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Int J Mol Sci. 2017 Mar 18;18(3). pii: E661. doi: 10.3390/ijms18030661.

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

Author information

1
Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. meadon@iupui.edu.
2
Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. meadon@iupui.edu.
3
Juno Therapeutics, Seattle, WA 98109, USA. ronaldhause@junotherapeutics.com.
4
Department of Biological Sciences, University of Notre Dame, South Bend, IN 46556, USA. astark1@nd.edu.
5
Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. yicheng@iu.edu.
6
Department of Biology, Department of Computer Science, Loyola University Chicago, Chicago, IL 60660, USA. Hwheeler1@luc.edu.
7
Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. ksburges@iu.edu.
8
Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. eabenson@iu.edu.
9
Department of Medicine, University of Chicago, Chicago, IL 60637, USA. pcunning@medicine.bsd.uchicago.edu.
10
Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. rbacalla@iu.edu.
11
Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. pdaghe2@iu.edu.
12
Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. tskaar@iu.edu.
13
Department of Medicine, University of Chicago, Chicago, IL 60637, USA. edolan@medicine.bsd.uchicago.edu.

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.

KEYWORDS:

HOXD10; TGIF1; colistin; lymphoblastoid cell line; nephrotoxicity

PMID:
28335481
PMCID:
PMC5372673
DOI:
10.3390/ijms18030661
[Indexed for MEDLINE]
Free PMC Article

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