Heritable and non-genetic factors as variables of pharmacologic phenotypes in lymphoblastoid cell lines.
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.
Department of Human Genetics, University of Chicago, Chicago, IL, USA.
A L
AL
Stark
W
W
Zhang
S
S
Mi
S
S
Duan
P H
PH
O'Donnell
R S
RS
Huang
M E
ME
Dolan
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D055106:Genome-Wide Association Study; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide
D000970:Antineoplastic Agents; D000255:Adenosine Triphosphate