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Mol Metab. 2019 Mar 18. pii: S2212-8778(19)30130-9. doi: 10.1016/j.molmet.2019.03.004. [Epub ahead of print]

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

Author information

1
Imperial College London, Department of Genomics of Common Disease, London, UK; University of Lille, CNRS, Institute Pasteur de Lille, UMR 8199 - EGID, F-59000, Lille, France.
2
University of Lille, CNRS, Institute Pasteur de Lille, UMR 8199 - EGID, F-59000, Lille, France.
3
Imperial College London, Department of Genomics of Common Disease, London, UK.
4
Sanofi-Aventis Deutschland GmbH, Diabetes Research, Frankfurt, Germany.
5
Department of Visceral-Thoracic-Vascular Surgery, University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden, 01307, Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden, 01307, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), 85764, Neuherberg, Germany.
6
University of Pisa, Department of Clinical and Experimental Medicine, Pisa, Italy.
7
Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden, 01307, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), 85764, Neuherberg, Germany.
8
Lilly Research Laboratories, Eli Lilly, 46285-0001, Indianapolis, IN, USA.
9
Vital-IT Group, Swiss Institute of Bioinformatics, 1015, Lausanne, Switzerland.
10
Center for Integrative Genomics, University of Lausanne, Genopode Building, Lausanne, 1015, Switzerland.
11
Imperial College London, Department of Genomics of Common Disease, London, UK; University of Lille, CNRS, Institute Pasteur de Lille, UMR 8199 - EGID, F-59000, Lille, France. Electronic address: p.froguel@imperial.ac.uk.

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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 × 10-24; PPP p-value = 3.64 × 10-24) and PSPH (OD p-value = 3.92 × 10-26; PPP p-value = 3.64 × 10-24). 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.

CONCLUSIONS:

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:

Genetics; Islets; Laser capture microdissection; Type 2 diabetes; eQTLs

PMID:
30956117
DOI:
10.1016/j.molmet.2019.03.004
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