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Decreased STARD10 expression is associated with defective insulin secretion in humans and mice

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Title: Decreased STARD10 expression is associated with defective insulin secretion in humans and mice
Authors: Carrat, GR
Hu, M
Nguyen-Tu, MS
Chabosseau, P
Gaulton, K
Van de Bunt, M
Siddiq, A
Falchi, M
Thurner, M
Canouil, M
Pattou, F
Leclerc, I
Pullen, TJ
Cane, MC
Prabhala, P
Greenwald, W
Schulte, A
Marchetti, P
Ibberson, M
Macdonald, P
Manning-Fox, JE
Gloyn, AL
Froguel, P
Solimena, M
McCarthy, MI
Rutter, GA
Item Type: Journal Article
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.
Issue Date: 26-Jan-2017
Date of Acceptance: 20-Dec-2016
URI: http://hdl.handle.net/10044/1/43554
DOI: https://dx.doi.org/10.1016/j.ajhg.2017.01.011
ISSN: 1537-6605
Publisher: Elsevier (Cell Press)
Start Page: 238
End Page: 256
Journal / Book Title: American Journal of Human Genetics
Volume: 100
Issue: 2
Copyright Statement: © 2017 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: Commission of the European Communities
Medical Research Council (MRC)
Société Francophone du Diabète
Wellcome Trust
Funder's Grant Number: 115005
MR/K001981/1
pfec/cc 12-010
098424/Z/12/ZR
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
GENOME-WIDE ASSOCIATION
PANCREATIC BETA-CELL
DIABETES SUSCEPTIBILITY LOCI
GENETIC ARCHITECTURE
GLYCEMIC TRAITS
TRANSFER PROTEIN
RISK VARIANTS
GTTT-REPEAT
IN-VIVO
TYPE-2
ARAP1
GWAS
STARD10
diabetes
genetics
insulin
islet
mouse
secretion
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine
Epidemiology, Public Health and Primary Care



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