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Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism.

Author:
  • Joao Fadista
  • Petter Vikman
  • Emilia Ottosson Laakso
  • Ines Mollet
  • Jonathan Esguerra
  • Jalal Taneera
  • Petter Storm
  • Peter Osmark
  • Claes Ladenvall
  • Rashmi Prasad
  • Karin B Hansson
  • Francesca Finotello
  • Kristina Uvebrant
  • Jones Ofori
  • Barbara Di Camillo
  • Ulrika Krus
  • Corrado Cilio
  • Ola Hansson
  • Lena Eliasson
  • Anders Rosengren
  • Erik Renström
  • Claes Wollheim
  • Leif Groop
Publishing year: 2014
Language: English
Pages: 13924-13929
Publication/Series: Proceedings of the National Academy of Sciences
Volume: 111
Issue: 38
Document type: Journal article
Publisher: National Acad Sciences

Abstract english

Genetic variation can modulate gene expression, and thereby phenotypic variation and susceptibility to complex diseases such as type 2 diabetes (T2D). Here we harnessed the potential of DNA and RNA sequencing in human pancreatic islets from 89 deceased donors to identify genes of potential importance in the pathogenesis of T2D. We present a catalog of genetic variants regulating gene expression (eQTL) and exon use (sQTL), including many long noncoding RNAs, which are enriched in known T2D-associated loci. Of 35 eQTL genes, whose expression differed between normoglycemic and hyperglycemic individuals, siRNA of tetraspanin 33 (TSPAN33), 5'-nucleotidase, ecto (NT5E), transmembrane emp24 protein transport domain containing 6 (TMED6), and p21 protein activated kinase 7 (PAK7) in INS1 cells resulted in reduced glucose-stimulated insulin secretion. In addition, we provide a genome-wide catalog of allelic expression imbalance, which is also enriched in known T2D-associated loci. Notably, allelic imbalance in paternally expressed gene 3 (PEG3) was associated with its promoter methylation and T2D status. Finally, RNA editing events were less common in islets than previously suggested in other tissues. Taken together, this study provides new insights into the complexity of gene regulation in human pancreatic islets and better understanding of how genetic variation can influence glucose metabolism.

Keywords

  • Endocrinology and Diabetes

Other

Published
  • Diabetes and Endocrinology
  • Islet cell exocytosis
  • Islet patophysiology
  • Cellular Autoimmunity
  • ISSN: 1091-6490
Erik Renström
E-mail: erik.renstrom [at] med.lu.se

Deputy head of department

Department of Clinical Sciences, Malmö

+46 40 39 11 57

+46 40 39 11 57

Principal investigator

Islet patophysiology

+46 40 39 11 57

+46 40 39 11 57

20-3-308

33

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00