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Heritable and non-genetic factors as variables of pharmacologic phenotypes in lymphoblastoid cell lines

The Pharmacogenomics Journal volume 10, pages 505–512 (2010)Cite this article

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Abstract

Publicly available genetic and expression data on lymphoblastoid cell lines (LCLs) make them a unique resource for understanding the genetic underpinnings of pharmacological outcomes and disease. LCLs have been used for pharmacogenomic discovery and validation of clinical findings associated with drug response. However, variation in cellular growth rate, baseline Epstein–Barr virus (EBV) copy number and ATP levels can all be confounders in such studies. Our objective is to better define confounding variables that affect pharmacological end points in LCLs. To this end, we evaluated the effect of these three variables on drug-induced cytotoxicity in LCLs. The drugs evaluated included daunorubicin, etoposide, carboplatin, cisplatin, cytarabine, pemetrexed, 5′-deoxyfluorouridine, vorinostat, methotrexate, 6-mercaptopurine, and 5-fluorouracil. Baseline ATP or EBV copy number were not significantly correlated with cellular growth rate or drug-induced cytotoxicity. In contrast, cellular growth rate and drug-induced cytotoxicity were significantly, directly related for all drugs except vorinostat. Importantly, cellular growth rate is under appreciable genetic influence (h2=0.30–0.39) with five suggestive linkage regions across the genome. Not surprisingly, a percentage of SNPs that significantly associate with drug-induced cytotoxicity also associate with cellular growth rate (P⩽0.0001). Studies using LCLs for pharmacologic outcomes should therefore consider that a portion of the genetic variation explaining drug-induced cytotoxicity is mediated via heritable effects on growth rate.

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Abbreviations

5′-DFUR:

5′-deoxyfluorouridine

5-FU:

5-fluorouracil

AraC:

cytarabine

ASN:

Asian

ATP:

adenosine tri-phosphate

CEPH:

Centre d'Etude du Polymorphisme Humain

CEU:

Caucasians

DNA:

deoxyribonucleic acid

EBV:

Epstein–Barr virus

h2:

heritability

HapMap:

International HapMap Project

LOD:

logarithm of odds

LCL/s:

lymphoblastoid cell line/s

QTDT:

Quantitative Transmission Disequilibrium Test

RNA:

ribonucleic acid

SNP/s:

single nucleotide polymorphism/s

YRI:

Yoruba

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Acknowledgements

This work was supported by the Pharmacogenetics of Anticancer Agents Research Group by the National Institute of Health/National Institute of General Medical Sciences Grant U01GM61393, data deposits are supported by UO1GM61374 (http://pharmgkb.org/) and NIH/NCI Breast SPORE P50 CA125183. We acknowledge Dr Sunita J Shukla, Dr Christine M Hartford, Ms Bridget E McIlwee, and Mr Wasim Bleibel for results from their cytotoxicity growth inhibition experiments and Mr Steven J Stark for excellent technical assistance.

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Authors and Affiliations

  1. Department of Human Genetics, University of Chicago, Chicago, IL, USA

    A L Stark

  2. Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA

    W Zhang, S Mi, S Duan, P H O'Donnell, R S Huang & M E Dolan

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  1. A L Stark
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  2. W Zhang
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  7. M E Dolan
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Correspondence to M E Dolan.

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Stark, A., Zhang, W., Mi, S. et al. Heritable and non-genetic factors as variables of pharmacologic phenotypes in lymphoblastoid cell lines. Pharmacogenomics J 10, 505–512 (2010). https://doi.org/10.1038/tpj.2010.3

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