Next Article in Journal
Melatonin MT1 and MT2 Receptors in the Ram Reproductive Tract
Next Article in Special Issue
Role of Free Radicals and Biotransformation in Trichloronitrobenzene-Induced Nephrotoxicity In Vitro
Previous Article in Journal
Assessment of Antioxidant and Cytoprotective Potential of Jatropha (Jatropha curcas) Grown in Southern Italy
Previous Article in Special Issue
Establishment of HK-2 Cells as a Relevant Model to Study Tenofovir-Induced Cytotoxicity
Article Menu
Issue 3 (March) cover image

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2017, 18(3), 661; doi:10.3390/ijms18030661

Genetic Variants Contributing to Colistin Cytotoxicity: Identification of TGIF1 and HOXD10 Using a Population Genomics Approach

1
Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
2
Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
3
Juno Therapeutics, Seattle, WA 98109, USA
4
Department of Biological Sciences, University of Notre Dame, South Bend, IN 46556, USA
5
Department of Biology, Department of Computer Science, Loyola University Chicago, Chicago, IL 60660, USA
6
Department of Medicine, University of Chicago, Chicago, IL 60637, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Monica Valentovic
Received: 15 February 2017 / Revised: 15 March 2017 / Accepted: 16 March 2017 / Published: 18 March 2017
(This article belongs to the Special Issue Nephrotoxicity)
View Full-Text   |   Download PDF [4187 KB, uploaded 18 March 2017]   |  

Abstract

Colistin sulfate (polymixin E) is an antibiotic prescribed with increasing frequency for severe Gram-negative bacterial infections. As nephrotoxicity is a common side effect, the discovery of pharmacogenomic markers associated with toxicity would benefit the utility of this drug. Our objective was to identify genetic markers of colistin cytotoxicity that were also associated with expression of key proteins using an unbiased, whole genome approach and further evaluate the functional significance in renal cell lines. To this end, we employed International HapMap lymphoblastoid cell lines (LCLs) of Yoruban ancestry with known genetic information to perform a genome-wide association study (GWAS) with cellular sensitivity to colistin. Further association studies revealed that single nucleotide polymorphisms (SNPs) associated with gene expression and protein expression were significantly enriched in SNPs associated with cytotoxicity (p ≤ 0.001 for gene and p = 0.015 for protein expression). The most highly associated SNP, chr18:3417240 (p = 6.49 × 10−8), was nominally a cis-expression quantitative trait locus (eQTL) of the gene TGIF1 (transforming growth factor β (TGFβ)-induced factor-1; p = 0.021) and was associated with expression of the protein HOXD10 (homeobox protein D10; p = 7.17 × 10−5). To demonstrate functional relevance in a murine colistin nephrotoxicity model, HOXD10 immunohistochemistry revealed upregulated protein expression independent of mRNA expression in response to colistin administration. Knockdown of TGIF1 resulted in decreased protein expression of HOXD10 and increased resistance to colistin cytotoxicity. Furthermore, knockdown of HOXD10 in renal cells also resulted in increased resistance to colistin cytotoxicity, supporting the physiological relevance of the initial genomic associations. View Full-Text
Keywords: colistin; lymphoblastoid cell line; nephrotoxicity; TGIF1; HOXD10 colistin; lymphoblastoid cell line; nephrotoxicity; TGIF1; HOXD10
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Eadon, M.T.; Hause, R.J.; Stark, A.L.; Cheng, Y.-H.; Wheeler, H.E.; Burgess, K.S.; Benson, E.A.; Cunningham, P.N.; Bacallao, R.L.; Dagher, P.C.; Skaar, T.C.; Dolan, M.E. Genetic Variants Contributing to Colistin Cytotoxicity: Identification of TGIF1 and HOXD10 Using a Population Genomics Approach. Int. J. Mol. Sci. 2017, 18, 661.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top