Article

Cotsapas, C., Prokunina-Olsson L., Welch C., Saxena R., Weaver C., Usher N., Guiducci C., Bonakdar S., Turner N., LaCroix B., and Hall JL. 2010. Expression analysis of loci associated with type 2 diabetes in human tissues. Diabetologia 53: 2334-39.

Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA USA
Diabetologia (Impact Factor: 6.88). 11/2010; 53:2334-39. DOI: 10.1007/s00125-010-1861-2
Source: PubMed

ABSTRACT Genetic mapping has identified over 20 loci contributing to genetic risk of type 2 diabetes. The next step is to identify the genes and mechanisms regulating the contributions of genetic risk to disease. The goal of this study was to evaluate the effect of age, height, weight and risk alleles on expression of candidate genes in diabetes-associated regions in three relevant human tissues.
METHODS:
We measured transcript abundance for WFS1, KCNJ11, TCF2 (also known as HNF1B), PPARG, HHEX, IDE, CDKAL1, CDKN2A, CDKN2B, IGF2BP2, SLC30A8 and TCF7L2 by quantitative RT-PCR in human pancreas (n = 50), colon (n = 195) and liver (n = 50). Tissue samples were genotyped for single nucleotide polymorphisms (SNPs) associated with type 2 diabetes. The effects of age, height, weight, tissue and SNP on RNA expression were tested by linear modelling.
RESULTS:
Expression of all genes exhibited tissue bias. Immunohistochemistry confirmed the findings for HHEX, IDE and SLC30A8, which showed strongest tissue-specific mRNA expression bias. Neither age, height nor weight were associated with gene expression. We found no evidence that type 2 diabetes-associated SNPs affect neighbouring gene expression (cis-expression quantitative trait loci) in colon, pancreas and liver.
CONCLUSIONS/INTERPRETATION:
This study provides new evidence that tissue-type, but not age, height, weight or SNPs in or near candidate genes associated with increased risk of type 2 diabetes are strong contributors to differential gene expression in the genes and tissues examined.

0 Followers
 · 
230 Views
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Since disease susceptibility of the intestine exhibits an anatomical bias, we propose that the chromatin landscape, especially the site-specific epigenetic differences in histone modification patterns throughout the colonic longitudinal axis, contributes to the differential incidence of site-specific pathology. To test this hypothesis, we assessed the chromatin structure associated with gene expression profiles in the rat proximal and distal colon by globally correlating chromatin immunoprecipitation next generation sequencing analysis (ChIP-Seq) with mRNA transcription (RNA-Seq) data. Crypts were isolated from the proximal and distal colonic regions of rats, and mRNA gene expression profiles were generated using RNA-Seq. The remaining isolated crypts were crosslinked and chromatin immunoprecipitated using antibodies against H3K4me3, H3K9me3, and RNA Polymerase II. Globally, RNA-Seq results indicated that 540 genes were differentially expressed between the proximal and distal colon. Gene ontology analysis indicated that crypt location significantly impacted both chromatin and transcriptional regulation of genes involved in enterocyte movement, lipid metabolism, lymphatic development and immune cell trafficking. Gene function analysis indicated that the PI3-Kinase signaling pathway was regulated in a site-specific manner, e.g., proto-oncogenes, JUN, FOS, and ATF, were up-regulated in the distal colon. Middle and long non-coding RNAs (lncRNAs) were also detected in the colon, including select lncRNAs formerly only detected in the rat nervous system. In summary, distinct combinatorial patterns of histone modifications exist in the proximal versus distal colon. These site-specific differences may explain the differential effects of chemoprotective agents on cell transformation in the ascending (proximal) and descending (distal) colon.
    Physiological Genomics 10/2013; 45(24). DOI:10.1152/physiolgenomics.00136.2013 · 2.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Rationale The rationale was to utilize a bioinformatics approach to identify miRNA binding sites in genes with single nucleotide mutations (SNPs) to discover pathways in heart failure (HF). Objective The objective was to focus on the genes containing miRNA binding sites with miRNAs that were significantly altered in end-stage HF and in response to a left ventricular assist device (LVAD). Methods and Results BEDTools v2.14.3 was used to discriminate SNPs within predicted 3′UTR miRNA binding sites. A member of the miR-15/107 family, miR-16, was decreased in the circulation of end-stage HF patients and increased in response to a LVAD (p<0.001). MiR-16 decreased Vacuolar Protein Sorting 4a (VPS4a) expression in HEK 293T cells (p<0.01). The SNP rs16958754 was identified in the miR-15/107 family binding site of VPS4a which abolished direct binding of miR-16 to the 3′UTR of VPS4a (p<0.05). VPS4a was increased in the circulation of end-stage HF patients (p<0.001), and led to a decrease in the number of HEK 293T cells in vitro (p<0.001). Conclusions We provide evidence that miR-16 decreases in the circulation of end-stage HF patients and increases with a LVAD. Modeling studies suggest that miR-16 binds to and decreases expression of VPS4a. Overexpression of VPS4a decreases cell number. Together, these experiments suggest that miR-16 and VPS4a expression are altered in end-stage HF and in response to unloading with a LVAD. This signaling pathway may lead to reduced circulating cell number in HF.
    PLoS ONE 07/2014; 9(7):e101509. DOI:10.1371/journal.pone.0101509 · 3.53 Impact Factor

Full-text (2 Sources)

Download
97 Downloads
Available from
May 31, 2014