title: Decreased STARD10 Expression Is Associated with Defective Insulin Secretion in Humans and Mice.
abstract: Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in β cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, β-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca2+dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult β cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in β cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the β cell.
authors.affiliation: Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, Hammersmith Hospital, du Cane Road, London W12 0NN, UK.
authors.forename: Gaelle R
authors.initials: GR
authors.lastname: Carrat
authors.affiliation: Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, Hammersmith Hospital, du Cane Road, London W12 0NN, UK.
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.affiliation: Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, Hammersmith Hospital, du Cane Road, London W12 0NN, UK.
authors.forename: Marie-Sophie
authors.initials: MS
authors.lastname: Nguyen-Tu
authors.affiliation: Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, Hammersmith Hospital, du Cane Road, London W12 0NN, UK.
authors.forename: Pauline
authors.initials: P
authors.lastname: Chabosseau
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Gaulton
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford OX3 7LJ, UK.
authors.forename: Martijn
authors.initials: M
authors.lastname: van de Bunt
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London W12 0NN, UK.
authors.forename: Afshan
authors.initials: A
authors.lastname: Siddiq
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London W12 0NN, UK; Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK.
authors.forename: Mario
authors.initials: M
authors.lastname: Falchi
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford OX3 7LJ, UK.
authors.forename: Matthias
authors.initials: M
authors.lastname: Thurner
authors.affiliation: European Genomic Institute for Diabetes (EGID), 59045 Lille, France; Lille University, 59655 Villeneuve d'Ascq Cédex, France.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Canouil
authors.affiliation: European Genomic Institute for Diabetes (EGID), 59045 Lille, France; Lille University, 59655 Villeneuve d'Ascq Cédex, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Pattou
authors.affiliation: Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, Hammersmith Hospital, du Cane Road, London W12 0NN, UK.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Leclerc
authors.affiliation: Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, Hammersmith Hospital, du Cane Road, London W12 0NN, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Pullen
authors.affiliation: Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, Hammersmith Hospital, du Cane Road, London W12 0NN, UK.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cane
authors.affiliation: Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, Hammersmith Hospital, du Cane Road, London W12 0NN, UK.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Prabhala
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: William
authors.initials: W
authors.lastname: Greenwald
authors.affiliation: Sanofi-Aventis Deutschland GmbH, 65926 Frankfurt am Main, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Schulte
authors.affiliation: Department of Endocrinology and Metabolism, University of Pisa, 56126 Pisa, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Ibberson
authors.affiliation: Alberta Diabetes Institute Islet Core and Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
authors.affiliation: Alberta Diabetes Institute Islet Core and Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Manning Fox
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford OX3 7LJ, UK; Oxford NIHR Biomedical Research Centre, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London W12 0NN, UK; European Genomic Institute for Diabetes (EGID), 59045 Lille, France; Lille University, 59655 Villeneuve d'Ascq Cédex, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.affiliation: Paul Langerhans Institute of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine, TU Dresden, 01307 Dresden, Germany; German Center for Diabetes Research (DZD e.V), 85764 Neuherberg, Germany; Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors.forename: Michele
authors.initials: M
authors.lastname: Solimena
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford OX3 7LJ, UK; Oxford NIHR Biomedical Research Centre, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, Hammersmith Hospital, du Cane Road, London W12 0NN, UK. Electronic address: g.rutter@imperial.ac.uk.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics*; D011384:Proinsulin / Q000097:blood / Q000378:metabolism; D040641:Quantitative Trait Loci; D059467:Transcriptome; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C446513:ARAP1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D007328:Insulin; D010750:Phosphoproteins; C488090:STARD10 protein, human; C488091:Stard10 protein, mouse; C030363:lipid transfer protein; D000098682:Steroidogenic Acute Regulatory Protein; D011384:Proinsulin
keywords: ARAP1; GWAS; STARD10; diabetes; genetics; insulin; islet; mouse; secretion