title: Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism.
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.
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden; joao.fadista@med.lu.se Leif.Groop@med.lu.se.
authors.forename: João
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Petter
authors.initials: P
authors.lastname: Vikman
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Emilia Ottosson
authors.initials: EO
authors.lastname: Laakso
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Inês Guerra
authors.initials: IG
authors.lastname: Mollet
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Jonathan Lou
authors.initials: JL
authors.lastname: Esguerra
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Jalal
authors.initials: J
authors.lastname: Taneera
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Petter
authors.initials: P
authors.lastname: Storm
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Peter
authors.initials: P
authors.lastname: Osmark
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Claes
authors.initials: C
authors.lastname: Ladenvall
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Rashmi B
authors.initials: RB
authors.lastname: Prasad
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Karin B
authors.initials: KB
authors.lastname: Hansson
authors.affiliation: Department of Information Engineering, University of Padova, 35131 Padova, Italy; and.
authors.forename: Francesca
authors.initials: F
authors.lastname: Finotello
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Kristina
authors.initials: K
authors.lastname: Uvebrant
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Jones K
authors.initials: JK
authors.lastname: Ofori
authors.affiliation: Department of Information Engineering, University of Padova, 35131 Padova, Italy; and.
authors.forename: Barbara
authors.initials: B
authors.lastname: Di Camillo
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Ulrika
authors.initials: U
authors.lastname: Krus
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Corrado M
authors.initials: CM
authors.lastname: Cilio
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Ola
authors.initials: O
authors.lastname: Hansson
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Anders H
authors.initials: AH
authors.lastname: Rosengren
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden;
authors.forename: Erik
authors.initials: E
authors.lastname: Renström
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden; Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Claes B
authors.initials: CB
authors.lastname: Wollheim
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, 20502 Malmö, Sweden; joao.fadista@med.lu.se Leif.Groop@med.lu.se.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
mesh_terms: D015720:5'-Nucleotidase / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000235:genetics; D023281:Genomics; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007515:Islets of Langerhans; D008297:Male; D017393:RNA Editing / Q000502:physiology; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics; D059470:Tetraspanins / Q000096:biosynthesis / Q000235:genetics; D059467:Transcriptome / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D054462:p21-Activated Kinases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D058851:GPI-Linked Proteins; D062085:RNA, Long Noncoding; C505521:TSPAN33 protein, human; D059470:Tetraspanins; D033921:Vesicular Transport Proteins; C443802:PAK5 protein, human; D054462:p21-Activated Kinases; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D005947:Glucose