Identification of novel type 1 diabetes candidate genes by integrating genome-wide association data, protein-protein interactions, and human pancreatic islet gene expression.

Diabetes
Regine BergholdtFlemming Pociot

Abstract

Genome-wide association studies (GWAS) have heralded a new era in susceptibility locus discovery in complex diseases. For type 1 diabetes, >40 susceptibility loci have been discovered. However, GWAS do not inevitably lead to identification of the gene or genes in a given locus associated with disease, and they do not typically inform the broader context in which the disease genes operate. Here, we integrated type 1 diabetes GWAS data with protein-protein interactions to construct biological networks of relevance for disease. A total of 17 networks were identified. To prioritize and substantiate these networks, we performed expressional profiling in human pancreatic islets exposed to proinflammatory cytokines. Three networks were significantly enriched for cytokine-regulated genes and, thus, likely to play an important role for type 1 diabetes in pancreatic islets. Eight of the regulated genes (CD83, IFNGR1, IL17RD, TRAF3IP2, IL27RA, PLCG2, MYO1B, and CXCR7) in these networks also harbored single nucleotide polymorphisms nominally associated with type 1 diabetes. Finally, the expression and cytokine regulation of these new candidate genes were confirmed in insulin-secreting INS-1 β-cells. Our results provide novel insight to the...Continue Reading

References

Sep 1, 1994·Diabetologia·J NerupT Lorenzen
Feb 16, 2002·Methods : a Companion to Methods in Enzymology·K J Livak, T D Schmittgen
Mar 28, 2002·Nucleic Acids Research·A J EnrightC A Ouzounis
Apr 17, 2002·Cell·Yoko FujimotoThomas F Tedder
Nov 25, 2003·The Journal of Immunology : Official Journal of the American Association of Immunologists·Yoichi OikawaTakao Saruta
Dec 19, 2003·Nucleic Acids Research·Minoru KanehisaMasahiro Hattori
Sep 2, 2005·Nature·Steve E CalvanoUNKNOWN Inflamm and Host Response to Injury Large Scale Collab. Res. Program
Mar 24, 2006·Nature·Nevan J KroganJack F Greenblatt
Apr 21, 2006·Immunological Reviews·Alexander Hoffmann, David Baltimore
Jul 26, 2006·Proceedings of the National Academy of Sciences of the United States of America·Yongliang ZhangChen Dong
Nov 30, 2006·Annals of the New York Academy of Sciences·E P K Mensah-BrownM L Lukic
Feb 10, 2007·BMC Bioinformatics·Rickard Sandberg, Ola Larsson
Feb 17, 2007·European Journal of Immunology·Ana C M Davalos-MisslitzReinhold Förster
Oct 9, 2007·Nature Genetics·Miguel Angel PujanaMarc Vidal
Oct 18, 2007·Molecular Systems Biology·Han-Yu ChuangTrey Ideker
Dec 1, 2007·Endocrine Reviews·Marc Y DonathThomas Mandrup-Poulsen
Oct 23, 2008·Nucleic Acids Research·Lars J JensenChristian von Mering
Feb 4, 2009·Cell Metabolism·Fabienne T SchulthessKathrin Maedler
Mar 17, 2009·Human Molecular Genetics·Sergio E BaranziniMichael R Barnes
Mar 18, 2009·Diabetes·Juliet A EmamaulleeA M James Shapiro
Apr 17, 2009·The New England Journal of Medicine·Joel N Hirschhorn
May 12, 2009·Nature Genetics·Jeffrey C BarrettUNKNOWN Type 1 Diabetes Genetics Consortium
Aug 14, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Andrea P MartinSergio A Lira
Jan 22, 2010·PLoS Computational Biology·Rod K NibbeMark R Chance
Feb 18, 2010·PloS One·Ulrike NaumannMarcus Thelen
Mar 3, 2010·PLoS Genetics·Naomi R WrayPeter M Visscher
Mar 30, 2010·American Journal of Human Genetics·Hua ZhongEric E Schadt
Jul 1, 2010·Diabetes·Flemming PociotJørn Nerup
Oct 19, 2011·Nature Reviews. Genetics·Constantin Polychronakos, Quan Li

❮ Previous
Next ❯

Citations

Aug 9, 2013·Current Diabetes Reports·Joachim Storling, Caroline Anna Brorsson
Jun 27, 2012·Journal of Cardiovascular Translational Research·Claudiu V KomorowskyMatthias Kretzler
May 8, 2013·Trends in Endocrinology and Metabolism : TEM·Scott A Soleimanpour, Doris A Stoffers
Feb 18, 2014·Cytokine & Growth Factor Reviews·Alessandro AntonelliPoupak Fallahi
Jan 24, 2014·Clinical & Developmental Immunology·Simone Kennedy BedoyaJoseph Larkin
Jul 2, 2014·Proceedings of the National Academy of Sciences of the United States of America·Tina FløyelFlemming Pociot
May 13, 2014·Critical Reviews in Clinical Laboratory Sciences·Edgard DelvinBernard Salle
Sep 26, 2015·Journal of Autoimmunity·James A PearsonLi Wen
Dec 3, 2015·European Journal of Endocrinology·Jonàs Juan-MateuDécio L Eizirik
Sep 18, 2013·Diabetes, Obesity & Metabolism·I Santin, D L Eizirik
Jan 31, 2013·Annals of the New York Academy of Sciences·Natalie Nokoff, Marian Rewers
Apr 2, 2014·Translational Research : the Journal of Laboratory and Clinical Medicine·Justin S Johnson, Carmella Evans-Molina
Mar 30, 2016·Nature Reviews. Endocrinology·Anne Op de Beeck, Decio L Eizirik
Jun 4, 2014·Biochimica Et Biophysica Acta·Kasper Lage
Feb 25, 2014·Methods : a Companion to Methods in Enzymology·Tao ZengLuonan Chen
Nov 19, 2013·Current Opinion in Genetics & Development·Hannah CarterTrey Ideker
Mar 31, 2015·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Qingyang Huang
Oct 23, 2012·Cellular Signalling·Balachandar VenkatesanBysani Chandrasekar
Apr 17, 2013·Molecular and Cellular Endocrinology·Leif Groop, Flemming Pociot
Sep 29, 2012·Current Opinion in Immunology·Xinli Hu, Mark Daly
May 11, 2016·Nature Communications·Jeffrey R MillmanDouglas A Melton
Jul 15, 2016·Pediatric Diabetes·Flemming PociotLotte B Nielsen
Oct 30, 2016·Translational Research : the Journal of Laboratory and Clinical Medicine·Fraser W ScottJennifer A Crookshank
Aug 23, 2017·Genes·Samuel T Jerram, Richard David Leslie
Jul 19, 2017·Journal of Molecular Endocrinology·Zodwa DlaminiRodney Hull
Jul 25, 2018·Oncotarget·Eckhard U AltReza Izadpanah
May 28, 2017·Diabetologia·Simon E Regnell, Åke Lernmark
Jan 16, 2018·Clinical & Translational Immunology·Flemming Pociot
Apr 1, 2020·Frontiers in Endocrinology·Haipeng PangZhiguang Zhou
Sep 24, 2015·Current Diabetes Reports·Tina FløyelFlemming Pociot

❮ Previous
Next ❯

Datasets Mentioned

BETA
GDS3158
GDS3011
GDS2939
GDS2516
GDS2478

Methods Mentioned

BETA
Low
Density Array
PCR

Software Mentioned

R
Ensembl
FatiGO
STRING

Related Concepts

Related Feeds

American Diabetes Association Journals

Discover the latest diabetes research published by the journals from the American Diabetes Association.

Autoimmune Diabetes & Tolerance

Patients with type I diabetes lack insulin-producing beta cells due to the loss of immunological tolerance and autoimmune disease. Discover the latest research on targeting tolerance to prevent diabetes.