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Expression and functional assessment of candidate type 2 diabetes susceptibility genes identify four new genes contributing to human insulin secretion.

Mol Metab. 2017 Apr 08;6(6):459-470. eCollection 2017 Jun
Fatou K Ndiaye 1 , Ana Ortalli 1 , Mickaël Canouil 1 , Marlène Huyvaert 1 , Clara Salazar-Cardozo 1 , Cécile Lecoeur 1 , Marie Verbanck 1 , Valérie Pawlowski 1 , Raphaël Boutry 1 , Emmanuelle Durand 1 , Iandry Rabearivelo 1 , Olivier Sand 1 , Lorella Marselli 2 , Julie Kerr-Conte 3 , Vikash Chandra 4 , Raphaël Scharfmann 4 , Odile Poulain-Godefroy 1 , Piero Marchetti 2 , François Pattou 3 , Amar Abderrahmani 5 , Philippe Froguel 5 , Amélie Bonnefond 5
Fatou K Ndiaye 1 , Ana Ortalli 1 , Mickaël Canouil 1 , Marlène Huyvaert 1 , Clara Salazar-Cardozo 1 , Cécile Lecoeur 1 , Marie Verbanck 1 , Valérie Pawlowski 1 , Raphaël Boutry 1 , Emmanuelle Durand 1 , Iandry Rabearivelo 1 , Olivier Sand 1 , Lorella Marselli 2 , Julie Kerr-Conte 3 , Vikash Chandra 4 , Raphaël Scharfmann 4 , Odile Poulain-Godefroy 1 , Piero Marchetti 2 , François Pattou 3 , Amar Abderrahmani 5 , Philippe Froguel 5 , Amélie Bonnefond 5
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[No authors listed]

Author information
  • 1 CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, 59000 Lille, France.
  • 2 Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy.
  • 3 Inserm U1190, EGID, CHU Lille, University of Lille, 59000 Lille, France.
  • 4 Inserm U1016, Institut Cochin, Faculté de Médecine, Paris Descartes University, Sorbonne Paris Cité, 75014 Paris, France.
  • 5 Department of Genomics of Common Disease, Imperial College London, W12 0NN London, United Kingdom.

摘要


OBJECTIVES:Genome-wide association studies (GWAS) have identified >100 loci independently contributing to type 2 diabetes (T2D) risk. However, translational implications for precision medicine and for the development of novel treatments have been disappointing, due to poor knowledge of how these loci impact T2D pathophysiology. Here, we aimed to measure the expression of genes located nearby T2D associated signals and to assess their effect on insulin secretion from pancreatic beta cells. METHODS:The expression of 104 candidate T2D susceptibility genes was measured in a human multi-tissue panel, through PCR-free expression assay. The effects of the knockdown of beta-cell enriched genes were next investigated on insulin secretion from the human EndoC-βH1 beta-cell line. Finally, we performed RNA-sequencing (RNA-seq) so as to assess the pathways affected by the knockdown of the new genes impacting insulin secretion from EndoC-βH1, and we analyzed the expression of the new genes in mouse models with altered pancreatic beta-cell function. RESULTS:We found that the candidate T2D susceptibility genes' expression is significantly enriched in pancreatic beta cells obtained by laser capture microdissection or sorted by flow cytometry and in EndoC-βH1 cells, but not in insulin sensitive tissues. Furthermore, the knockdown of seven T2D-susceptibility genes (CDKN2A, GCK, HNF4A, KCNK16, SLC30A8, TBC1D4, and TCF19) with already known expression and/or function in beta cells changed insulin secretion, supporting our functional approach. We showed first evidence for a role in insulin secretion of four candidate T2D-susceptibility genes (PRC1, SRR, ZFAND3, and ZFAND6) with no previous knowledge of presence and function in beta cells. RNA-seq in EndoC-βH1 cells with decreased expression of PRC1, SRR, ZFAND6, or ZFAND3 identified specific gene networks related to T2D pathophysiology. Finally, a positive correlation between the expression of Ins2 and the expression of Prc1, Srr, Zfand6, and Zfand3 was found in mouse pancreatic islets with altered beta-cell function. CONCLUSIONS:This study showed the ability of post-GWAS functional studies to identify new genes and pathways involved in human pancreatic beta-cell function and in T2D pathophysiology.

KEYWORDS: EndoC-βH1, Expression analysis, Genome-wide association study, Insulin secretion, RNAi screening, Type 2 diabetes