scholarly journals Genetic regulation of RNA splicing in human pancreatic islets

2021 ◽  
Author(s):  
Goutham Atla ◽  
Silvia Bonas-Guarch ◽  
Mirabai Cuenca ◽  
Anthony Beucher ◽  
Javier Garcia-Hurtado ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
Genetic Variants ◽  
Rna Splicing ◽  
Genetic Regulation ◽  
Susceptibility Loci ◽  
Camp Production ◽  
Human Pancreatic Islets ◽  
Effector Genes

Genetic variants that influence transcriptional regulation in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D). For many susceptibility loci, however, the mechanisms are unknown. We examined splicing QTLs (sQTLs) in islets from 399 donors and observed that genetic variation has a widespread influence on splicing of genes with important functions in islet biology. In parallel, we profiled expression QTLs, and used transcriptome-wide association and co-localization studies to assign islet sQTLs or eQTLs to T2D susceptibility signals that lacked candidate effector genes. We found novel T2D associations, including an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effectors revealed overrepresented pathways, including regulators of G-protein-mediated cAMP production. This data exposes an underappreciated layer of genetic regulation in pancreatic islets, and nominates molecular mediators of T2D susceptibility.

scholarly journals Global Epigenomic Analysis of Primary Human Pancreatic Islets Provides Insights into Type 2 Diabetes Susceptibility Loci

2010 ◽  
Vol 12 (5) ◽  
pp. 443-455 ◽  
Author(s):  
Michael L. Stitzel ◽  
Praveen Sethupathy ◽  
Daniel S. Pearson ◽  
Peter S. Chines ◽  
Lingyun Song ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
Susceptibility Loci ◽  
Diabetes Susceptibility ◽  
Human Pancreatic Islets

scholarly journals Global Epigenomic Analysis of Primary Human Pancreatic Islets Provides Insights into Type 2 Diabetes Susceptibility Loci

2010 ◽  
Vol 12 (6) ◽  
pp. 683 ◽  
Author(s):  
Michael L. Stitzel ◽  
Praveen Sethupathy ◽  
Daniel S. Pearson ◽  
Peter S. Chines ◽  
Lingyun Song ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
Susceptibility Loci ◽  
Diabetes Susceptibility ◽  
Human Pancreatic Islets

scholarly journals Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Sophie Bauer ◽  
Charlotte Wennberg Huldt ◽  
Kajsa P. Kanebratt ◽  
Isabell Durieux ◽  
Daniela Gunne ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
Ex Vivo ◽  
Functional Coupling ◽  
Human Pancreatic Islets ◽  
Diabetes Model

scholarly journals γ-Aminobutyric acid (GABA) signalling in human pancreatic islets is altered in type 2 diabetes

Diabetologia ◽  
2012 ◽  
Vol 55 (7) ◽  
pp. 1985-1994 ◽  
Author(s):  
J. Taneera ◽  
Z. Jin ◽  
Y. Jin ◽  
S. J. Muhammed ◽  
E. Zhang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
Aminobutyric Acid ◽  
Human Pancreatic Islets

scholarly journals Publisher Correction: Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Sophie Bauer ◽  
Charlotte Wennberg Huldt ◽  
Kajsa P. Kanebratt ◽  
Isabell Durieux ◽  
Daniela Gunne ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
Ex Vivo ◽  
Functional Coupling ◽  
Human Pancreatic Islets ◽  
Diabetes Model

scholarly journals Laser capture microdissection of human pancreatic islets reveals novel eQTLs associated with type 2 diabetes

2019 ◽  
Vol 24 ◽  
pp. 98-107 ◽  
Author(s):  
Amna Khamis ◽  
Mickaël Canouil ◽  
Afshan Siddiq ◽  
Hutokshi Crouch ◽  
Mario Falchi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
Laser Capture Microdissection ◽  
Human Pancreatic Islets ◽  
Laser Capture

scholarly journals Palmitate induces a pro-inflammatory response in human pancreatic islets that mimics CCL2 expression by beta cells in type 2 diabetes

Diabetologia ◽  
2010 ◽  
Vol 53 (7) ◽  
pp. 1395-1405 ◽  
Author(s):  
M. Igoillo-Esteve ◽  
L. Marselli ◽  
D. A. Cunha ◽  
L. Ladrière ◽  
F. Ortis ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Inflammatory Response ◽  
Pancreatic Islets ◽  
Beta Cells ◽  
Human Pancreatic Islets ◽  
Ccl2 Expression

scholarly journals Islet Gene View - a tool to facilitate islet research

2018 ◽  
Author(s):  
Olof Asplund ◽  
Petter Storm ◽  
Vikash Chandra ◽  
Emilia Ottosson-Laakso ◽  
Gad Hatem ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Genetic Variants ◽  
Scientific Community ◽  
Regulation Of Gene Expression ◽  
Web Resource ◽  
Islet Hormones

AbstractChanges in the hormone-producing pancreatic islets are central culprits in type 2 diabetes (T2D) pathogenesis. Characterization of gene expression in islets how it is altered in T2D are therefore vital in understanding islet function and T2D pathogenesis. We leveraged RNA-sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. The IGW combines expression data for a given gene with phenotypical data such as T2D status, BMI, HbA1c, insulin secretion, purity of islets, etc.), regulation of gene expression by genetic variants e.g., expression quantitative trait loci (eQTLs) and relationship with expression of islet hormones. In IGW, 285 differentially expressed genes (DEGs) were identified in T2D donors islets compared to controls. Forty percent of the DEGs showed cell-type enrichment and a large proportion of them were significantly co-expressed with islet hormone-encoding genes like glucagon (GCG, 56%), amylin (IAPP, 52%), insulin (INS, 44%) and somatostatin (SST, 24%). Inhibition of two DEGs, UNC5D and SERPINE2 impaired glucose-stimulated insulin secretion and impacted cell survival in a human beta-cell model.Significance StatementWe present Islet Gene View (IGW), a web resource facilitating information on gene expression in human pancreatic islets from organ donors easily accessible to the scientific community. In IGW, we explored RNA expression from 188 donor-islets and examined their relationship with islet phenotypes including insulin secretion and expression of genes encoding islet hormones. GWAS have shown 403 genetic variants associated with risk of type 2 diabetes (T2D) risk, however, the target genes and function of these variants in islets are largely unknown. By linking T2D risk variants to expression in islets from T2D and non-diabetic donors as well as islet phenotypes, use of IGW provided new insight into mechanisms by which variants in these loci may increase risk of T2D.

scholarly journals Identification of novel non-synonymous variants associated with type 2 diabetes-related metabolites in Korean population

2019 ◽  
Vol 39 (10) ◽  
Author(s):  
Tae-Joon Park ◽  
Heun-Sik Lee ◽  
Young Jin Kim ◽  
Bong-Jo Kim
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Variants ◽  
Multiple Testing ◽  
Association Studies ◽  
Linear Regression Analysis ◽  
Genetic Regulation ◽  
Genome Wide Association Studies ◽  
Functional Variants ◽  
Genome Wide

Abstract Metabolome-genome wide association studies (mGWASs) are useful for understanding the genetic regulation of metabolites in complex diseases, including type 2 diabetes (T2D). Numerous genetic variants associated with T2D-related metabolites have been identified in previous mGWASs; however, these analyses seem to have difficulty in detecting the genetic variants with functional effects. An exome array focussed on potentially functional variants is an alternative platform to obtain insight into the genetics of biochemical conversion processes. In the present study, we performed an mGWAS using 27,140 non-synonymous variants included in the Illumina HumanExome BeadChip and nine T2D-related metabolites identified by a targetted metabolomics approach to evaluate 2,338 Korean individuals from the Korea Association REsource (KARE) cohort. A linear regression analysis controlling for age, sex, BMI, and T2D status as covariates was performed to identify novel non-synonymous variants associated with T2D-related metabolites. We found significant associations between glycine and CPS1 (rs1047883) and PC ae C36:0 and CYP4F2 (rs2108622) variants (P<2.05 × 10−7, after the Bonferroni correction for multiple testing). One of the two significantly associated variants, rs1047883 was newly identified whereas rs2108622 had been previously reported to be associated with T2D-related traits. These findings expand our understanding of the genetic determinants of T2D-related metabolites and provide a basis for further functional validation.

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