of the cytoskeleton.
    [Show full text]
  • Chapter 14: Genetics of Type 2 Diabetes
    CHAPTER 14 GENETICS OF TYPE 2 DIABETES Jose C. Florez, MD, PhD, Miriam S. Udler, MD, PhD, and Robert L. Hanson, MD, MPH Dr. Jose C. Florez is Chief of the Diabetes Unit and an investigator in the Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, and Co-Director of the Program in Metabolism and Institute Member in the Broad Institute, Cambridge, MA, and Associate Professor in the Department of Medicine, Harvard Medical School, Boston, MA. Dr. Miriam S. Udler is Clinical Fellow in the Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, and Postdoctoral Fellow in the Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, and Research Fellow in the Department of Medicine, Harvard Medical School, Boston, MA. Dr. Robert L. Hanson is Clinical Investigator and Head, Genetic Epidemiology and Statistics Unit in the Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ. SUMMARY Type 2 diabetes is thought to result from a has been found to have a stronger effect insufficient sample sizes to detect small combination of environmental, behavioral, than the rs7903146 SNP in TCF7L2, which effects, a nearly exclusive focus on popu- and genetic factors, with the heritability itself has only a modest effect (odds ratio lations of European descent, an imperfect of type 2 diabetes estimated to be in the ~1.4). Nonetheless, GWAS findings have capture of uncommon genetic variants, range of 25% to 72% based on family and illustrated novel pathways, pointed toward an incomplete ascertainment of alternate twin studies.
    [Show full text]
  • Recent Progress in Genetic and Epigenetic Research on Type 2 Diabetes
    OPEN Experimental & Molecular Medicine (2016) 48, e220; doi:10.1038/emm.2016.7 & 2016 KSBMB. All rights reserved 2092-6413/16 www.nature.com/emm REVIEW Recent progress in genetic and epigenetic research on type 2 diabetes Soo Heon Kwak1 and Kyong Soo Park1,2,3 Type 2 diabetes (T2DM) is a common complex metabolic disorder that has a strong genetic predisposition. During the past decade, progress in genetic association studies has enabled the identification of at least 75 independent genetic loci for T2DM, thus allowing a better understanding of the genetic architecture of T2DM. International collaborations and large-scale meta- analyses of genome-wide association studies have made these achievements possible. However, whether the identified common variants are causal is largely unknown. In addition, the detailed mechanism of how these genetic variants exert their effect on the pathogenesis of T2DM requires further investigation. Currently, there are ongoing large-scale sequencing studies to identify rare, functional variants for T2DM. Environmental factors also have a crucial role in the development of T2DM. These could modulate gene expression via epigenetic mechanisms, including DNA methylation, histone modification and microRNA regulation. There is evidence that epigenetic changes are important in the development of T2DM. Recent studies have identified several DNA methylation markers of T2DM from peripheral blood and pancreatic islets. In this review, we will briefly summarize the recent progress in the genetic and epigenetic research on
    [Show full text]
  • Integration of Human Pancreatic Islet Genomic Data Refines Regulatory
    bioRxiv preprint doi: https://doi.org/10.1101/190892; this version posted February 3, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Integration of human pancreatic islet genomic data refines 2 regulatory mechanisms at Type 2 Diabetes susceptibility loci 3 Matthias Thurner1,2, Martijn van de Bunt1,2, Jason M Torres1, Anubha Mahajan1, 4 Vibe Nylander2, Amanda J Bennett2, Kyle Gaulton3, Amy Barrett2, Carla Burrows2, 5 Christopher G Bell4,5, Robert Lowe6, Stephan Beck7, Vardhman K Rakyan6, Anna L 6 Gloyn1,2,8, Mark I McCarthy*1,2,8 7 8 1. The Wellcome Trust Centre for Human Genetics, University of Oxford, UK 9 2. Oxford Centre for Diabetes, Endocrinology and Metabolism, University, of 10 Oxford, Oxford, UK 11 3. Department of Pediatrics, University of California, San Diego, US 12 4. Department of Twin Research & Genetic Epidemiology, Kings College London, 13 London, UK 14 5. MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, 15 UK 16 6. Centre for Genomics and Child Health, Blizard Institute, Barts and The London 17 School of Medicine and Dentistry, London, UK 18 7. Department of Cancer Biology, UCL Cancer Institute, University College 19 London, London, UK 20 8. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK 21 22 *Corresponding author ([email protected]) 23 24 Abstract 25 Human genetic studies have emphasised the dominant contribution of 26 pancreatic islet dysfunction to development of Type 2 Diabetes (T2D).
    [Show full text]
  • Expression Signatures of the Lipid-Based Akt Inhibitors Phosphatidylinositol Ether Lipid Analogues in NSCLC Cells
    Author Manuscript Published OnlineFirst on May 6, 2011; DOI: 10.1158/1535-7163.MCT-10-1028 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Expression signatures of the lipid-based Akt inhibitors phosphatidylinositol ether lipid analogues (PIAs) in NSCLC cells Chunyu Zhang1, Abdel G. Elkahloun2, Hongling Liao3, Shannon Delaney1, Barbara Saber1, Betsy Morrow1, Joell J. Gills1, M. Christine Hollander1, George C. Prendergast4 and Phillip A. Dennis1* 1Medical Oncology Branch, Center for Cancer Research, NCI, Bethesda, MD 20892 2Cancer Genetics Branch, NHGRI, NIH, Bethesda, MD 20892 3Sequencing Facility, SAIC-Frederick, NCI at Frederick, Gaithersburg, MD 20877 4Lankenau Institute for Medical Research, Wynnewood, PA 19096 Running Title: Expression profiling of PIAs Keywords: Akt, microarray, PIA, RhoB, NSCLC Abbreviations: PI3K, phosphatidylinositol 3’ kinase; NSCLC, non-small cell lung cancer; PIA, phosphatidylinositol ether lipid analogue; LY, LY294002; MAPK, mitogen-activated protein kinase This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract NCI Contract NO1-CO-12400. *To whom correspondence should be addressed- 37 Convent Dr., Rm. 1118B, Bethesda, MD 20892, USA Phone: (301)-496-0929. Fax: (301)-435-4345. E-mail: [email protected] The authors have no conflict of interest. The manuscript has 4809 words (excluding references), 4 figures and 2 tables. 1 Downloaded from mct.aacrjournals.org on September 29, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 6, 2011; DOI: 10.1158/1535-7163.MCT-10-1028 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]
  • A Genome-Wide Association Study of Gestational Diabetes Mellitus in Korean Women
    ORIGINAL ARTICLE A Genome-Wide Association Study of Gestational Diabetes Mellitus in Korean Women Soo Heon Kwak,1 Sung-Hoon Kim,2 Young Min Cho,1 Min Jin Go,3 Yoon Shin Cho,3 Sung Hee Choi,1 Min Kyong Moon,1 Hye Seung Jung,1 Hyoung Doo Shin,4 Hyun Min Kang,5 Nam H. Cho,6 In Kyu Lee,7 Seong Yeon Kim,1 Bok-Ghee Han,3 Hak C. Jang,1 and Kyong Soo Park1,8 Knowledge regarding the genetic risk loci for gestational diabetes explain only a limited part of the expected heritability of mellitus (GDM) is still limited. In this study, we performed a two- type 2 diabetes (11). A complementary approach to im- stage genome-wide association analysis in Korean women. In the prove our insight into the genetics of diabetes might in- stage 1 genome scan, 468 women with GDM and 1,242 nondiabetic volve the identification of genetic risk loci in a different control women were compared using 2.19 million genotyped or subtype of diabetes, such as gestational diabetes mellitus imputed markers. We selected 11 loci for further genotyping in (GDM). This approach could enable us to compare the stage 2 samples of 931 case and 783 control subjects. The joint genetic risk factors between type 2 diabetes and GDM and effect of stage 1 plus stage 2 studies was analyzed by meta- relate the similarities and dissimilarities to the patho- analysis. We also investigated the effect of known type 2 diabetes physiology of the two closely related diseases. variants in GDM.
    [Show full text]