Journal Article

Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism

Storm, Petter, Krus, Ulrika, Eliasson, Lena, Finotello, Francesca, Vikman, Petter, Di Camillo, Barbara, Ladenvall, Claes, Prasad, Rashmi B., Groop, Leif, Uvebrant, Kristina, Cilio, Corrado M., Hansson, Ola, Esguerra, Jonathan Lou, Osmark, Peter, Mollet, Inês Guerra, Laakso, Emilia Ottosson, Ofori, Jones K., Taneera, Jalal, Fadista, João, Hansson, Karin B., Rosengren, Anders H., Wollheim, Claes B., Renström, Erik

2014

Overview

Significance We provide a comprehensive catalog of novel genetic variants influencing gene expression and metabolic phenotypes in human pancreatic islets. The data also show that the path from genetic variation (SNP) to gene expression is more complex than hitherto often assumed, and that we need to consider that genetic variation can also influence function of a gene by influencing exon usage or splice isoforms (sQTL), allelic imbalance, RNA editing, and expression of noncoding RNAs, which in turn can influence expression of target genes. Genetic variation can modulate gene expression, and thereby phenotypic variation and susceptibility to complex diseases such as type 2 diabetes (T2D). Here we harnessed the potential of DNA and RNA sequencing in human pancreatic islets from 89 deceased donors to identify genes of potential importance in the pathogenesis of T2D. We present a catalog of genetic variants regulating gene expression (eQTL) and exon use (sQTL), including many long noncoding RNAs, which are enriched in known T2D-associated loci. Of 35 eQTL genes, whose expression differed between normoglycemic and hyperglycemic individuals, siRNA of tetraspanin 33 (TSPAN33), 5′-nucleotidase, ecto (NT5E), transmembrane emp24 protein transport domain containing 6 (TMED6), and p21 protein activated kinase 7 (PAK7) in INS1 cells resulted in reduced glucose-stimulated insulin secretion. In addition, we provide a genome-wide catalog of allelic expression imbalance, which is also enriched in known T2D-associated loci. Notably, allelic imbalance in paternally expressed gene 3 (PEG3) was associated with its promoter methylation and T2D status. Finally, RNA editing events were less common in islets than previously suggested in other tissues. Taken together, this study provides new insights into the complexity of gene regulation in human pancreatic islets and better understanding of how genetic variation can influence glucose metabolism.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: 5'-Nucleotidase - biosynthesis / 5'-Nucleotidase - genetics / Allelic imbalance / Beta cells / Biological Sciences / Cell Line / Clinical Medicine / Diabetes Mellitus, Type 2 - genetics / Diabetes Mellitus, Type 2 - metabolism / Endocrinology and Diabetes / Endokrinologi och diabetes / exons / Female / gene expression / Genes / Genetic diversity / Genetic loci / Genetic variance / genetic variation / Genomics / Glucose / Glucose - genetics / Glucose - metabolism / GPI-Linked Proteins - biosynthesis / GPI-Linked Proteins - genetics / Humans / Islets of Langerhans / Klinisk medicin / Male / Medical and Health Sciences / Medicin och hälsovetenskap / Metabolism / non-coding RNA / P values / p21-Activated Kinases - biosynthesis / p21-Activated Kinases - genetics / Pancreas / Pathogenesis / phenotype / Phenotypic variations / RNA editing / RNA Editing - physiology / RNA, Long Noncoding - biosynthesis / RNA, Long Noncoding - genetics / Sequencing / single nucleotide polymorphism / Tetraspanins - biosynthesis / Tetraspanins - genetics / Transcription factors / Transcriptome - physiology / transcriptomics / Type 1 diabetes mellitus / Type 2 diabetes mellitus / Vesicular Transport Proteins - biosynthesis / Vesicular Transport Proteins - genetics