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

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State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_5EA2C0408F1C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Laser capture microdissection of human pancreatic islets reveals novel eQTLs associated with type 2 diabetes.
Journal
Molecular metabolism
Author(s)
Khamis A., Canouil M., Siddiq A., Crouch H., Falchi M., Bulow M.V., Ehehalt F., Marselli L., Distler M., Richter D., Weitz J., Bokvist K., Xenarios I., Thorens B., Schulte A.M., Ibberson M., Bonnefond A., Marchetti P., Solimena M., Froguel P.
ISSN
2212-8778 (Electronic)
ISSN-L
2212-8778
Publication state
Published
Issued date
06/2019
Peer-reviewed
Oui
Volume
24
Pages
98-107
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Genome wide association studies (GWAS) for type 2 diabetes (T2D) have identified genetic loci that often localise in non-coding regions of the genome, suggesting gene regulation effects. We combined genetic and transcriptomic analysis from human islets obtained from brain-dead organ donors or surgical patients to detect expression quantitative trait loci (eQTLs) and shed light into the regulatory mechanisms of these genes.
Pancreatic islets were isolated either by laser capture microdissection (LCM) from surgical specimens of 103 metabolically phenotyped pancreatectomized patients (PPP) or by collagenase digestion of pancreas from 100 brain-dead organ donors (OD). Genotyping (> 8.7 million single nucleotide polymorphisms) and expression (> 47,000 transcripts and splice variants) analyses were combined to generate cis-eQTLs.
After applying genome-wide false discovery rate significance thresholds, we identified 1,173 and 1,021 eQTLs in samples of OD and PPP, respectively. Among the strongest eQTLs shared between OD and PPP were CHURC1 (OD p-value=1.71 × 10 <sup>-24</sup> ; PPP p-value = 3.64 × 10 <sup>-24</sup> ) and PSPH (OD p-value = 3.92 × 10 <sup>-26</sup> ; PPP p-value = 3.64 × 10 <sup>-24</sup> ). We identified eQTLs in linkage-disequilibrium with GWAS loci T2D and associated traits, including TTLL6, MLX and KIF9 loci, which do not implicate the nearest gene. We found in the PPP datasets 11 eQTL genes, which were differentially expressed in T2D and two genes (CYP4V2 and TSEN2) associated with HbA1c but none in the OD samples.
eQTL analysis of LCM islets from PPP led us to identify novel genes which had not been previously linked to islet biology and T2D. The understanding gained from eQTL approaches, especially using surgical samples of living patients, provides a more accurate 3-dimensional representation than those from genetic studies alone.
Keywords
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics, Cytochrome P450 Family 4/genetics, Diabetes Mellitus, Type 2/genetics, Diabetes Mellitus, Type 2/pathology, Humans, Islets of Langerhans/metabolism, Kinesin/genetics, Laser Capture Microdissection, Membrane Proteins/genetics, Peptide Synthases/genetics, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genetics, Islets, Laser capture microdissection, Type 2 diabetes, eQTLs
Pubmed
Web of science
Open Access
Yes
Create date
15/04/2019 17:29
Last modification date
27/04/2020 5:20
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