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Corrado Cilio

Professor

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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

Summary, in 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.

Department/s

  • Genomics, Diabetes and Endocrinology
  • Diabetes - Islet Cell Exocytosis
  • Diabetes - Islet Patophysiology
  • Division of Molecular Medicine and Gene Therapy
  • Diabetes - Immunovirology
  • EXODIAB: Excellence in Diabetes Research in Sweden

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

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology
  • Diabetes - Islet Cell Exocytosis
  • Diabetes - Islet Patophysiology
  • Diabetes - Immunovirology

ISBN/ISSN/Other

  • ISSN: 1091-6490