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

Mol Metab. 2019 Jun;24:98-107. doi: 10.1016/j.molmet.2019.03.004. Epub 2019 Mar 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Kinesins / genetics
  • Laser Capture Microdissection
  • Membrane Proteins / genetics
  • Peptide Synthases / genetics
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • KIF9 protein, human
  • MLX protein, human
  • Membrane Proteins
  • CYP4V2 protein, human
  • Cytochrome P450 Family 4
  • Kinesins
  • Peptide Synthases
  • TTLL6 protein, human