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

Fadista, Joao LU ; Vikman, Petter LU ; Ottosson Laakso, Emilia LU ; Mollet, Ines LU ; Esguerra, Jonathan LU ; Taneera, Jalal LU ; Storm, Petter LU ; Osmark, Peter LU ; Ladenvall, Claes LU and Prasad, Rashmi LU , et al. (2014) In Proceedings of the National Academy of Sciences 111(38). p.13924-13929
Abstract
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... (More)
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. (Less)
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Proceedings of the National Academy of Sciences
volume
111
issue
38
pages
13924 - 13929
publisher
National Acad Sciences
external identifiers
  • pmid:25201977
  • wos:000341988200060
  • scopus:84907222786
ISSN
1091-6490
DOI
10.1073/pnas.1402665111
language
English
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yes
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450b0429-fa4a-47c5-8ada-05d3121e122e (old id 4691998)
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http://www.ncbi.nlm.nih.gov/pubmed/25201977?dopt=Abstract
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2014-10-04 21:17:24
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2017-11-05 03:20:09
@article{450b0429-fa4a-47c5-8ada-05d3121e122e,
  abstract     = {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.},
  author       = {Fadista, Joao and Vikman, Petter and Ottosson Laakso, Emilia and Mollet, Ines and Esguerra, Jonathan and Taneera, Jalal and Storm, Petter and Osmark, Peter and Ladenvall, Claes and Prasad, Rashmi and Hansson, Karin B and Finotello, Francesca and Uvebrant, Kristina and Ofori, Jones and Di Camillo, Barbara and Krus, Ulrika and Cilio, Corrado and Hansson, Ola and Eliasson, Lena and Rosengren, Anders and Renström, Erik and Wollheim, Claes and Groop, Leif},
  issn         = {1091-6490},
  language     = {eng},
  number       = {38},
  pages        = {13924--13929},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism.},
  url          = {http://dx.doi.org/10.1073/pnas.1402665111},
  volume       = {111},
  year         = {2014},
}