TY - JOUR
T1 - Mycophenolic acid response biomarkers
T2 - A cell line model system-based genome-wide screen
AU - Wu, Tse Yu
AU - Fridley, Brooke L.
AU - Jenkins, Gregory D.
AU - Batzler, Anthony
AU - Wang, Liewei
AU - Weinshilboum, Richard M.
N1 - Funding Information:
This work was supported in part by a Predoctoral Fellowship Award from the American Heart Association to TYW ( 09PRE2080377 ); by NIH grants R01 GM28157 , U19 GM61388 (The Pharmacogenomics Research Network), R01 CA132780 , K22 CA130828 and R01 CA138461 ; and by a PhRMA Foundation “Center of Excellence Award in Clinical Pharmacology”. The study sponsors had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of this report; and no role in the decision to submit this manuscript for publication.
PY - 2011/8
Y1 - 2011/8
N2 - Mycophenolic acid (MPA) is commonly used to treat patients with solid organ transplants during maintenance immunosuppressive therapy. Response to MPA varies widely, both for efficacy and druginduced toxicity. A portion of this variation can be explained by pharmacokinetic and pharmacodynamic factors, including genetic variation in MPA-metabolizing UDP-glucuronyltransferase isoforms and the MPA targets, inosine monophosphate dehydrogenase 1 and 2. However, much of the variation in MPA response presently remains unexplained. We set out to determine whether there might be additional genes that modify response to MPA by performing a genome-wide association study between basal gene mRNA expression profiles and an MPA cytotoxicity phenotype using a 271 human lymphoblastoid cell line model system to identify and functionally validate genes that might contribute to variation in MPA response. Our association study identified 41 gene expression probe sets, corresponding to 35 genes, that were associated with MPA cytotoxicity as a drug response phenotype (p<1×10-6). Follow-up siRNA-mediated knockdown-based functional validation identified four of these candidate genes, C17orf108, CYBRD1, NASP, and RRM2, whose knockdown shifted the MPA cytotoxicity curves in the direction predicted by the association analysis. These studies have identified novel candidate genes that may contribute to variation in response to MPA therapy and, as a result, may help make it possible to move toward more highly individualized MPA-based immunosuppressive therapy.
AB - Mycophenolic acid (MPA) is commonly used to treat patients with solid organ transplants during maintenance immunosuppressive therapy. Response to MPA varies widely, both for efficacy and druginduced toxicity. A portion of this variation can be explained by pharmacokinetic and pharmacodynamic factors, including genetic variation in MPA-metabolizing UDP-glucuronyltransferase isoforms and the MPA targets, inosine monophosphate dehydrogenase 1 and 2. However, much of the variation in MPA response presently remains unexplained. We set out to determine whether there might be additional genes that modify response to MPA by performing a genome-wide association study between basal gene mRNA expression profiles and an MPA cytotoxicity phenotype using a 271 human lymphoblastoid cell line model system to identify and functionally validate genes that might contribute to variation in MPA response. Our association study identified 41 gene expression probe sets, corresponding to 35 genes, that were associated with MPA cytotoxicity as a drug response phenotype (p<1×10-6). Follow-up siRNA-mediated knockdown-based functional validation identified four of these candidate genes, C17orf108, CYBRD1, NASP, and RRM2, whose knockdown shifted the MPA cytotoxicity curves in the direction predicted by the association analysis. These studies have identified novel candidate genes that may contribute to variation in response to MPA therapy and, as a result, may help make it possible to move toward more highly individualized MPA-based immunosuppressive therapy.
KW - C17orf108
KW - CYPRD1
KW - Mycophenolic acid
KW - NASP
KW - Pharmacogenomics
KW - RRM2
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UR - http://www.scopus.com/inward/citedby.url?scp=84860389864&partnerID=8YFLogxK
U2 - 10.1016/j.intimp.2011.02.027
DO - 10.1016/j.intimp.2011.02.027
M3 - Article
C2 - 21396482
AN - SCOPUS:84860389864
SN - 1567-5769
VL - 11
SP - 1057
EP - 1064
JO - International Immunopharmacology
JF - International Immunopharmacology
IS - 8
ER -